Evaluation of Sex-Specific Data in 
 
Medical Device Clinical Studies 
 
Guidance for Industry and Food and 
Drug Administration Staff 
 
 
 
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 OCallaghan 
(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 Research Contains 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 .................................................... 24 
      Contains 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 ......................................................................................................................... 26 
 
 
      Contains Nonbinding Recommendations 
 
 
 
Evaluation of Sex-Specific Data in  
Medical Device Clinical Studies  
 
Guidance for Industry and Food and Drug 
Administration Staff  
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking 
on this topic.  It does not create or confer any rights for or on any person and does not 
operate to bind FDA or the public.  You can use an alternative approach if the approach 
satisfies the requirements of the applicable statutes and regulations.  If you want to discuss 
an alternative approach, contact the FDA staff responsible for implementing this 
guidance.  If you cannot identify the appropriate FDA staff, call the appropriate number 
listed on the title page of this guidance.  
 
 
I.  Introduction 
This document provides guidance on the study and evaluation of sex-specific data in 
medical device clinical studies.  The purpose of this guidance is to outline the FDAs 
expectations regarding sex-specific patient enrollment, data analysis, and reporting of 
study information.  The primary intent is to improve the quality and consistency of 
available data 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.  This information can be of benefit to 
patients and their medical providers, as well as clinical researchers and others.   
 
The specific objectives of this guidance are to: 1) encourage the consideration of sex and 
associated covariates (e.g., body size, plaque morphology, etc.) during the study design 
stage; 2) provide recommendations for study design and conduct to encourage 
appropriate enrollment of each sex (e.g., in proportions generally representative of the 
demographics of disease distribution, if appropriate); 3) outline recommended sex-
specific statistical analyses of study data with a framework for considering sex-specific 
data when interpreting overall study outcomes; and 4) specify FDAs expectations for 
reporting sex-specific information in summaries and labeling for approved or cleared 
medical devices. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory 
requirements are cited.  The use of the word should in Agency guidances means that 
something is suggested or recommended, but not required.  
    1  Contains Nonbinding Recommendations 
 
 
 
II.  Scope 
This guidance is intended for devices that require clinical information in support of a 
marketing submission, whether a premarket notification (510(k)), premarket approval (PMA) 
application, Evaluation of Automatic Class III Designation (de novo request), or 
humanitarian device exemption (HDE) application.  The recommendations contained herein 
also apply to post-approval study (PAS) submissions and postmarket surveillance (PS) 
studies conducted in accordance with Section 522 of the Food, Drug and Cosmetic Act, 
where noted.   
 
Sex1 is not the only demographic variable that may affect device performance.  While this 
guidance focuses on the impact of sex, some of its recommendations may also be used to 
promote study enrollment and data analysis adequately accounting for other demographic 
variables, such as age, race, and ethnicity. 2 
 
The impact of demographic variables may apply more to certain types of products or diseases 
than others.  For example, certain OB/GYN and urology devices may be intended for use in 
single-sex populations, so studies of these devices would not be expected to address the 
potential for sex differences in outcome.  Additionally, some in vitro diagnostic (IVD) device 
clinical studies are conducted on de-identified left over specimens so it may not be possible to 
obtain demographic information, including sex.  As a result, evaluation of sex-specific data 
would not be possible in these cases.  
 
FDA recommends the use of this guidance document as a supplement to other FDA guidance, 
in particular, any relevant device-specific guidance.  Consultation with the FDA primary 
reviewing division is advised.   
 
 
III.  Background  
Certain elements described in this guidance have been emphasized in Agency regulations 
and/or policy in the past.  Over recent decades the Agencys views, as well as those of 
the medical community in general, have evolved regarding women in clinical studies.   
 
Prior to developing the policy set forth in this guidance, FDA publicly sought input from a 
variety of experts and stakeholders regarding the study and evaluation of women in clinical 
studies for medical devices.  On June 2, 2008, various government agencies, physician 
professional societies, and patient advocacy groups participated in a public workshop to 
                                                 
1 Public comment indicated interest in addressing unique considerations regarding the  participation of lesbian, 
gay, bisexual, transgender, and queer (LGBTQ), intersex, and gender non-conforming (GNC) individuals in 
clinical studies.  The analyses of sex-specific data related to these groups fall outside the scope of this guidance; 
other forums, such as the Health of Women Program, could be used to explore these issues. 
<http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm346073.htm>   
2 
Consult the Agency-wide guidance for industry Collection of Race and Ethnicity Data in Clinical Trials, 
which was issued September 2005.  FDA guidance documents are available at 
http://www.fda.gov/ForIndustry/FDABasicsforIndustry/ucm234622.htm. 
    2  Contains Nonbinding Recommendations 
 
 
 
discuss ways to overcome barriers to understanding the impact of sex differences on clinical 
outcomes, with a focus on clinical study conduct and statistical analysis.  On December 9, 
2008, FDAs Center for Devices and Radiological Health (CDRH) and an industry trade 
association co-hosted a second public meeting to facilitate discussion in anticipation of 
issuance of FDA guidance on this subject.3  This guidance document reflects the 
recommendations generated in these and other public fora and in subsequent internal Agency 
discussions.  It is intended to provide guidance on the design and conduct of clinical studies 
to improve sex-specific information about the safety and effectiveness of approved new 
medical devices. 
 
The terms sex and gender are often used interchangeably in the scientific literature and 
popular press.  However, according to a 2001 consensus report from the Institute of 
Medicine, the terms have distinct definitions which should be used consistently to describe 
research results.4  The differences of greatest interest to FDA are those associated with 
biological factors (sex5); however most medical device studies rely on patient self-reported 
values (gender6).  For the purposes of this guidance document we use the term sex, with the 
understanding that for most medical device studies gender is used as a surrogate for sex.  
This guidance focuses on addressing potential differences in study design, conduct, 
outcomes, and interpretation that should be considered to ensure sex-specific issues are 
adequately addressed in clinical studies. 
 
A. Why consider sex differences? 
Certain medical products elicit different responses in women compared to men.  
Differences may be attributable to intrinsic factors (e.g., genetics, hormones, body size, 
sex-specific physiology), extrinsic factors (e.g., diet, sociocultural issues, environment) 
or interactions between these factors.  For example, there may be medical conditions that 
are unique to a certain sex, ethnic or racial group which should be considered in study 
recruitment and in reporting of results.  Additionally, differences in patient-reported 
outcomes between certain groups, for example how men and women report pain 
differently, may suggest a sex difference in outcome, but they may not necessarily be 
related to the medical device itself. 
 
Covariates associated with female sex (e.g., size, age, co-morbidities, past pregnancies) 
may be responsible for certain differences in safety, effectiveness, or design attributes 
such as failure mode.  Fluctuations associated with hormonal changes (e.g., onset of 
puberty, menstrual cycle, menopause, oral contraceptive or hormone replacement therapy 
use) may interact with clinical outcomes.  Additionally, the menstrual cycle is associated 
                                                 
3 http://www.regulations.gov/#!documentDetail;D=FDA-2008-N-0038-0089     
4 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. 
5 Sex refers to the classification of living things, generally as male or female according to their reproductive 
organs and functions assigned by chromosomal complement. 
6 Gender refers to a persons self representation as male or female, or how that person is responded to by social 
institutions based on the individuals gender presentation.  Gender is rooted in biology, and shaped by 
environment and experience.  
    3  Contains Nonbinding Recommendations 
 
 
 
with hormonally-mediated differences in metabolism or changes in fluid balance which 
could lead to intra-subject variability. 
 
 
Following are examples where sex differences affect FDAs regulatory considerations: 
 
1.  Ventricular Assist Devices (VADs) provide mechanical circulatory support for 
patients with heart failure.  One study of a next-generation VAD showed that 
in subjects treated with the investigational device, female sex or covariates 
associated with sex (body surface area, BSA) were found to be correlated with 
a higher rate of stroke in women as compared to men (18% vs. 6%).  There 
were also trends toward increased rates of bleeding and infection in women 
compared to men.  There did not appear to be differences in primary 
effectiveness outcome of survival (to cardiac transplantation or 180 days of 
support while being listed as status United Network for Organ Sharing 
(UNOS) 1A/1B for transplant).  The strength of these conclusions is somewhat 
limited by the sample size (150 men and 44 women).  The FDA Advisory 
Committee recommended that a post-approval study be conducted which 
would include adequate collection of data regarding both sex and body surface 
area to determine if differences exist in device performance.  (Thoratec 
HeartMate II, Summary of Safety and Effectiveness:  
http://www.accessdata.fda.gov/cdrh_docs/pdf6/P060040b.pdf) 
 
2.  Cardiac Resynchronization Therapy Defibrillators (CRT-D) provide two 
functions.  As an implantable cardioverter defibrillator (ICD) it senses 
dangerous abnormal heart rhythms and then delivers a shock to stop the 
abnormal rhythm, allowing the normal rhythm to resume. As cardiac 
resynchronization therapy, it generates small electrical impulses to coordinate 
the beating of the left and right ventricles so that they work together more 
efficiently to pump blood throughout the body.  In one study, the benefit of 
CRT-D therapy over ICD alone (benefit defined as reduction in the composite 
endpoint of all-cause mortality or first heart failure event) was observed to be 
greater in women than men (77% versus 42%).  Left Bundle Branch Block 
(LBBB) is a marker of an electrical conduction disorder in the heart and has 
been associated with a greater benefit in patients receiving CRT; the 
proportion of subjects with LBBB in this study was significantly greater in 
women than men (87% versus 65%).  These findings are considered 
exploratory since the sex-specific analysis was post hoc.  There did not appear 
to be differences in primary safety outcome of system-related complication-
free survival within 91 days post implant.  The FDA Advisory Committee 
recommended that two post-approval studies be conducted that would include 
adequate collection of data regarding the effects of the therapy in patients 
fulfilling the approved indication. 
 
3.  Hip joint deterioration can lead to pain, stiffness or difficulty walking.  When 
these symptoms do not respond to conservative treatment, such as physical 
    4  Contains Nonbinding Recommendations 
 
 
 
therapy, patients may be advised to undergo total hip replacement (THR) or 
hip resurfacing.  As part of this treatment, patients may receive a metal-on-
metal (MoM) hip implant in which the ball and socket of the device are 
both made from metal.7  In June 2012, the Orthopaedic and Rehabilitation 
Devices Advisory Panel met to discuss the clinical performance of MoM hip 
implants as well as associated adverse events, including early device failure 
and the need for revision surgery.8  The THR and hip resurfacing studies that 
identified revision rates by sex show that the revision rate appeared higher 
among women 3-5 years post implant in most studies.  Sex-specific revision 
rates in THR studies ranged between 2.7% to 19.8% for women and 0 and 
14.6% for men.  Sex-specific revision rates in the resurfacing studies ranged 
between 0 and 27.6% for women and 1.4% and 8.97% for men.9  Differences 
in sex-specific revision rates and the basis for these differences were a 
recurring concern throughout the panel discussion.  From this information, 
FDA recommendations for orthopedic surgeons include that women may be at 
risk for increased device wear and/or adverse local tissue reactions and should 
be followed more closely. 
 
 
B. Participation of Women in Clinical Studies 
Historically, women have been under-represented in or excluded from many clinical 
studies.  This has led to a lack of information available for women and their physicians 
regarding the risks and benefits of many medical treatments and diagnostic procedures.  
 
1.  Lack of Available Data for Women 
Concerns about representation of women in U.S. clinical trials initially surfaced 
in the drug context.  In the mid-1970s, legislation and subsequent regulations and 
guidelines conveyed the recommendations of FDA and many in the medical and 
scientific community that women of child-bearing potential be excluded from 
drug studies to protect the fetus from exposure to unknown drugs.10  However, it 
soon became apparent that this policy contributed to compromis[ing] the quality 
of health information available to women as well as the health care they 
receive.11   
 
                                                 
7 Metal-on-Metal Hip Implants. 
<http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/MetalonMetalHi
pImplants/default.htm> Page last updated 1/17/2013 
8 2012 Meeting Materials of the Orthopaedic and Rehabilitation Devices Panel. 
<http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdv
isoryCommittee/OrthopaedicandRehabilitationDevicesPanel/ucm309184.htm> Page last updated 10/18/2012. 
9 FDA Executive Summary Memorandum. Metal-on-Metal Hip Implant Systems. June 27-28, 2012. 
<http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/Medical
DevicesAdvisoryCommittee/OrthopaedicandRehabilitationDevicesPanel/UCM309302.pdf> 
10 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). 
11 Women's health. Report of the Public Health Service Task Force on Women's Health Issues. Public Health 
Rep. 1985 JanFeb; 100(1): 73106.  
    5  Contains Nonbinding Recommendations 
 
 
 
The Government Accountability Office (GAO) audited clinical study information 
submitted to FDA in support of drug marketing applications, and concluded in a 
1992 report that women were significantly underrepresented, and sex-specific 
data analysis was performed in less than 50% of drug studies.12  The following 
year, the FDA issued a Guideline for the Study and Evaluation of Gender 
Differences in the Clinical Evaluation of Drugs which encouraged participation 
of women in early phase (dosing) studies, required data collection on sex 
differences, and encouraged consideration of the effect of menstrual cycle and 
potential interaction with oral contraception or hormone replacement therapy.13  
In 1994, CDRH discussed addressing the possibility of gender bias in 
submissions and review documentation for new medical devices.14   
 
A 2001 report by the GAO on FDA-reviewed drug studies found that women 
accounted for 52% of total study enrollees, but approximately 30% of the study 
documents examined did not report outcomes by sex, and almost 40% did not report 
enrollment demographics.15  Since then, the FDA Office of Special Health Issues 
published a 2003 report which showed improvements in the inclusion of women and 
sex-specific analysis and reporting in drug studies for most medical areas except 
AIDS, oncology, and heart disease.16 
 
In medical device studies, an evaluation of cardiovascular PMAs reported in 2009 
showed pivotal studies that reported sex enrolled an average of 33.9% women.17  In a 
2013 report to Congress responding to requirements in Section 907 of FDASIA 
regarding demographic subgroup data in medical product clinical studies, FDA 
showed that participation rates for women varied by device product area, a 
phenomenon attributable to a number of factors that can influence interpretation and 
clinical relevance of demographic information (e.g., intended population, disease 
prevalence, etc.).  Additionally, 88% of the PMA applications reviewed for the report 
contained a sex subgroup analysis, and 63% of these applications contained 
statements in the device labeling and/or FDA summary review on sex subgroup 
analysis.18 
                                                 
12 United States General Accounting Office. Womens Health.  FDA Needs to Ensure More Study of Gender 
Differences in Prescription Drug Testing.  (http://archive.gao.gov/d35t11/147861.pdf). 
13 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126835.pdf 
14 CDRH ODE Annual Report FY1994. 
15 United States General Accounting Office. Womens Health. Women Sufficiently Represented in New Drug 
Testing, but FDA Oversight Needs Improvement.  (http://www.gao.gov/new.items/d01754.pdf, ed,: 2001). 
16 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. 
(http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ParticipatinginClinicalTrials/ucm19778
8.htm.)  
17 Kramer DB, Mallis E, Zuckerman BD, Zimmerman BA, Maisel WH. Premarket Clinical Evaluation of Novel 
Cardiovascular Devices: Quality Analysis of Premarket Clinical Studies Submitted to the Food and Drug 
Administration 20002007. Am J Therapeutics. 2009. 
18 FDA Report. Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved 
Medical Products. August 2013. 
http://www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/
SignificantAmendmentstotheFDCAct/FDASIA/UCM365544.pdf 
    6  Contains Nonbinding Recommendations 
 
 
 
 
2.  Barriers to Enrollment of Women 
Women may be less likely to enroll in clinical studies.  There are myriad suspected 
reasons for the continued lower participation rates of women in clinical studies in 
certain product areas.  Some of the key reasons suggested at the June 2008 FDA 
workshop include:  
 
  Lack of understanding about main obstacles to participation of women in 
clinical research; 
 
  Fear of fetal consequences if a female participant becomes pregnant (e.g., 
effects of radiographic assessments or concomitant drug therapy); 
 
  Inclusion/exclusion criteria potentially not needed to define the study 
population may unintentionally exclude women (e.g., upper age limit); 
 
  Lack of understanding about differences in disease etiology and 
pathophysiology may lead to under-diagnosis and under-referral of women; 
 
  Investigator and sponsor avoidance of female patients due to the perception 
that it takes more time and money to recruit them; and  
 
  Family responsibilities limiting womens ability to commit time for study 
follow-up.   
 
In addition to the list above, in a 2009 report to Congress,19 FDA further identified 
barriers to the participation of subsets of the general population and medically 
underserved populations in the context of drug trials.  This report included public 
comments submitted in response to a Notice in the Federal Register (74 FR 1695) 
seeking information on specific impediments to participation of certain groups in 
clinical studies; what practices currently exist to increase participation in clinical 
studies; and whether additional approaches are necessary to increase the participation 
of certain subsets of the general population in clinical studies.  The recommendations 
and best practices submitted in response to the FR Notice, along with FDAs 
identification of particular areas of concern, are summarized in Part II of the 2009 
report to Congress. Lower rates of participation by women in device clinical studies 
may also be attributable in part to limitations of manufacturing certain medical 
devices to accommodate anatomical differences between women and men; for 
                                                 
19 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 Advertisings 
Ability to Communicate to Subsets of the General Population; Barriers to the Participation of Population 
Subsets in Clinical Drug Trials.  
http://www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/
SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/FDAAAImplement
ationChart/UCM213016.pdf. 
    7  Contains Nonbinding Recommendations 
 
 
 
example, technology may not yet be developed to manufacture smaller sizes or 
certain configurations of some devices which could increase use in women.  
 
Where ongoing enrollment data demonstrate an underrepresentation of women 
enrolling in the study, sponsors are encouraged to investigate the reason for lack of 
enrollment and consider the approaches in Section IV.B.1. to enhance enrollment.  It 
may be informative to evaluate whether the demographic distribution varies at 
different key time points (e.g., at screening, after evaluation of study 
inclusion/exclusion criteria, after consent, and at various follow-up time points).  For 
example, if the proportion of women drops significantly after screening for 
inclusion/exclusion criteria, this may suggest that the study criteria may need to be 
examined to reduce inappropriate, unintentional exclusion of women.  Similarly, 
cutoffs excluding patients with smaller body surface area (BSA) may exclude large 
proportions of female patients who may otherwise benefit from treatment.  Removing 
such exclusions (entirely or through parallel cohort studies) could improve the 
participation rates of women in the overall study.  Information regarding changes in 
demographic distribution at key time points in study screening, enrollment, and 
follow-up can provide insight into methods to substantially lower barriers to 
enrollment of women, as well as other subgroups of study participants, (e.g., 
flexibility in follow-up visit scheduling with consideration of child care or elder care 
services during appointments).  Changes to a study protocol and informed consent 
may be made based on demographic distribution information with appropriate 
notification to and approval from the IRB and FDA, where necessary. 
 
Sponsors may also wish to consider resources  the National Institutes of Health 
developed,20, 21, 22 or discussion with academic and contract research organizations, 
and high-enrolling clinical study sites, in determining practices best suited to achieve 
appropriate enrollment with respect to demographic groups, and to provide 
investigator training about these techniques. 
 
Some specific examples of strategies to increase inclusion are discussed in Section 
IV.B below.  
 
 
                                                 
20 NIH Office of Research on Womens 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.  
http://orwh.od.nih.gov/research/inclusion/index.asp. 
21 The National Institute of Mental Health developed a resource document (Points to Consider about 
Recruitment and Retention While Preparing a Clinical Research Study), which outlines common issues that 
can impact clinical recruitment and retention, and strategies to address these issues.  
http://www.nimh.nih.gov/research-funding/grants/recruitment-points-to-consider-6-1-05.pdf. 
22 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. https://accrualnet.cancer.gov.  
    8  Contains Nonbinding Recommendations 
 
 
 
IV.  Recommendations for Achieving Appropriate 
Enrollment  
 
It remains important that clinical trials include diverse populations which reflect the intended 
population, whenever possible and appropriate.  In general, to achieve an unbiased estimate 
of treatment effect in the general population, sponsors should plan to enroll representative 
proportions of women and men (e.g., consistent with disease prevalence).  However, in cases 
where disease science or prior clinical study results suggest treatment effect in only one sex, 
sponsors may need to intentionally enroll sufficient numbers to support valid analysis (i.e., a 
sample size sufficient for sex-specific claims). 
 
Historically, many medical device clinical studies have not enrolled proportions of women 
that reflect the underlying disease distribution in the affected population.  This can be 
problematic because the ability to detect differences in response to treatment is markedly 
diminished if there is no or limited clinical experience with the product in the subgroup of 
interest.  This has contributed to a substantial lack of available data regarding the risks and 
benefits of medical device use in women.   
 
 
A. Consideration of Potential Sex Differences 
To understand potential sex differences that may be relevant to the clinical evaluation of 
your device, we recommend that you investigate whether sex differences may or may not 
exist for the disease or condition which your device is intended to treat or diagnose in the 
following areas:23 
  sex-specific prevalence; 
  sex-specific diagnosis and treatment patterns; 
  identification of proportions of women included in past studies for the target 
indication; 
  identification of any known clinically meaningful sex differences in outcomes 
related to either safety or effectiveness 
If information demonstrating sex differences is available, it should be included in your 
study and submission documents as described in the following sections.  FDA recognizes 
that such information is limited in some device development programs (e.g., those based 
on testing of de-identified non-annotated specimens). 
 
1.  For New or Ongoing Studies (IDE study design/early enrollment stage) 
You should include the information described above as part of the risk analysis 
section of your investigational plan (see 21 CFR 812.25(c)).  We also recommend 
that you summarize this information in your study protocol and investigator training 
                                                 
23 The intent is to provide context based on disease science. Sponsors may consider providing similar 
information related to other demographic groups such as age, race, ethnicity, co-morbidities, etc.   
    9  Contains Nonbinding Recommendations 
 
 
 
materials to explain the importance of enrolling appropriate proportions of women.  
For studies which are already enrolling under an approved (or conditionally 
approved) IDE where there is inadequate enrollment of women, FDA and the sponsor 
should discuss an appropriate path to communicate this new information to 
investigators without introducing bias to the study. 
 
2.  For Completed Studies (marketing application stage) 
Where available background information or clinical study results suggest there are 
clinically meaningful sex differences, you should include 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, and in your labeling (see Section VI 
below for more details). 
 
3.  For Postmarket Studies (PAS or 522 PS stage) 
Where available background information or clinical study results suggest there are 
clinically meaningful sex differences, you should include this information in interim 
reports and in the results section of your final report.  If warranted, you should also 
submit revised labeling to include this information. 
 
B. Study Design and Conduct 
As discussed Section III.B., women have been historically under-represented in clinical 
studies of medical devices; therefore, the approaches described below are aimed at 
increasing enrollment of women in your study.  However, in fields where men may be 
under-represented (e.g., breast cancer diagnosis, bone density scans) we recommend that 
you adapt these or other methods to increase enrollment of men if the intended 
population also includes men.  Some of these methods may also be adapted to increase 
enrollment of other typically underrepresented groups, such as racial and ethnic 
minorities. 
 
1.  For New or Ongoing Studies (IDE study design/early enrollment stage) 
You should develop and describe your plan to prospectively enroll proportions of 
each sex in your study which are appropriate based on the contextual information 
provided in Section IV. A. (e.g., consistent with the sex-specific prevalence of the 
disease or condition which your device is intended to treat or diagnose).  To enhance 
enrollment of women, the approaches described below may be considered, with 
appropriate caution designed to avoid introducing bias or jeopardizing data validity. 
 
a.  Target investigational sites where recruitment of women can be more easily 
facilitated (e.g., womens clinics). 
 
    10  Contains Nonbinding Recommendations 
 
 
 
b.  Consider alternative communication strategies (as used in the Womens 
Health Initiative study24) for study recruitment, informed consent documents, 
and patient materials. 
 
c.  If women are likely to benefit from your device but may not meet certain 
study enrollment criteria, consider revising the enrollment criteria, when 
appropriate, or consider parallel cohorts for collecting data on device use in 
women. 
 
d.  Responsibly enroll women of child-bearing age with appropriate risk 
reduction to avoid pregnancy during clinical trial participation.  
 
e.  Include provisions to encourage certain target enrollment for women (e.g., 
maintain open enrollment for women until pre-specified proportion is 
reached). 
 
f.  Investigate reasons for under-enrollment or non-enrollment of women or other 
key demographic groups (e.g., periodically evaluate screening logs for all 
patients who are screened but not ultimately enrolled in studies).   
 
g.  Plan focused efforts to enroll women under a continued access study.25 
 
h.  Consider factors that generally increase recruitment and retention such as 
community or local health care practitioner involvement in recruiting or 
referring patients, incentives or compensation (e.g., for transportation costs), 
and presentation of the benefits of participating in the study (e.g., send a 
newsletter to subjects to maintain interest). 
 
i.  Consider flexibility in follow-up visit scheduling with provision of child care 
or elder care services during appointments or to allow various opportunities 
that match subjects' schedules, which may include evenings and weekends.  
 
j.  For in vitro diagnostic tests and diagnostic devices, include samples from both 
women and men at the cutoff selection and validation stages.   
 
2.  For Completed Studies (marketing application stage) 
If available evidence suggests that there may be clinically meaningful sex differences 
in outcomes (related to safety and/or effectiveness) with your device, results should 
then be discussed within your marketing application and considered in the context of 
available alternative treatments to determine whether additional data collection (for 
men and/or women) are needed to address a clinically important question before the 
                                                 
24 J. Hays, et al. The Womens Health Initiative Recruitment Methods and Results. Ann Epidemiol 
2003;13:S18S77. 
25 CDRH Guidance on IDE Policies and Procedures (1998): 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080202.htm.
   
    11  Contains Nonbinding Recommendations 
 
 
 
device is marketed.  Consideration should also be given to whether results support 
market approval in one sex, with additional pre-market data collection in the other 
sex; or whether market approval is supported for both sexes, with post-market studies 
to gain further information regarding any observed sex differences.  The FDA team 
may recommend that you consider: 
 
a.  Planning focused efforts to enroll women or men under a continued access 
study 
 
b.  Including provisions to encourage certain target enrollment for women or men 
(e.g., maintain open enrollment for women until a pre-specified proportion is 
reached). 
 
3.  For Postmarket Studies (PAS or 522 PS stage) 
You should develop and describe your plan to enroll and retain proportions of women 
and men in your study that are consistent with the sex-specific prevalence of the type 
of disease or condition that your device is intended to treat or diagnose.  For PAS 
designed for continued follow-up of the pivotal study cohort, FDA may determine 
that additional study of one sex is warranted if the pre-market study data suggest 
there are clinically meaningful sex differences.  To enhance enrollment of women or 
men, we recommend that you undertake the following:   
 
a.  Consider whether outstanding questions warrant specific post-market 
evaluation in female-only or male-only studies based, for example, on sex-
specific signals observed in pre-market clinical studies or known sex 
differences in the underlying disease or the response to concomitant treatment 
or therapies that may affect safety or effectiveness.  
 
b.  Target investigational sites where recruitment of needed populations can be 
more easily facilitated (e.g., womens clinics). 
 
c.  Consider alternative communication strategies (as used in the Womens 
Health Initiative study26) for study recruitment, informed consent documents 
and patient labeling. 
 
d.  Periodically evaluate screening logs to identify reasons for under-enrollment 
of women or men or other key demographic groups.   
 
e.  Consider factors that increase recruitment such as community or local health 
care practitioner involvement in recruiting or referring patients, incentives or 
compensation (e.g., for transportation costs), and presentation of the benefits 
of participating in the study (e.g., send a newsletter to subjects to stimulate 
interest). 
                                                 
26 J. Hays, et al. The Womens Health Initiative Recruitment Methods and Results. Ann Epidemiol 
2003;13:S18S77. 
    12  Contains Nonbinding Recommendations 
 
 
 
 
f.  Consider flexibility in follow-up visit scheduling with provision of child care 
or elder care services during appointments or to allow various opportunities 
that match subjects' schedules, which may include evenings and weekends. 
 
We also recommend that sponsors and clinical study investigators consider the 
approaches described below, which can help avoid or minimize loss-to-follow up of 
subjects (regardless of sex). 
 
Sponsor Responsibilities 
 
a.  Develop a follow-up plan that details follow-up goals, frequency of contacts, 
and number and type of contact for patients missing a follow-up visit. 
 
b.  Demonstrate interest in the subjects (e.g., send newsletter to subjects to 
maintain interest). 
 
c.  Monitor follow-up rates closely so that follow-up problems can be identified 
and addressed as soon as possible. 
 
d.  Report subject accountability data as part of the study report. 
 
Investigator Responsibilities  
 
a.  Counsel subjects about the importance of returning to follow-up during 
informed consent and follow-up visits. 
  
b.  Remind subjects of upcoming scheduled follow-up visits.  
 
c.  Attempt to locate/return patients who miss scheduled clinic visits. 
  
d.  Obtain proxy information to use when unable to contact a study subject. 
 
e.  Ask  subjects who withdraw during the study to provide the reason for 
withdrawal and ask them whether the investigator may contact them once 
more at the end of the study follow-up to assess the experience with device 
 
f.  Demonstrate interest in the subjects (e.g., telephone follow-up after surgery, 
particularly if the device is implantable). 
 
 
 
 
    13  Contains Nonbinding Recommendations 
 
 
 
V.  Considering Sex in Study Design and Data 
Interpretation 
 
Differences between men and women range from the obvious (e.g., sexual organs, body fat 
distribution) to the less obvious (e.g., bone density, blood viscosity).  Genetic sex can affect 
all levels of biological organization (cell, organ, organ system, and organism), including 
susceptibility to disease.  Differences across the sexes in the incidence and severity of certain 
diseases may be related to differences in exposures, routes of entry and processing of a 
foreign agent, and cellular responses.  In addition, differences in health and illness are 
influenced by an individuals experiences and interaction with the environment, which may 
be affected by sex.27 Therefore, unless the investigational device is intended for use in only 
one sex (e.g., pregnancy test, or PSA testing), it is important that the variation in data across 
sex be considered in both study design and interpretation of study data. 
 
A. Statistical Concepts for Assessing Heterogeneity Across Sex Groups  
There may be a substantial difference in how a device performs in women versus men in 
terms of safety or effectiveness. Thorough investigation of heterogeneity across sex groups, 
especially for primary safety and effectiveness endpoints, should be conducted.  
Heterogeneity here refers to a difference in outcome across sexes.  Statistical hypothesis tests 
can be performed to detect heterogeneity, and methods of statistical inference for estimating 
its magnitude are also available. 
 
When multiple treatment groups are considered, a form of heterogeneity is treatment by sex 
interaction, which measures the magnitudes of differences in outcome across treatments in 
one sex compared with the other.  The concept of treatment by sex interaction applies to a 
study endpoint (such as probability of survival, adverse event rate) involving the comparison 
between two treatments.  It is important to distinguish between qualitative versus quantitative 
interactions.   Qualitative treatment by sex interaction for a parameter refers to the situation 
where one treatment is superior to the other in one sex, but not in the opposite sex.  
Quantitative treatment by sex interaction refers to the situation where one treatment is 
superior to the other in both sexes but by different amounts (See Figure 1 below).   
 
                                                 
27 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. 
    14  Contains Nonbinding Recommendations 
 
 
 
Quantitative Interaction Qualitative Interaction
0.80 0.80
0.70 0.70
0.60 0.60
0.50 0.50
0.40 0.40
0.30 0.30
0.20 0.20
0.10 0.10
0.00 0.00
male female male female
Control Treatment Control Treatment
       
Figure 1. Illustrations of quantitative (left graph) and qualitative (right graph) interactions.  
Statistical hypothesis tests of treatment by sex interaction have been widely utilized to detect 
treatment effect heterogeneity across sex.  Most of the tests of interaction in common use 
have as their null hypotheses the absence of treatment by sex interaction.  As statistical tests, 
their significance levels should be pre-specified in the investigational plan.  Note, however, 
that the power of such tests may be unspecified.  Therefore, lack of statistical significance for 
a test of treatment by sex interaction may not convincingly evidence the absence of clinically 
relevant interaction.  By the same token, moderate statistical significance may not 
convincingly evidence the presence of clinically relevant interaction.  While statistically 
significant interactions will be investigated for their clinical meaningfulness, interactions 
without associated statistical significance may also be examined for clinical reasons specific 
to the design and endpoint.   
 
For studies involving a single treatment with a single device (one-arm study), heterogeneity 
across sex groups can be assessed only for that single treatment and device.  The concept of 
treatment by sex interaction has no direct applicability in such studies.  To assess 
heterogeneity, statistical hypothesis tests comparing two sex groups under the (single) study 
treatment may be utilized, and in this specific context they are often subject  to limitations 
similar to those besetting the aforementioned statistical tests of treatment by sex interaction.      
 
Other patient characteristics (e.g., body size, co-morbidities, age) correlated with sex 
sometimes might explain apparent sex differences in clinical outcomes.  If differences 
between men and women are observed, FDA recommends that a sponsor investigate 
potential explanation of the differences by other patient characteristics.   
 
  1.    For New or Ongoing Studies (IDE study design/early enrollment stage) 
 
  The Statistical Analysis Plan (SAP) in the protocol should include pre-specified plans 
for addressing the issues described in the sections below.  
    15  Contains Nonbinding Recommendations 
 
 
 
  It remains important that clinical trials include diverse populations that reflect the 
intended population, whenever possible and appropriate.  In general, to achieve an 
unbiased estimate of treatment effect in the general population, sponsors should 
provide a strategy to enroll representative proportions of women and men (e.g., 
consistent with disease prevalence). 
  Sponsors should make an effort to identify in advance any key covariates that might 
explain possible differences across sexes, to plan to collect data on these covariates, 
and to pre-specify a modeling approach to investigate the extent to which these 
covariates can explain the observed differences. 
 
   2.    For Completed Studies (marketing application stage) 
In general, all studies should report descriptive statistics for outcomes of interest by sex as 
detailed in Section C below.  After overall effectiveness and safety have been investigated, 
the influence of sex on primary endpoints for both safety and effectiveness should be 
assessed.  If any clinically meaningful sex differences are suspected, either based on pre-
specified or exploratory post hoc analyses, sponsors should discuss with FDA to determine 
whether additional data are needed to address any remaining sex-specific questions of safety 
or effectiveness 
 
 
      3.    For Postmarket Studies (PAS or 522 PS stage)   
For PAS involving continuing data collection on PMA cohort patients, we recommend that 
you conduct the analyses described in Section C below for all follow-up time points. 
For PAS (or 522 PS studies) involving newly enrolled patients, you should include the 
analyses described in Section C below as part of a pre-specified statistical analysis plan in 
your protocol.  Furthermore, if results from sex-specific analyses of pre-market data suggest 
there may be a clinically meaningful difference in outcomes, you should consult with the 
Division of Epidemiology to determine whether this should also be incorporated into the 
study design and hypothesis for your PAS.    
When exploring sex-related differences during analysis of data from a PAS or 522 PS study, 
we recommend you address the issue of confounding by using multivariate analyses adjusted 
for patient characteristics that may confound the relationship between sex and study 
outcomes (e.g., smaller size, diabetes, etc.). 
 
B. Recommendations for Sex-Specific Statistical Elements in Study Design  
When Sex Group Differences are Anticipated 
  If, based on previous studies, literature, or disease science, important differences in 
the benefit-risk profile of a medical device are anticipated between men and women, 
clinical study design should take this into consideration.   
    16  Contains Nonbinding Recommendations 
 
 
 
  For devices that are appropriate for both men and women, where background 
information or previous clinical study results point to the potential existence of a 
clinically meaningful difference by sex, the study may need to be powered to evaluate 
treatment effect for both sex groups if the intended claim is for both sexes.  In other 
words, sponsors may need to intentionally enroll sufficient number of patients in each 
sex group to allow valid analysis (i.e., a sample size sufficient for sex-specific 
claims); a stratified study design with outcome analyses by sex may be needed.  
  A single study can be designed to support marketing approval for the combined 
population of men and women or one sex only.   A common key element of all such 
study designs is successful control of Type 1 error rates at the desired levels, taking 
into account the multiplicity due to the two ways to claim study success.  Just as with 
any study having a complex design, the sponsor is encouraged to talk to FDA early.   
  Although rarely done, it is possible to plan a study that simultaneously investigates 
the overall treatment effect and the effect on only one subgroup such as women (or 
men).  This would be done if the claim were for the entire population or just one pre-
identified sex.  One approach would be to allocate some fraction f of the overall Type 
I error rate (alpha) to the investigation of the overall inferential procedure and the 
rest to investigating the particular subgroup.  In the hypothesis testing framework, the 
study would then be  successful if either the overall test were significant at level f 
times alpha or the subgroup was effective at level (1-f) times alpha. 
  Studies may be designed to investigate overall treatment effect in the combined 
population, and if positive, conduct pre-specified secondary analyses in one sex or 
another. 
 
Pre-specifying Assessment of Heterogeneity Across Sex Groups in Study Design 
  Unless a device to be studied is intended for use in only one sex (e.g., pregnancy test, 
PSA testing), it is important that variability in data across sex groups and its 
interpretation be considered in the study design even if no substantial sex difference 
is expected at the design stage.  
  The statistical analysis plan should include a strategy for assessing heterogeneity 
across sexes, since FDA recommends such an assessment as an integral part of 
interpreting study results for every submission.  In particular, the heterogeneity 
assessment can serve as the basis for poolability conditions for studies with pre-
specified success criteria expressed in terms of data pooled across sex groups.  Such 
poolability conditions bear some resemblance to those commonly used for 
determining whether data can appropriately be pooled for analysis across different 
clinical sites.  Poolability conditions may be specified as statistical hypothesis tests, 
which, for studies involving the comparison of two treatments, would typically be 
tests of treatment by sex interaction.  The interaction tests should ideally be able to 
detect interaction of relevant magnitude measured on pertinent parameters with a 
reasonably high probability, and this goal should guide the choice of appropriate 
significance level.   
    17  Contains Nonbinding Recommendations 
 
 
 
Additional Considerations for Particular Study Design Types 
  For one-arm studies: 
o  Sponsors should provide strategy for assessing heterogeneity across sex 
groups. 28  The specific methodology could vary; if the methodology requires 
any assumptions, the validity of these assumptions should be investigated.   
o  Sponsors may also consider sex-specific objective performance criteria (OPC) 
or performance goals.  It may be used for sex-specific claims. It is important 
to control overall type 1 error rate to support any multiple claims based on 
hypothesis testing. 
  For comparative studies: 
o  Sponsors should pre-specify interaction testing.  The validity of any 
assumptions should be investigated. 
o  Sponsors may consider powering for sex-specific claims when sex-subgroup 
differences are anticipated.   If seeking multiple claims based on hypothesis 
testing, it is important to control overall type 1 error rate. 
o  If the control is non-randomized or historical and patient-level data exist, then 
the interaction can be investigated in conjunction with a propensity score data 
analysis. 
o  For randomized controlled trials, sponsors may consider sex as a stratification 
variable in the randomization process if clinically meaningful sex difference is 
anticipated. 
 
Special Considerations for Diagnostic Devices 
For in vitro diagnostic assays, imaging devices, and diagnostic devices in which a cutoff is 
used, sponsors should include data from both women and men both at the cutoff selection 
and cutoff validation stages.  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, 
diseased and non-diseased).  Separate cutoffs for men and women should be used only when 
there is reason to believe separate cutoffs are needed based on previous evidence or if the 
data in the current clinical study provide evidence for different cutoffs.  The use of separate 
cutoffs may affect study design and sample size calculations.  Analysis by sex of clinical 
performance measures such as sensitivity, specificity, positive and negative likelihood ratios, 
and positive and negative predictive values should be performed.  Analysis of reference 
intervals with regard to mean (median) values, standard deviation and percentiles should be 
performed for men and women separately.  Separate reference intervals for men and women 
should be considered only if they will be clinically useful and when there is reason to believe 
such intervals are needed based on previous evidence.  For new measurands, if the 
information necessary to decide these questions is not available, but the data of the reference 
                                                 
28 This type of analysis is currently conducted for the purposes of determining whether data can appropriately 
be pooled for analysis. 
    18  Contains Nonbinding Recommendations 
 
 
 
interval study indicate sex-specific differences, reference intervals should be presented for 
men and women separately and for combined data.  Situations may arise in which an assay or 
device has high overall accuracy (e.g., very high sensitivity and specificity); when this 
occurs, subgroup analysis may not be warranted.   
 
C. Recommendations for Analysis and Interpretation of Sex-Specific Data 
in Completed Studies 
 
Sex-Specific Analysis 
In general, all studies should report descriptive statistics for outcomes of interest, including 
the estimate of variance or standard deviation (as applicable), by sex.  At the primary follow-
up time-point, regardless of the potentially limited statistical power of these sex-specific 
subgroup analyses, data should be examined for clinically meaningful sex differences in each 
of the following: 
o  primary effectiveness endpoint(s); 
o  primary safety endpoint(s); and 
o  key secondary endpoints.  
 
  After overall effectiveness and safety have been investigated, the influence of sex on 
primary endpoints for both safety and effectiveness (and in some cases for important 
secondary endpoints as well) should be assessed.   
  It is important to carry out all analyses set forth in the Statistical Analysis Plan 
(SAP).  FDA expects sponsors to plan and conduct analyses to evaluate heterogeneity 
by sex, including treatment by sex interaction when applicable, as described in 
previous sections. 
  In some cases the test for treatment by sex interaction (or heterogeneity in general) 
may have adequate power to detect only a very large interaction (or heterogeneity) 
but may fail to detect a smaller yet clinically important interaction (or heterogeneity).  
Such situations may arise when the number of patients in one or both of the sex 
groups is small, in which case additional data from men or women (or both) may be 
required.  Observed heterogeneity could exist across sexes due to large variability 
associated with small sample sizes; interpretation of clinical meaningfulness may be 
premature in those cases.  Consultation with FDA is recommended. 
  For recommendations on interpreting data, see Section D below. 
 
Additional Considerations for Data Analysis in Particular Study Design Types 
  For one-arm studies: 
    19  Contains Nonbinding Recommendations 
 
 
 
o  If overall treatment effect is neither statistically significant nor clinically 
meaningful, subgroup analyses are not recommended.  In such cases, analysis 
likely raises questions about data to support marketing application. 
o  If no significant difference is observed across sexes, data may be poolable 
across sex.   
o  If a significant difference is observed across sexes, it is important to explore 
whether the difference remains significant after adjusting for other covariates.  
If not, data may be poolable across sex.   
o  If difference remains significant after adjusting for other covariates, data may 
not be poolable across sex.  Additional data may be required to appropriately 
evaluate the effect of sex on the study endpoints.  In these cases, discussion 
with FDA is advised.   
  For comparative studies: 
o  If overall treatment effect is not statistically significant and clinically 
meaningful, subgroup analyses are not recommended.  In such cases, analysis 
likely raises questions about data to support marketing application. 
o  If there is evidence of an interaction of treatment by sex, it is important to 
describe the nature of interaction (qualitative or quantitative) and assess the 
clinical importance of the differences.  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.   
o  If no significant interaction effect between treatment and sex is observed for 
the outcome of interest, data may be poolable across sex.  However, the 
decision about the validity of pooling the data should be based on the size of 
the observed interaction effect as well as its clinical importance.   
o  If a treatment effect difference is noted across sexes, it is usually helpful to 
perform additional analyses to investigate possible explanations for this 
difference using variables such as body size (e.g., body mass index), bone 
density or concomitant illness (e.g., diabetes).  If significant interaction effect 
between treatment and sex is observed, explore whether this remains 
significant after adjusting for other covariates.  If not, data may be poolable 
across sex.    
o  If the interaction effect remains significant after adjusting for other covariates, 
data may not be poolable across sex.  Additional data may be required to 
appropriately evaluate the effect of sex on the study endpoints. In these cases, 
discussion with FDA is advised.   
o  If a significant treatment by sex interaction has been identified, it may be 
helpful to investigate if there is a sex difference in treatment group only, 
control group only, or both.  Alternately, the interaction could be explored by 
assessing whether there is a treatment difference in women only, men only, or 
both.   
    20  Contains Nonbinding Recommendations 
 
 
 
D. Interpretation of Sex-Specific Data 
If any clinically meaningful sex differences are found, either based on pre-specified or 
exploratory post hoc analyses, you should discuss with FDA whether additional data are 
needed to address any remaining sex-specific questions.  
 
If results of your analysis suggest that there is insufficient data to assess whether sex is 
associated with clinically meaningful differences in outcome, FDA may determine that 
clinical data from additional subjects in one or both sexes may be needed pre- or 
post-market to address potential sex-specific questions related to safety or effectiveness. 
 
Although expected to be rare, in cases where clinically meaningful differences between 
the sexes are observed in safety or effectiveness, FDA may request additional 
confirmatory studies in one or both sexes, implement specific pre- or post-approval study 
conditions, and/or modify the design of subsequent studies. 
 
There are limitations to interpreting clinically meaningful differences in small data sets.  
Mean differences could exist between sexes due to small samples sizes; interpretation 
about whether they are clinically meaningful may be premature in many cases. 
 
VI.  Recommendations for Reporting Sex-Specific 
Information in Applications and Public Documents 
Confidential submissions to FDA contain detailed analyses of clinical study data, which may 
include a variety of sex-specific analyses.  However, public documents, including labeling 
and FDA summaries of review (e.g., SSED) for medical devices approved in the past, are 
inconsistent with regard to the degree of information reported on device performance in 
demographic subgroups.  Although sponsors may be most interested in the generalizability of 
the findings, individual patients and their medical providers may 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(ies) with respect to device 
performance in women and men is linked to the proportions of each sex in your 
study(ies).  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, if known.  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 collected, we 
recommend that you report these by demographic subgroup as well as overall.   
    21  Contains Nonbinding Recommendations 
 
 
 
 
  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].  Among subjects in the treatment group, m1/n1 (p1%) were women, and m2/n2 
(p2%) of subjects in the control group were women. 
 
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, including the labeling.  A summary of 
this information should also be included in your draft PMA Summary of Safety and 
Effectiveness, 510(k) Summary, or de novo decision 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)  
Information regarding sex-specific outcomes analyses should be described in the labeling 
and summaries of review, regardless of whether the analyses are pre-specified or post 
hoc.  Covariates that might explain possible outcome differences between sexes should 
be described.  
  If outcome differences by sex are statistically significant and clinically 
meaningful, you should report the results of the outcome analyses.   
  If results of these analyses suggest a sex difference in an endpoint or event that is 
clinically meaningful but not statistically significant, you should report the 
findings descriptively.   
    22  Contains Nonbinding Recommendations 
 
 
 
  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.  To provide appropriate context, describe prior 
scientific evidence suggesting that clinically meaningful differences by 
sex are expected, or describe statistical limitations of analyses. 
 
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. 
 
If clinically meaningful sex differences in safety or effectiveness are observed, or if 
there are potential differences that might require follow-up studies, data on benefits 
and risks should be described separately for women and men in labeling and review 
summaries.    
 
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 meaningful signal is detected in your final analysis, FDA may 
recommend changes to your approved labeling and review summaries, which you 
  
should submit with your final study report.
 
    23  Contains Nonbinding Recommendations 
 
 
 
APPENDIX 1  DECISION FRAMEWORK 
We encourage the use of existing scientific data (e.g., previous studies, disease science) to 
determine whether there is a hypothesis for a clinically meaningful sex difference for your 
device.  When there is a hypothesis for a clinically meaningful sex difference, the following 
decision trees provide a framework in deciding when various sex-specific statistical 
recommendations apply for different clinical study designs. 
RECOMMENDATIONS FOR SEX-SPECIFIC STATISTICAL DESIGN 
 
Follow Recommendations associated with study design  
 
    24  Contains Nonbinding Recommendations 
 
 
 
DECISION FRAMEWORK 
 
RECOMMENDATIONS FOR SEX-SPECIFIC STATISTICAL ANALYSES FOR 
COMPLETED STUDIES - ONE ARM STUDIES  
(Objective Performance Criterion, Performance goal, Observational Study) 
 
 
 
    25  Contains Nonbinding Recommendations 
 
 
 
DECISION FRAMEWORK 
 
RECOMMENDATIONS FOR SEX-SPECIFIC STATISTICAL ANALYSES FOR 
COMPLETED STUDIES - COMPARATIVE STUDIES 
 
 
 
 
    26