Contains Nonbinding Recommendations 
Evaluation and Reporting of Age-, 
Race-, and Ethnicity-Specific Data in 
Medical Device Clinical Studies
 
______________________________________________________________________________ 
Guidance for Industry and  
Food and Drug Administration Staff 
 
Document issued on September 12, 2017.  
 
The draft of this document was issued on June 20, 2016. 
 
For questions about this document regarding CDRH-regulated devices, contact CDRH at 301-
796-5900 or CDRHPatientDiversity@fda.hhs.gov or CDRHClinicalEvidence@fda.hhs.gov. 
 
For questions about this document regarding CBER-regulated devices, contact the Office of 
Communication, Outreach, and Development (OCOD) at 1-800-835-4709 or 240-402-8010. 
 
 
 
 
 
 
 
 
 
 
      U.S. Department of Health and Human Services 
  Food and Drug Administration 
 
Center for Devices and Radiological Health 
Center for Biologics Evaluation and Research 
 
 
 
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  Contains Nonbinding Recommendations 
Preface 
 
Public Comment 
 
You may submit electronic comments and suggestions at any time for Agency consideration to 
http://www.regulations.gov .  Submit written comments to the Dockets Management Staff, Food 
and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852.  
Identify all comments with the docket number FDA-2016-D-0734.  Comments may not be acted 
upon by the Agency until the document is next revised or updated. 
 
Additional Copies 
 
CDRH 
 
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 1500626 to identify the guidance you are requesting. 
 
CBER 
 
Additional copies are available from the Center for Biologics Evaluation and Research (CBER) 
Office of Communication, Outreach, and Development (OCOD), 10903 New Hampshire Ave., 
WO71, Room 3128, Silver Spring, MD 20903, or by calling 1-800-835-4709 or 240-402-8010, 
by email, ocod@fda.hhs.gov, or from the Internet at  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio
n/Guidances/default.htm.  
 
 
 
 
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  Contains Nonbinding Recommendations 
Table of Contents 
 
I.  INTRODUCTION ................................................................................................................................................ 5 
II.  SCOPE ............................................................................................................................................................... 6 
III.  BACKGROUND .................................................................................................................................................. 7 
A.  SECTION 907 OF THE FOOD AND DRUG ADMINISTRATION SAFETY AND INNOVATION ACT (FDASIA) ............. 8 
B.  TERMINOLOGY .................................................................................................................................................. 8 
(1)  Age ............................................................................................................................................................... 8 
(2)  Race and Ethnicity ....................................................................................................................................... 9 
C.  WHY CONSIDER AGE-, RACE-, AND ETHNICITY-SPECIFIC DIFFERENCES ........................................................ 10 
(1)  Age ............................................................................................................................................................. 10 
(2)  Race and Ethnicity ..................................................................................................................................... 11 
D.  PARTICIPATION OF AGE-, RACE-, AND ETHNICITY-SPECIFIC SUBGROUPS IN CLINICAL TRIALS ...................... 12 
(1)  Barriers to Enrollment ................................................................................................................................ 12 
(2)  Enrollment Resources ................................................................................................................................ 13 
IV.  RECOMMENDATIONS FOR ACHIEVING APPROPRIATE ENROLLMENT ......................................................... 14 
A.  CONSIDERATION OF POTENTIAL AGE-, RACE-, AND ETHNICITY-SPECIFIC DIFFERENCES ................................ 15 
(1)  Study Design, Early Enrollment Stage ....................................................................................................... 15 
(2)  Premarket Submission Stage ...................................................................................................................... 16 
(3)  Postmarket Submission Stage .................................................................................................................... 16 
B.  PLANNING FOR DIVERSE STUDY RECRUITMENT .............................................................................................. 16 
(1)  Study Design, Early Enrollment Stage ....................................................................................................... 17 
(2)  Premarket Submission Stage ...................................................................................................................... 18 
(3)  Postmarket Submission Stage .................................................................................................................... 19 
C.  CONSIDERATIONS FOR STUDY FOLLOW-UP VISITS .......................................................................................... 19 
V.  CONSIDERING AGE, RACE, AND ETHNICITY IN STUDY DESIGN, ANALYSIS, AND INTERPRETATION OF 
STUDY RESULTS .......................................................................................................................................................... 20 
A.  ASSESSING HETEROGENEITY ACROSS AGE, RACIAL, AND ETHNIC SUBGROUPS ............................................. 21 
(1)  Study Design, Early Enrollment Stage ....................................................................................................... 22 
(2)  Premarket Submission Stage ...................................................................................................................... 22 
(3)  Postmarket Submission Stage .................................................................................................................... 23 
B.  DESIGNING STUDIES: RECOMMENDATIONS FOR SUBGROUP SPECIFIC STATISTICAL ELEMENTS ...................... 23 
(1)  Recommendations When Subgroup Differences are Anticipated .............................................................. 24 
(2)  Recommendations for Pre-specifying Assessment of Heterogeneity ......................................................... 24 
(3)  Additional Design Recommendations for Comparative and One-arm Studies .......................................... 24 
C.  COMPLETED STUDIES: RECOMMENDATIONS FOR ANALYSIS OF SUBGROUP-SPECIFIC DATA ........................... 25 
D.  INTERPRETATION OF AGE-, RACE-, AND ETHNICITY-SPECIFIC DATA .............................................................. 26 
VI.  RECOMMENDATIONS FOR SUBMITTING AGE-, RACE-, AND ETHNICITY-SPECIFIC DATA IN SUBMISSIONS 
TO THE AGENCY AND REPORTING IN PUBLIC DOCUMENTS ...................................................................................... 26 
A.  ENROLLMENT DEMOGRAPHICS, BASELINE CHARACTERISTICS & CO-MORBIDITIES ....................................... 27 
(1)  IDE Stage ................................................................................................................................................... 28 
(2)  Premarket Submission Stage ...................................................................................................................... 28 
(3)  Postmarket Submission Stage .................................................................................................................... 28 
B.  AGE-, RACE-, AND ETHNICITY-SPECIFIC OUTCOMES (SAFETY OR EFFECTIVENESS, OR PROBABLE BENEFIT FOR 
HDES) ...................................................................................................................................................................... 29 
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(1)  Premarket Submission Stage ...................................................................................................................... 31 
(2)  Postmarket Submission Stage .................................................................................................................... 31 
APPENDIX 1  DECISION FRAMEWORK ...................................................................................................................... 32 
FIGURE 1: RECOMMENDATIONS FOR DEMOGRAPHIC SUBGROUP-SPECIFIC STATISTICAL STUDY DESIGN ................ 33 
FIGURE 2: RECOMMENDATIONS FOR DEMOGRAPHIC SUBGROUP-SPECIFIC STATISTICAL ANALYSIS FOR ONE-ARM 
STUDIES (OBJECTIVE PERFORMANCE CRITERION, PERFORMANCE GOAL, OBSERVATIONAL STUDY) ....................... 34 
FIGURE 4: RECOMMENDATIONS FOR SUBMITTING AND REPORTING SUBGROUP-SPECIFIC PARTICIPATION AND 
OUTCOME INFORMATION ......................................................................................................................................... 36 
 
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  Contains Nonbinding Recommendations 
Evaluation and Reporting of Age-, 
Race-, and Ethnicity-Specific Data in 
Medical Device Clinical Studies 
 
 
Guidance for Industry and  
Food and Drug Administration Staff  
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on 
FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff 
or Office responsible for this guidance as listed on the title page.  
 
I.  Introduction  
 
The purpose of this guidance is to outline the FDAs expectations and provide recommendations 
for the evaluation and reporting of age-, race-, and ethnicity-specific data in medical device 
clinical studies. The primary intent of these recommendations is to improve the quality, 
consistency, and transparency of data regarding the performance of medical devices within 
specific age, racial, and ethnic groups.  Proper evaluation and reporting of this data can benefit 
patients, clinicians, researchers, regulators, and others.  Additionally, it is important that clinical 
trials include diverse populations that reflect the intended use population.  In general, to achieve 
an unbiased estimate of treatment effect in the general population, sponsors should develop a 
strategy to enroll diverse populations including representative proportions of relevant age, racial, 
and ethnic subgroups, which are consistent with the intended use population of the device.  This 
guidance includes recommendations and considerations to assist sponsors in developing such a 
strategy. FDA recognizes the practical challenges in achieving the appropriate enrollment of 
diverse populations. This guidance includes recommendations to overcome barriers to 
enrollment in order to balance these recommendations with least burdensome principles. 
 
This guidance extends the policy set forth in the FDAs Evaluation of Sex-Specific Data in 
Medical Device Clinical Studies Guidance1 to additional demographic subgroups of age, race, 
and ethnicity.  This guidance also extends and complements FDAs Collection of Race and 
                                                           
1 See FDAs guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283707.pdf. 
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  Contains Nonbinding Recommendations 
Ethnicity Data in Clinical Trials Guidance, which, for collecting and reporting race- and 
ethnicity-specific information in clinical trials, recommended the use of the standardized 
approach developed by the Office of Management and Budget (OMB).2  
 
The specific objectives of this guidance are to:  
1)  encourage the collection and consideration during the study design stage of relevant age, 
race, ethnicity, and associated covariates (e.g., body size, biomarkers, bone density) for 
devices for which safety, effectiveness (or, for humanitarian device exemptions (HDEs), 
probable benefit), or benefit-risk profile is expected to vary across these groups;  
2)  outline recommended analyses of study subgroup data, with a framework for considering 
demographic data when interpreting overall study outcomes; and  
3)  specify FDAs expectations for reporting age-, race-, and ethnicity-specific information 
in summaries and labeling for approved or cleared medical devices. 
 
FDA's 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 guidance means that something is suggested or 
recommended, but not required. 
II.  Scope 
 
This guidance is intended for devices that include 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 HDE application.  The 
recommendations contained herein also apply to post-approval study submissions and 
postmarket surveillance studies, where noted.   
 
Age, race, and ethnicity are not the only demographic variables that may affect device 
performance. While this guidance focuses on the impact of age, race, and ethnicity, some of the 
recommendations may also be used to promote study enrollment and data analysis adequately 
accounting for other demographic variables, such as sex3 and geographic location (e.g., rural).  
Other patient characteristics, such as emotional, physical, sensory, and cognitive capabilities, can 
often be important variables when evaluating medical device safety and effectiveness (or 
probable benefit for HDEs); however, these will not be addressed within this guidance.  For 
further information related to these user considerations please see the FDAs Design 
Considerations for Devices Intended for Home Use Guidance.4 
 
                                                           
2 See FDAs guidance Collection of Race and Ethnicity Data in Clinical Trials http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-afda-gen/documents/document/ucm126396.pdf.  
3 See FDAs guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283707.pdf. 
4 See FDAs guidance Design Considerations for Devices Intended for Home Use http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-meddev-gen/documents/document/ucm331681.pdf. 
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  Contains Nonbinding Recommendations 
The impact of demographic variables on device safety, effectiveness (or probable benefit, for 
HDEs), or benefit-risk profile may be greater for certain types of products or diseases than 
others.  For example, certain dermatology devices may have different considerations for use in a 
specific racial or ethnic population.  Similarly, certain orthopedic devices may have different 
considerations for use in specific age groups.  Studies of devices intended only for certain groups 
(e.g., pediatrics) would not be expected to address the potential differences in outcome for 
groups outside the intended use population.  Additionally, some in vitro diagnostic (IVD) device 
clinical studies are conducted on de-identified leftover specimens, so it may not be possible to 
obtain demographic information, such as age, race, or ethnicity.  As a result, evaluation of age-, 
race-, and ethnicity-specific data would not be possible in these cases.  Furthermore, for 
companion diagnostic devices undergoing accelerated approval, FDA advises sponsors to consult 
with the primary review Division or Branch.5    
 
When clinically relevant differences in treatment effect are anticipated across age, racial, or 
ethnic groups, it is important to consider proper clinical study design, sufficient enrollment of 
subgroups to allow meaningful analysis, and controlling of study-wise Type 1 error for overall 
and subgroup-specific hypothesis testing, if appropriate and feasible. 
 
FDA recommends the use of this guidance document as a supplement to other FDA guidance 
where applicable, in particular, any relevant device-specific guidance, as well as FDAs 
Collection of Race and Ethnicity Data in Clinical Trials guidance.6   
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 age, race, and ethnicity 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 age, race, and ethnicity 
in clinical studies for medical devices.  On April 9, 2015, the Institute of Medicine convened a 
public workshop of various government agencies, physician professional societies, and patient 
advocacy groups to discuss strategies for ensuring diversity, inclusion, and meaningful 
participation in clinical trials.7  This guidance document reflects the recommendations generated 
in this and other public fora.  It is intended to provide guidance on the design, conduct, and 
reporting of clinical studies to improve age-, race-, and ethnicity-specific information about the 
safety and effectiveness (or probable benefit for HDEs) of approved and cleared new medical 
devices. 
                                                           
5 See FDAs guidance Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with 
Food and Drug Administration Staff 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf.  
6 See FDAs guidance Collection of Race and Ethnicity Data in Clinical Trials http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-afda-gen/documents/document/ucm126396.pdf. 
7 Institute of Medicine Workshop: Strategies for Ensuring Diversity, Inclusion, and Meaningful Participation in Clinical Trials. 
April 9, 2015. Agenda and presentations available at 
http://iom.nationalacademies.org/Activities/SelectPops/HealthDisparities/2015-APR-09.aspx. 
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  Contains Nonbinding Recommendations 
 
A.  Section 907 of the Food and Drug Administration Safety 
and Innovation Act (FDASIA) 
 
Section 907 of the Food and Drug Administration Safety and Innovation Act (FDASIA)8 
directed the Agency to publish and provide to Congress a Report, followed by an Action 
Plan outlining recommendations... to improve the completeness and quality of analyses 
of data on demographic subgroups [including sex, age, race, and ethnicity] in summaries 
of product safety and effectiveness data [or probable benefit for HDEs] and in 
labeling;...on the inclusion of such data, or the lack of availability of such data in 
labeling; [and] to...improve the public availability of such data to patients, health care 
providers, and researchers.  In that Action Plan, CDRH committed to develop this 
guidance, as an action to improve the completeness, quality, and public availability of 
demographic subgroup data from medical device clinical studies.9 
 
B.  Terminology 
(1)  Age 
 
When evaluating age-specific data, clinical studies should plan to group subjects 
by age groups as appropriate for the disease condition. Standardizing age 
categories may not be appropriate for all devices; however, more discrete age 
groupings should be considered. For example, you may group older patients for 
analysis at 65-74 years old, and 75-84 years old, rather than simply older/younger 
than 65. 
 
FDA does not define a specific age for the geriatric population due to the different 
considerations for the wide variety of medical devices and diagnostics.  However, 
we recommend stratifying age (e.g. 65-74, 75 years) based on relevant disease 
characteristics. 
 
Device regulations define the pediatric population as any patient less than 22 
years of age.10  It should be noted that this may differ from the drug and biologic 
regulations but, for purposes of this guidance, the definition of pediatric patient in 
21 CFR 814.3(s) should be used.  This population should be further subdivided 
                                                           
8 Food and Drug Administration Safety and Innovation Act, P.L. 112-144, July 9, 2012.   
9 See FDAs Report on Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical 
Products (August, 2013), FDAs Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data 
(August, 2014), and other related information including public feedback and FDAs current progress, at:  
https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/U
CM365544.pdf.  
10 21 CFR 814.3(s) defines pediatric patients as patients who are 21 years of age or younger (that is, from birth through the 
twenty-first year of life, up to but not including the twenty-second birthday) at the time of the diagnosis or treatment. Available at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=814.3.  
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  Contains Nonbinding Recommendations 
into several age groups as described in guidance, or by developmental milestones 
as appropriate.11, 12 
(2)  Race and Ethnicity 
 
In accordance with FDAs guidance Collection of Race and Ethnicity Data in 
Clinical Trials,13 patients may self-identify in both an ethnic and racial category 
(e.g., Hispanic-White, Hispanic-Black).  That guidance specified that OMB 
stated that its race and ethnicity categories were not anthropologically or 
scientifically-based designations, but instead were categories that described the 
sociocultural construct of our society.  The Department of Health and Human 
Services (HHS) chose to adopt these standardized categories for its agencies that 
report statistics, because the categories are relevant to assessing various health 
related data, including public health surveillance and research.  FDA recommends 
the submission of applications containing clinical study data with ethnic and 
racial demographic data captured as two distinct categories.      
 
More granular race-specific data may be important depending on the disease or 
condition (e.g., if the condition is substantially more prevalent or varied in course 
for Ashkenazi Jewish or Han Chinese).  Additionally, FDA acknowledges that 
other ethnic and racial categories may be appropriate depending on the study 
population, (e.g., in global studies involving sites and patients outside the United 
States (OUS) permissible under local laws).  The categories and identification 
method should be defined in the study protocol. 
 
Collection and combination of data from OUS study sites may result in 
confounding issues of ethnicity and standard of care.  OUS sites may not 
categorize race and ethnicity in the same manner as U.S. sites or may define 
certain racial or ethnicity groups differently than do U.S. sites (e.g., Caucasian 
vs white in European vs. U.S. data).  Additionally, the standard of care at OUS 
sites may not be equivalent.  These differences may make it difficult to combine 
racial and ethnic subgroup data from OUS sites. However, in some cases, 
differences in race and ethnicity may be controlled with the inclusion of clear 
definitions in the protocol which may allow for combining U.S. and OUS race- 
and ethnicity-specific data.  The acceptability of this approach may differ across 
                                                           
11 See FDAs guidance Premarket Assessment of Pediatric Medical Devices. This guidance subdivides the pediatric age group as 
follows:  
  Newborn (neonate)  from birth to 1 month of age 
  Infant  greater than 1 month to 2 years of age 
  Child  greater than 2 to 12 years of age 
  Adolescent  greater than 12 through 21 years of age 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089742.pdf. 
12 See FDAs guidance Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm444591.pdf.  
13 See FDAs guidance Collection of Race and Ethnicity Data in Clinical Trials http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-afda-gen/documents/document/ucm126396.pdf. 
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  Contains Nonbinding Recommendations 
clinical or product areas, so we recommend you discuss any such plans for 
combining data with the primary review Division or Branch. 
C.  Why Consider Age-, Race-, and Ethnicity-Specific 
Differences 
(1)  Age 
Consideration of different age populations (particularly pediatric and older 
patients, who are often underrepresented in clinical trials) can be important for 
proper characterization of a devices safety and effectiveness (or probable benefit 
for HDEs) in the patient population.  In the 2013 FDASIA 907 Report,14 of the 
approved PMAs evaluated for the Report, only 40% publicly reported an age-
based analysis of outcomes data.  The amount of age information available was 
inconsistent and often not detailed enough to analyze device performance related 
to age.  The manner in which the age descriptive statistics are presented (e.g., 
mean, median, standard deviation, distribution) in a submission may affect data 
interpretation.  Proper study of device use in both older and pediatric populations 
is important when the device is likely to be used for these subgroups. 
Older patients and pediatric patients often have co-morbidities, concomitant 
therapies, or development considerations that could interact with the 
investigational device effects and impact device performance.  Older patients may 
have age-related covariates such as characteristics of bone density, metabolism, 
digestion, synovial fluid, etc. that could affect the performance of medical 
devices. In addition, the benefits or adverse effects of medical devices may be age 
dependent. A medical device might adversely affect the development of a 
pediatric patient but have no detrimental effect on an adult.  In the case of 
intraocular lenses, devices are used to treat vision loss in adults and children, with 
the potential added benefit of improving future visual development in a young 
child.15  For these reasons, it is important to consistently consider the potential 
impact of age on device effects, and to plan studies and analyses accordingly. 
FDA provides guidance on developing medical devices for pediatric population 
subgroups (e.g., neonates, infants, children, and adolescents).11  FDA has several 
device-related initiatives that aim to address challenges in the pediatric 
subpopulation. In 2007, Congress enacted the Pediatric Medical Device Safety 
and Improvement Act (PMDSIA) as part of the Food and Drug 
14 See FDA Report: Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products, 
issued August 2013, required under FDASIA Section 907. 
http://www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmend
mentstotheFDCAct/FDASIA/UCM365544.pdf.  
15 Institute of Medicine (US) Committee on Clinical Research Involving Children; Field MJ, Behrman RE, editors. Ethical 
Conduct of Clinical Research Involving Children. Washington (DC): National Academies Press (US); 2004. 2, The Necessity and 
Challenges of Clinical Research Involving Children. Available from: http://www.ncbi.nlm.nih.gov/books/NBK25553/.  
10  Contains Nonbinding Recommendations 
Administration Amendments Act of 2007 (FDAAA),16 which provides that FDA 
may extrapolate adult data when appropriate.   
 
PMDSIA also requires certain medical device applications to include, if readily 
available, a description of any pediatric subpopulations that suffer from the 
disease or condition that the device is intended to treat, diagnose, or cure and the 
number of affected pediatric patients.17  FDA issued a guidance document 
outlining the implementation of this provision (FDA Guidance: Providing 
Information about Pediatric Uses of Medical Devices).18  
(2)  Race and Ethnicity 
 
While the U.S. population demographic is changing, diverse representation in 
clinical trials remains a challenge, and inconsistent analysis and reporting 
contributes to a persistent lack of publicly available data on device performance in 
diverse ethnic and racial groups.  The 2013 FDASIA 907 Report showed a 
distinct lack of publicly reported race- and ethnicity-specific data for medical 
devices.19 Only 27% of the studies reviewed contained a race- or ethnicity-
specific subgroup analysis, and only 16% had public statements regarding a race- 
or ethnicity-specific analysis.  
 
There are several devices where differences in effect were observed that were 
correlated with race and ethnicity.  For example, differences in skin structure and 
physiology can affect response to dermatologic and topically applied products.20  
Mortality rates of patients on dialysis have been shown to differ across racial and 
ethnic groups.21  FDA encourages sponsors to collect race- and ethnicity-specific 
data according to the recommendations in the FDA Guidance Collection of Race 
and Ethnicity Guidance Document.22  
                                                           
16 See PMDSIA, Title III, Public Law 110-85. Available at http://www.gpo.gov/fdsys/pkg/PLAW-110publ85/pdf/PLAW-
110publ85.pdf.  
17 Consult Pediatric uses of devices (21 U.S.C.  360e-1). Available at  
http://www.gpo.gov/fdsys/pkg/USCODE-2010-title21/html/USCODE-2010-title21-chap9-subchapV-partA-sec360e-1.htm. 
18 See FDAs guidance Providing Information about Pediatric Uses of Medical Devices 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM339465.pdf.  
19 See FDAs Report on Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical 
Products (August, 2013), FDAs Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data 
(August, 2014), and other related information including public feedback and FDAs current progress, at:  
https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/U
CM365544.pdf. 
20 Taylor, Susan C. "Skin of color: biology, structure, function, and implications for dermatologic disease." Journal of the 
American Academy of Dermatology 46.2 (2002): S41-S62. 
21 Yan, Guofen, et al. "The relationship of age, race, and ethnicity with survival in dialysis patients." Clinical Journal of the 
American Society of Nephrology 8.6 (2013): 953-961. 
22 See FDAs guidance Collection of Race and Ethnicity Data in Clinical Trials http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-afda-gen/documents/document/ucm126396.pdf.. 
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  Contains Nonbinding Recommendations 
D.  Participation of Age-, Race-, and Ethnicity-Specific 
Subgroups in Clinical Trials 
 
It is important that clinical trials include diverse populations that reflect the intended 
population, especially when clinically meaningful differences in safety, effectiveness (or 
probable benefit, for HDEs), or benefit-risk profile are expected across these groups.  In 
general, to achieve an unbiased estimate of treatment effect in the general population, 
sponsors should develop a strategy to enroll diverse populations including relevant age, 
racial, and ethnic groups.   
 
Where possible, it is also important to enroll diverse populations throughout the enrolling 
sites, particularly in studies where surgical or operator skill may be of key importance. If 
patients enrolled at one site are predominantly of one demographic subgroup, it may be 
possible to incorrectly attribute differences in device performance or surgical skill to 
demographic subgroups; this should be considered when planning and analyzing trials.   
 
In general, study protocols should include pre-specified statistical plans for addressing 
these and other issues outlined in this guidance.  Unplanned subgroup analyses or those 
with inadequate sample size are generally not considered to be adequate to support 
statements in the labeling regarding the safety or effectiveness of the device.  However, 
the overall benefit-risk profile of the device will be considered. 
(1)  Barriers to Enrollment 
 
Recruiting subjects to clinical studies who represent the range of age, racial, and 
ethnic groups consistent with the intended use population of the device may 
present additional challenges.  There are numerous suspected reasons for low 
rates of participation by minority, older, and pediatric individuals in clinical 
trials.23  In 2009, FDA published a Report to Congress on identified barriers to 
enrollment in clinical drug trials and recommendations on how to address the 
disproportionately low enrollment of certain populations in clinical trials, 
especially those trials in which these populations are highly affected by or are 
likely to suffer worse outcomes from the disease being evaluated.24  FDA believes 
much of this information is relevant to medical device clinical trials as well.  
 
The following have been identified as potential barriers to enrollment: 
 
                                                           
23 Institute of Medicine Workshop: Strategies for Ensuring Diversity, Inclusion, and Meaningful Participation in Clinical Trials. 
April 9, 2015. Agenda and presentations available at 
http://iom.nationalacademies.org/Activities/SelectPops/HealthDisparities/2015-APR-09.aspx. 
24 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 issued September 2009. 
http://www.fda.gov/downloads/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmend
mentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/FDAAAImplementationChart/UCM214303.pdf.  
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  lack of understanding about the main obstacles to participation of different 
age, racial, and ethnic groups in clinical research; 
  inclusion/exclusion criteria that unintentionally exclude different age, racial, 
or ethnic groups (e.g., creatinine levels for African-Americans);25 
  lack of understanding about differences in disease etiology and 
pathophysiology may lead to under-diagnosis and under-referral of specific 
demographic subgroups; 
  patient concerns with being assigned to treatment versus control group, 
randomization, possible side effects, privacy, and historical mistrust of clinical 
trial ethics; 
  language, cultural, and health literacy differences between investigators and 
patients; 
  investigator and sponsor avoidance of specific age, racial, or ethnic groups of 
patients due to the perception that it is more difficult and potentially more 
expensive to recruit and maintain participation; 
  lack of diverse investigators in studies who may have access to a more diverse 
patient pool to recruit subjects; 
  pressure on investigators to quickly enroll patients regardless of demographic 
characteristics; 
  perceived ethical concerns among investigators regarding enrollment of 
certain demographic groups in clinical trials; 
  trial logistics (e.g., transportation, childcare) may disproportionately affect 
specific age, racial and ethnic groups ability to complete study follow-up 
visits; 
  disproportionate drop out and lost-to-follow-up rates;26, 27 and 
  type or location of study sites may limit participation of specific age, racial, or 
ethnic groups. 
(2)  Enrollment Resources 
 
Where ongoing enrollment data demonstrate an underrepresentation of certain 
subgroups enrolling in the study, sponsors are encouraged to investigate the 
reason(s) for lack of enrollment and consider the approaches in Section IV to 
enhance enrollment.  It may be informative to evaluate whether the demographic 
                                                           
25 Neal, Ryan C., et al. "Relationship of ethnic origin, gender, and age to blood creatine kinase levels." The American journal of 
medicine 122.1 (2009): 73-78. 
26 Institute of Medicine Workshop: Strategies for Ensuring Diversity, Inclusion, and Meaningful Participation in Clinical Trials. 
April 9, 2015. Agenda and presentations available at 
http://iom.nationalacademies.org/Activities/SelectPops/HealthDisparities/2015-APR-09.aspx. 
27 Wendler, David, et al. "Are racial and ethnic minorities less willing to participate in health research?" PLoS medicine 3.2 
(2006): 201. 
13 
  Contains Nonbinding Recommendations 
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).  Information regarding changes in demographic distribution at key time 
points in study screening, enrollment, and follow-up can provide insight into root 
causes of lower enrollment rates in these groups.  This analysis may help identify 
ways to substantially lower barriers to enrollment of age-, race-, and ethnicity-
specific subgroups that have been shown to improve enrollment rates and study 
retention rates in other subgroups of study subjects, (e.g., flexibility in follow-up 
visit scheduling, with consideration of child care or elder care services during 
appointments).26  Changes to a study protocol and informed consent may be made 
based on demographic distribution information with appropriate notification to 
and approval from an Institutional Review Board (IRB) and the FDA, where 
necessary.  
 
Sponsors may also wish to consider resources developed by the National 
Institutes of Health (NIH),28, 29, 30, 31 discussion with academic and contract 
research organizations, and practices of high-enrolling clinical study sites in 
determining practices best suited to achieve appropriate enrollment of 
demographic groups, and to provide investigator training about these techniques.  
Some specific examples of strategies to increase inclusion of diverse study 
populations are discussed in Section IV below. 
IV.  Recommendations for Achieving Appropriate 
Enrollment
 
 
Historically, many medical device clinical studies have not enrolled proportions of age, racial, 
and ethnic subgroups 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 certain age, racial, and ethnic subgroups.  Thus, it is important 
that clinical trials include diverse populations that reflect the intended population whenever 
possible and appropriate.  
 
                                                           
28 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. 
29 The National Institute of Mental Health developed a resource document (Points to Consider about Recruitment and Retention 
While Preparing a Clinical Research Study, June 2005), which outlines common issues that can impact clinical recruitment and 
retention, and strategies to address these issues.  
http://www.nimh.nih.gov/funding/grant-writing-and-application-process/recruitment-points-to-consider-6-1-05_34848.pdf. 
30 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.  
31 The National Institute on Minority Health and Health Disparities is active in the area of minority recruitment to trials. 
http://nimhd.nih.gov. 
14 
  Contains Nonbinding Recommendations 
In general, to achieve an unbiased estimate of treatment effect in the general population, 
sponsors should ideally plan to enroll representative proportions of age-, race-, and ethnicity-
specific subgroups that are consistent with the intended use population of the device, or justify in 
the investigational plan how the enrollment criteria will provide reasonable representation of the 
intended or affected population. A simple justification may suffice in cases where factors other 
than age, race, and ethnicity are primarily of interest. For example, anatomical size may be the 
primary factor for a device indicated for patients who demonstrate a particular anatomical size, 
even though anatomical size may vary according to age, race, or ethnicity.  
 
In cases where known disease science or prior clinical study results suggest a clinically 
meaningful difference in benefits or risks in one or more age, racial, or ethnic subgroups, 
sponsors should aim to enroll sufficient numbers of that demographic subgroup(s) to support 
robust analysis (i.e., a sample size sufficient for age, race, or ethnicity-specific claims or 
outcomes). 
 
To overcome some of the barriers to adequate representative enrollment, FDA recommends the 
following considerations as sponsors proceed with their device development plans. 
A.  Consideration of Potential Age-, Race-, and Ethnicity-
Specific Differences 
 
To understand potential age-, race-, and ethnicity-specific differences that may be 
relevant to the clinical evaluation of your device, we recommend that, for the disease or 
condition your device is intended to treat or diagnose, you identify and consider: 
 
  Age-, race-, and ethnicity-specific prevalence, if known;  
  Age-, race-, and ethnicity-specific diagnosis and treatment patterns, if known;  
  proportions of age-, race-, and ethnicity-specific subgroups included in past 
studies for the target indication, if known; and  
  any known clinically meaningful age-, race-, and ethnicity-specific differences in 
outcomes related to either safety or effectiveness (or probable benefit for HDEs).  
 
If information demonstrating age-, race-, and ethnicity-specific differences in these areas 
is available, you should consider this information when designing your study protocol 
and include a discussion about these considerations in your 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)  Study Design, Early Enrollment Stage 
 
You should include the information described above as part of your 
investigational plan (see 21 CFR 812.25(c)) for investigational device exemption 
(IDE) studies.  We also recommend that you summarize this information in your 
study protocol and investigator training materials to explain the importance of 
enrolling appropriate proportions of age, racial, and ethnic subgroups.   
15 
  Contains Nonbinding Recommendations 
 
For studies that are already enrolling under an approved (or conditionally 
approved) IDE, where there is inadequate enrollment of age, racial, and ethnic 
subgroups, you should discuss with FDA an appropriate path to communicate this 
new information to investigators and how to use it without introducing bias to the 
study. 
(2)  Premarket Submission Stage 
 
You should include this information as part of your marketing application in 
sections containing results of clinical investigations.  A summary of any known 
clinically meaningful age-, race-, and ethnicity-specific differences in disease 
course, outcomes, or benefit-risk profile should also be included in your 510(k) 
Summary and in your labeling (see Section VI below for more details). 
 
FDA staff should include this information in the PMA Summary of Safety and 
Effectiveness, HDE Summary of Safety and Probable Benefit, and De Novo 
decision summaries, which will be made publicly available on FDAs website. 
(3)  Postmarket Submission Stage 
 
You should include this information in interim reports and in the results section of 
your final report for mandated postmarket study(ies).  Where available 
background information or clinical study results suggest there are clinically 
meaningful age-, race-, and/or ethnicity-specific differences in disease course, 
outcomes, or benefit-risk profile, you should also submit revised labeling to 
include this information.  FDA encourages the use of postmarket data to modify 
labeling to support additional information regarding device safety or effectiveness 
and/or clarify how the device should be used. 
B.  Planning for Diverse Study Recruitment 
 
The approaches described below are aimed at increasing enrollment of age, racial, and 
ethnic subgroups in your study, as appropriate, with a goal of participation consistent 
with the intended use population of the device.  In general, when clinically meaningful 
differences in treatment effect are anticipated across age, racial, or ethnic groups, these 
effects should be considered during study planning.  Some of these methods may also be 
adapted to increase enrollment of other typically underrepresented groups.  These 
methods should be considered in addition to factors highlighted in the FDA guidance on 
Design Considerations for Pivotal Clinical Investigations for Medical Devices.32 
                                                           
32 See FDAs guidance Design Considerations for Pivotal Clinical Investigations for Medical Devices. 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM373766.pdf.  
16 
  Contains Nonbinding Recommendations 
(1)  Study Design, Early Enrollment Stage 
 
You should develop and describe your plan to prospectively include appropriate 
demographic subgroups in your study based on the contextual information 
provided in Section IV.A. (i.e., consistent with the intended use population, 
including age, racial, and ethnic prevalence of the disease or condition which your 
device is intended to treat or diagnose, if known).  To enhance enrollment of 
relevant age, racial, and ethnic subgroups, the approaches described below may be 
considered, with appropriate caution to avoid introducing bias or jeopardizing 
data validity. 
 
a.  Include a wide variety of investigational sites where recruitment of age, racial, 
and ethnic subgroups can be more easily facilitated (e.g., community clinics, 
nursing homes, pediatric hospitals, minority healthcare provider groups, urban 
hospitals).  
 
b.  Consider alternative communication strategies for study recruitment, informed 
consent documents, and patient materials (e.g., involvement of community-
based organizations and places of worship, patient reading materials in 
multiple languages with appropriate cultural references, patient reading 
materials appropriate for low-literacy populations, accommodations for the 
visual- and hearing-impaired, patient reading materials in electronic versions, 
use of social media). 
 
c.  If age-, race-, and ethnicity-specific subgroups are expected to benefit, or 
benefit differentially, from your device but may not meet certain study 
enrollment criteria, consider revising the enrollment criteria, when 
appropriate, or consider enrolling registries or parallel cohorts for collecting 
data on device use in particular age-, race-, and ethnicity-specific subgroups 
(e.g., a pediatric registry). 
 
d.  Consider including provisions to encourage diverse enrollment of relevant 
age, racial, and ethnic subgroups consistent with the intended use population. 
 
e.  Consider investigating reasons for under-enrollment or non-enrollment of age, 
racial, and ethnic subgroups or other key demographic groups (e.g., consider 
periodically evaluating screening logs for all patients who are screened but not 
ultimately enrolled in studies to identify and address root cause barriers to 
diverse enrollment).33  
 
f.  Consider planning focused efforts to enroll age, racial, and ethnic subgroups 
under a continued access study based on prior information or information 
                                                           
33 Wendler, David, et al. "Are racial and ethnic minorities less willing to participate in health research?" PLoS medicine 3.2 
(2006): 201. 
17 
  Contains Nonbinding Recommendations 
collected in a study.34 
 
g.  Consider factors that generally increase recruitment and retention such as 
utilizing community or local health care practitioners, minority health 
professional organizations, and patient advocacy groups for recruiting or 
referring patients; compensation for expenses (e.g., for transportation costs); 
and maintaining communication with subjects (e.g., sending a newsletter to 
subjects to maintain interest, using social media). 
 
h.  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. 
 
i.  For in vitro diagnostic tests and diagnostic devices, consider including 
samples from each age, racial, and ethnic subgroup at the cutoff selection and 
validation stages. For in vitro diagnostic devices in which a reference interval 
is provided, and for which differences are expected in certain demographic 
subgroups (e.g., B-Type Natriuretic Peptide (BNP) diagnostic test with age-
specific clinical cutoffs), also consider collecting data by demographic 
subgroup when appropriate.  
(2)  Premarket Submission Stage 
 
In your marketing submission, you should discuss study results (related to safety 
and/or effectiveness, or probable benefit for HDEs) and describe how any known, 
clinically meaningful age-, race-, and ethnicity-specific differences across 
subgroups may contribute to differences in benefit-risk profile in certain 
subpopulations.   
 
When determining whether additional data collection is needed to address a 
clinically important question before the device is marketed, consideration should 
be given to whether market approval/clearance is supported for the general 
population, with postmarket studies to gain further information regarding any 
observed age-, race-, or ethnicity-specific subgroup differences, or whether 
existing results support market approval/clearance in a specific age-, race-, or 
ethnicity-specific subgroup, but additional premarket data collection would be 
needed to generalize effects to a broader intended use population.  
 
If additional data is needed before the device is approved or cleared, FDA may 
recommend that you consider including provisions to encourage enrollment of 
diverse age, racial, or ethnic subgroups (e.g., modification of enrollment criteria 
to study outcomes in a specific subpopulation).  In such cases, we recommend 
                                                           
34 See FDAs Guidance on IDE Policies and Procedures 
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080202.htm.   
18 
  Contains Nonbinding Recommendations 
you discuss your plans to limit introducing bias or jeopardizing data validity with 
FDA. 
(3)  Postmarket Submission Stage 
 
We recommend you consider whether outstanding questions warrant postmarket 
evaluation in a specific age, racial, or ethnic subgroup.  For example, postmarket 
data collection may be warranted if premarket clinical studies reveal signals of 
potentially clinically meaningful outcome differences in age, racial, or ethnic 
subgroups, or if there are known subgroup differences in the underlying disease or 
the response to concomitant treatment or therapies that may affect safety or 
effectiveness (or probable benefit for HDEs).  In such instances, FDA may 
determine that additional study of a particular age, racial, or ethnic subgroup is 
warranted in the postmarket setting.   
 
You should develop and describe your plan to collect postmarket data on 
appropriate demographic subgroups in any mandated postmarket study(ies) based 
on outstanding questions described above, and/or based on the contextual 
information provided per Section IV.A. (e.g., consistent with the intended use 
population, including age, racial, or ethnic prevalence of the disease or condition 
that your device is intended to treat or diagnose, if known).  
 
To enhance enrollment of age, racial, or ethnic subgroups, we recommend that 
you consider the approaches specified in Section IV.B.1.   
C.  Considerations for Study Follow-up Visits 
 
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 age, racial, or ethnic subgroup).35 While proper study conduct 
and follow-up are concerns for all patients, regardless of age, race, or ethnicity, 
concerns about disproportionate dropout and loss to follow-up are potential barriers to 
diverse study representation of minorities and older patients.   The following 
considerations represent good clinical study principles that may improve diverse 
participation throughout the duration of the study. We encourage sponsors and 
clinical study investigators to consider these where appropriate. 
 
Sponsors should consider: 
 
a.  Developing a follow-up plan that details follow-up goals, frequency of 
scheduled follow-up visits, proxy contact information, and actions to be taken 
when a patient misses a follow-up visit. 
                                                           
35 National Research Council. 2010. The Prevention and Treatment of Missing Data in Clinical Trials. Washington, DC: The 
National Academies Press. 
19 
  Contains Nonbinding Recommendations 
b.  Demonstrating continued interest in the subjects (e.g., sending a newsletter to 
subjects to maintain interest). 
c.  Monitoring follow-up rates closely so that follow-up problems can be 
identified and addressed as soon as possible. 
d.  Reporting subject accountability data as part of the study report. 
 
Investigators should consider: 
 
a.  Participating in cultural competency training prior to study recruitment. 
b.  During informed consent and thereafter, counseling subjects about the 
importance of returning to follow-up. 
c.  Reminding subjects of upcoming follow-up visits. 
d.  Attempting to locate subjects who miss scheduled clinic visits and 
encouraging them to return. 
e.  Obtaining proxy contact information to use when unable to contact a study 
subject. 
f.  Asking subjects who withdraw during the study to provide the reason for 
withdrawal and whether the investigator may contact them once more at the 
end of the study follow-up to assess their experience with the device. 
g.  Providing close follow-up with subjects (e.g., telephone follow-up after 
surgery, particularly if the device is implantable). 
 
V.  Considering Age, Race, and Ethnicity in Study Design, 
Analysis, and Interpretation of Study Results 
 
Intrinsic and extrinsic biological differences across age, racial, and ethnic groups (e.g. gonad 
development, skin texture, skin color, hormone levels, metabolism, degenerative disease, bone 
density, cell receptors, genomic variations) exist that may influence the safety and effectiveness 
(or probable benefit for HDEs) of a device. For example, ionizing radiation exposure to pediatric 
patients from medical imaging procedures is of a different concern than that for adults because 
pediatric patients are more radiosensitive (i.e., the cancer risk per unit dose of ionizing radiation 
is higher).36  Additionally, age, race, and ethnicity may play a role in an individuals interaction 
with his/her environment, which in turn could affect an individuals health. For example, 
intermittent exposures to intense UV radiation leading to sunburns (e.g., through the use of 
tanning beds), especially in childhood and teen years, increase the risk of melanoma.37 
 
Due to the potential impact on safety and effectiveness (or probable benefit for HDEs), unless 
the investigational device is intended for use in only one age, racial, or ethnic group (e.g., 
neonatal devices), it is important that the variation in potential response or outcomes across age, 
                                                           
36 See FDAs website on Pediatric X-Ray Imaging, available at http://www.fda.gov/Radiation-
EmittingProducts/RadiationEmittingProductsandProcedures/MedicalImaging/ucm298899.htm. 
37 See FDAs website on Indoor Tanning: The Risks of Ultraviolet Rays, available at 
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm186687.htm.  
20 
  Contains Nonbinding Recommendations 
racial, and ethnic groups be accounted for both in study design and in analysis of results, as 
appropriate. 
 
Other patient characteristics (e.g., body size, diet, bone density, Fitzpatrick Scale Skin Type) that 
may be correlated with age, racial, or ethnic differences might sometimes explain apparent 
differences in clinical outcomes.  If differences between evaluated subgroups are observed in the 
clinical study, FDA recommends that a sponsor investigate whether other patient characteristics 
may explain the observed differences.  This will help users identify characteristics that can 
inform decision making for individual use. 
 
When using real-world evidence or real-world data collected from sources outside of traditional 
clinical trials, it is important to assess the intended use population and how well the 
representation of the intended use population is collected in the real-world evidence source. 
 
As discussed in Section III.B., demographic data can be collected and categorized in a variety of 
ways.  The categorization scheme you choose may impact your analysis (e.g., depending on 
whether age is treated as a categorical or continuous variable).  
A.  Assessing Heterogeneity Across Age, Racial, and Ethnic 
Subgroups 
 
There may be substantial differences in device safety and effectiveness (or probable 
benefit for HDEs) across age, racial, and ethnic subgroups.  Sponsors should investigate 
heterogeneity across these demographic subgroups of clinical interest, especially for 
primary safety and effectiveness endpoints (or probable benefit for HDEs).  
Heterogeneity here refers to a variation in outcome across subgroups.  Statistical 
hypothesis tests can be performed to detect heterogeneity, and methods of statistical 
inference for estimating its magnitude are also available.   As statistical tests, hypothesis 
test significance levels should be pre-specified in an investigational plan for premarket or 
postmarket studies.  Note, however, that the power of such tests may be unspecified.  
 
In some cases the test for treatment by subgroup interaction (or heterogeneity in general) 
may have adequate power to detect only a very large interaction (or heterogeneity), but 
may not detect a smaller yet potentially clinically meaningful interaction (or 
heterogeneity).  Tests for treatment by subgroup interaction may lack a significant 
interaction based on an interaction p-value. If an interaction is detected, sponsors should 
evaluate which subgroups are the same or different.  Such situations may arise when the 
number of patients in one or several of the age, racial, or ethnic groups is very small.  
Alternatively, observed heterogeneity across specific subgroups could be attributable to 
chance associated with small sample sizes.  Thus, the interpretation of clinical 
meaningfulness may be premature in those cases.  Additionally, sample sizes in 
subgroups may not be large enough to detect clinically meaningful differences in device 
safety or effectiveness (or probable benefit for HDEs).  Consultation with FDA is 
recommended in these cases to ensure appropriate interpretation of analysis results. 
 
21 
  Contains Nonbinding Recommendations 
For additional discussion of statistical concepts for assessing heterogeneity, please see 
Section V.A of the Evaluation of Sex-Specific Data in Medical Device Clinical Studies 
Guidance, hereafter referred to as the Sex-Specific Guidance.38   
 
The recommendations in the following sections of the Sex-Specific Guidance are 
applicable to the consideration of age, racial, and ethnic subgroups through the stages of 
product development and evaluation. 
(1)  Study Design, Early Enrollment Stage  
 
  When appropriate, the Statistical Analysis Plan (SAP)39 in the study protocol 
should include pre-specified plans for addressing the subgroup analysis issues 
described in the sections below.  
 
  In general, to achieve an unbiased estimate of treatment effect in the general 
population, sponsors should develop a strategy to enroll diverse populations 
including relevant age, racial, and ethnic groups. 
 
  If differences are anticipated, sponsors should make an effort to identify in 
advance any key covariates that might explain possible differences across 
subgroups, plan to collect data on these covariates, and pre-specify a modeling 
approach to investigate the extent to which these covariates can explain the 
observed differences. 
 
  Sponsors should consider whether clinical outcome measurements will or 
could differ across age-, race-, or ethnicity-specific subgroups. For example, 
keloid formation following wrinkle filler application may differ between 
pigmented and non-pigmented skin, a characteristic that varies with race 
and/or ethnic background.  Clinical measurements and endpoints in such a 
trial may differ across self-reported racial or ethnic subgroups, and this 
information should be captured accordingly. 
(2)  Premarket Submission Stage 
 
  In general, sponsors should submit descriptive statistics for outcomes of 
interest by demographic subgroup as detailed in Section C below.  After 
overall effectiveness (or probable benefit for HDEs) and safety have been 
investigated, pre-planned outcome analysis by age, race, and ethnicity for 
primary endpoints for both safety and effectiveness (or probable benefit for 
HDEs) should be conducted.  
 
                                                           
38 See FDAs guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283707.pdf. 
39 See FDAs guidance Design Considerations for Pivotal Clinical Investigations for Medical Devices. 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM373766.pdf. 
22 
  Contains Nonbinding Recommendations 
  When exploring age-, race-, or ethnicity-specific differences during analysis 
of premarket study data, we recommend you address the issue of confounding 
by using multivariable analyses adjusted for patient characteristics that may 
confound the relationship between the analyzed subgroup and study outcomes 
(e.g., body size, diabetes). 
 
  If any clinically meaningful differences are suspected, either based on pre-
specified or exploratory analyses, sponsors should discuss with FDA to 
determine whether additional data are needed to address any remaining 
subgroup-specific questions of safety or effectiveness (or probable benefit for 
HDEs).  
(3)  Postmarket Submission Stage 
 
  For any mandated postmarket study(ies) involving continuing data collection 
on PMA cohort patients for the evaluation of longer-term performance, we 
recommend that you conduct the analyses described in Section C below for all 
follow-up time points.  
 
  For any mandated postmarket study(ies) involving newly enrolled patients, 
you should include the analyses described in Section C below as part of a pre-
specified SAP in your protocol.  Furthermore, if results from demographic 
subgroup analyses of premarket data suggest there may be a clinically 
meaningful difference in outcomes, you should consult with FDA as to 
whether these differences should also be incorporated into the study design 
and hypothesis for your postmarket study.  
 
  When you are exploring age-, race-, or ethnicity-specific differences during 
analysis of data from any mandated postmarket study(ies), we recommend 
you address the issue of confounding.  This can be addressed by using 
multivariable analyses adjusted for patient characteristics that may confound 
the relationship between the analyzed subgroup and study outcomes (e.g., 
body size, diabetes). 
B.  Designing Studies: Recommendations for Subgroup 
Specific Statistical Elements  
 
FDA recommends sponsors consider the subgroup-specific statistical elements described 
in detail in Section V.B. of the Sex-Specific Guidance,40 which are applicable to the 
demographic subgroups outlined in this guidance.  Please refer to Figure 1 in the 
Appendix of this guidance for a summary of these recommendations.  The following 
specific topics apply to clinical trials for subgroup-specific outcome analyses: 
                                                           
40 See FDAs guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283707.pdf. 
23 
  Contains Nonbinding Recommendations 
(1)  Recommendations When Subgroup Differences are 
Anticipated 
 
When differences in treatment effect are clearly anticipated across age, racial, or 
ethnic groups based on biological basis and/or previous clinical experience, it is 
important to consider proper clinical study design, sufficient enrollment of 
subgroups to allow meaningful analysis, and controlling of study-wise Type 1 
error for overall and subgroup-specific hypothesis testing if appropriate.41   
(2)  Recommendations for Pre-specifying Assessment of 
Heterogeneity  
 
It is important that the SAP include a strategy for assessing heterogeneity across 
relevant demographic subgroups, and 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 combining data conditions for 
studies with pre-specified success criteria expressed in terms of combining data 
across subgroups.  Such combining data conditions bear some resemblance to 
those commonly used for determining whether data can appropriately be 
combined for analysis across different clinical sites. Combining data conditions 
may be specified as statistical hypothesis tests, which, for studies involving the 
comparison of two treatments, would typically be tests of treatment by subgroup 
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. 
 
Additionally, adaptive study design strategies to pre-specify subgroups of interest 
for interim analysis and potential population enrichment for success should be 
preplanned and specified in the SAP prior to the start of the study.42   
(3)  Additional Design Recommendations for Comparative and 
One-arm Studies 
 
Application of certain study design recommendations may prompt a different 
approach depending on whether studies are comparative or single-arm.  Please 
refer to Section V.B. of the Sex-Specific Guidance43 for details.  
                                                           
41 See FDAs guidance Design Considerations for Pivotal Clinical Investigations for Medical Devices. 
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM373766.pdf.  
42 See FDAs guidance Adaptive Designs for Medical Device Clinical Studies 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm446729.pdf.  
43 See FDAs guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283707.pdf. 
24 
  Contains Nonbinding Recommendations 
C.  Completed Studies: Recommendations for Analysis of 
Subgroup-Specific Data 
 
Please refer to the Appendix of this guidance for flowchart diagrams summarizing the 
recommendations for the analysis of subgroup-specific data in completed one-arm 
(Figure 2) and comparative studies (Figure 3).  For detailed recommendations on the 
analysis in completed one-arm or comparative studies, please see the Sex-Specific 
Guidance Section V.C.44  
 
In general, sponsors should submit descriptive statistics for enrolled patients and 
outcomes of interest, including the estimate of variance or standard deviation (as 
applicable) by age, racial, and ethnic groups.  At the primary follow-up time-point, 
regardless of the potentially limited statistical power of these specific subgroup analyses, 
data should be examined for clinically meaningful age-, race-, and ethnicity-specific 
differences in each of the following:  
 
  primary effectiveness (or probable benefit for HDEs) endpoint(s);  
o
  primary safety endpoint(s); and  
o
  key secondary endpoints.  
o
 
It is important to carry out all analyses set forth in the SAP.  FDA expects sponsors to 
plan for and conduct analyses to evaluate heterogeneity by demographic subgroups, 
including treatment by subgroup interaction when applicable, as described in previous 
sections. 
 
Unplanned subgroup analyses or those with inadequate sample size are generally not 
considered to be adequate to support statements in the labeling regarding the safety or 
effectiveness of the device. However, the overall benefit-risk profile of the device will be 
considered. 
 
  If there is evidence of heterogeneity, it is important to describe its nature and 
assess the clinical importance of the differences.  In some cases, the effect 
could be statistically significant, but not clinically meaningful, or clinically 
meaningful but not statistically significant.  In these cases, discussion with 
FDA is advised.  
  If a clinically meaningful and/or statistically significant difference is observed 
across certain subgroups (e.g., age less than 65 years old, between 65 and 75 
years old, and over 75 years old), it is important to investigate further about 
the cause and discuss with FDA.  Also, it is suggested to consider whether the 
observed heterogeneity could be mainly explained by other covariates, which 
are highly correlated with that subgroup and the treatment effect (e.g., 
confounders or effect modifiers).   
                                                           
44 See FDAs guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies 
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283707.pdf. 
25 
  Contains Nonbinding Recommendations 
If a difference remains clinically meaningful and/or statistically significant after consideration of 
other covariates, data may not be combined across subgroups.  In this case, discussion with FDA 
is recommended.  Sponsors should describe how any clinically meaningful differences across 
subgroups may contribute to differences in the benefit-risk profile in certain subpopulations. 
D.  Interpretation of Age-, Race-, and Ethnicity-Specific Data 
 
  If any clinically meaningful demographic subgroup differences are found, 
based either on pre-specified or exploratory analyses, you should discuss with 
FDA whether additional data are needed to address any remaining subgroup-
specific questions.  Hypotheses for exploratory analyses should be consistent 
with the literature of the natural history of the disease and its prevalence in 
subgroups or be consistent with the known pathophysiology. You should 
describe how any clinically meaningful differences across subgroups may 
contribute to differences in benefit-risk profile in certain subpopulations. 
 
  If results of your analysis suggest that there is insufficient data to assess whether 
age, race, or ethnicity is associated with clinically meaningful differences in 
outcome, FDA may determine that clinical data from additional subjects in one or 
several of demographic subgroups may be needed pre- or postmarket to address 
potential age-, race-, or ethnicity-specific questions related to safety or 
effectiveness (or probable benefit for HDEs) in any or all of those subgroups.  
 
  Although expected to be rare, in cases where clinically meaningful differences 
among the age, racial, or ethnic groups are observed in safety or effectiveness 
(or probable benefit for HDEs), FDA may request additional confirmatory 
studies, implement specific pre- or post-approval study conditions, and/or 
recommend modifications to the design of subsequent studies.  FDA will 
consider such requests in the context of a benefit-risk framework.  Sponsors 
should describe how any observed clinically meaningful differences across 
subgroups may affect overall benefit-risk profile in certain subpopulations. 
 
  There are limitations to interpreting clinically meaningful differences in small 
data sets or in larger studies in which certain subgroups are underrepresented. 
Mean differences could exist among demographic subgroups due to small sample 
sizes, and interpretation about whether they are clinically meaningful may be 
premature in many cases.  Alternatively, sample sizes may not be large enough to 
detect clinically meaningful differences in device safety or effectiveness (or 
probable benefit for HDEs).  Consultation with FDA is recommended in these 
cases. 
VI.  Recommendations for Submitting Age-, Race-, and Ethnicity-
Specific Data in Submissions to the Agency and Reporting in Public 
Documents 
 
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Confidential submissions to FDA contain detailed analyses of clinical study data, which may 
include a variety of age, racial, and ethnic subgroup analyses.  However, public documents, 
including labeling and FDA summaries of review (e.g., Summary of Safety and Effectiveness 
Data, De Novo Decision Summaries, 510(k) Summaries) for medical devices approved or 
cleared in the past are inconsistent with regard to the degree of information reported on device 
performance in demographic subgroups. The term submit refers to information submitted to 
the FDA for analysis, whereas the term report refers to information that should be included in 
publicly available documents (i.e., labeling,45 FDA review summaries).  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 (or probable benefit for HDEs) 
and potential adverse events associated with device use in a particular demographic subgroup.   
 
Please refer to Figure 4 in the Appendix for a flowchart summary of the below 
recommendations. 
A.  Enrollment Demographics, Baseline Characteristics & 
Co-Morbidities 
 
The strength of the conclusions of your clinical study(ies) with respect to device 
performance in age, racial, and ethnic subgroups is linked to the number of individuals in 
the age, racial, and ethnic subgroups in your study(ies).  FDA recommends that you 
submit and publicly report the number and proportion of subjects by age, racial, and 
ethnic groups who were treated or diagnosed with your device as part of a clinical study 
as follows: 
 
  You should submit and publicly report study demographics in terms of proportion 
enrolled and completed by subgroup.  You should discuss whether the proportions 
enrolled are consistent with the age, racial, and ethnic prevalence of disease, if 
known.  If proportions enrolled are substantially different than prevalence of 
disease by age, race, and ethnicity, if known, you should discuss generalizability 
of study findings to the demographic subgroups.  For studies with multiple 
cohorts, you should submit and publicly report enrollment proportions for each 
age, racial, and ethnic subgroup in each cohort. 
 
  If co-morbidities and/or other baseline characteristics are collected, you should 
analyze and submit these by demographic subgroup as well as overall. 
 
  If loss to follow-up disproportionally affects a particular subgroup (e.g., greater 
loss of older patients compared to younger patients), you should provide a 
discussion of differences across subgroups at different time points for the overall 
study sample and for each study arm.  Different patterns in missing data may 
introduce bias in the study conclusions.  
                                                           
45 See FDAs Guidance on Medical Device Patient Labeling 
http://www.fda.gov/downloads/MedicalDevices/MedicalDeviceRegulationandGuidance/GuidanceDocuments/ucm070801.pdf.  
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When publicly reporting, you may adapt the example language below or use similar 
language that incorporates the contents described above.  Conclusions should only be 
based on factual data and not be assumptions or inferences based on non-significant 
trends or exploratory analyses. 
 
Example Language: 
 
African-American women represented [%] of the total patients enrolled in the overall 
study.  The prevalence of [uterine fibroids] among African-American women in the U.S. 
is [%], according to [source].  Among subjects in the treatment group, m1/n1 (p1%) 
were African-American women, and m2/n2 (p2%) of subjects in the control group were 
African-American women. 
 
Pediatric patients were more likely to have [disease or diagnosis] compared to adults 
(p1% vs. p2%). 
 
Additionally, we recommend that you include this type of information in any applicable 
tables and charts. 
 
(1)  IDE Stage 
 
You should submit demographic information outlined above as part of your IDE 
annual progress reports. 
 
(2)  Premarket Submission Stage 
 
If your 510(k) submission includes clinical data, you should submit baseline 
demographic information outlined above as part of your submission in sections 
containing results of clinical investigations, including the labeling.  You should 
also report a summary of this information in your 510(k) Summary, which will be 
made publicly available on FDAs website upon clearance. 
 
FDA staff should include this information in the PMA Summary of Safety and 
Effectiveness, HDE Summary of Safety and Probable Benefit, and De Novo 
decision summaries, which will be made publicly available on FDAs website. 
 
(3)  Postmarket Submission Stage 
 
You should submit the demographic information outlined above in interim reports 
and in the final report for any mandated postmarket study(ies). 
 
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FDA staff should include this information in mandated study summaries, which 
are made publicly available on FDAs website, when appropriate. 
B.  Age-, Race-, and Ethnicity-Specific Outcomes (Safety or 
Effectiveness, or Probable Benefit for HDEs) 
 
Outcomes analyses by demographic subgroup should be reported in the labeling and 
review summaries, as outlined below.  Covariates that might explain possible outcome 
differences by age, race, and ethnicity should be described. 
 
  If outcome differences by age, race, and ethnicity are statistically significant 
and clinically meaningful, you should report the results of the outcome 
analyses.  You should also describe how such differences across subgroups 
affect the benefit-risk profile in certain subpopulations, as applicable. 
 
  If results of these analyses suggest an age-, race-, and/or ethnicity-specific 
difference in an endpoint or event that is clinically meaningful, but not 
statistically significant, you should report the findings descriptively.  
 
  If results of these analyses suggest no age-, race-, and/or ethnicity-specific 
differences in outcomes, you should report which analyses were conducted and 
that no clinically meaningful differences were found to be relevant.  
 
When publicly reporting, you may choose to adapt the example language and graph 
below, or you may use similar language, tables, and charts that incorporate the contents 
described above.  The example below is one option.  Alternatively, you may choose to 
illustrate performance separately by race and then by ethnicity, as the subgroups will be 
larger, improving the ability to ascertain subgroup effects.  
 
It should also be noted that where there are many subgroups with small sample size, one 
may observe considerable variability in treatment effect due to random chance. Any such 
variability should be interpreted with caution.  
 
Example Language & Graph: 
 
The study data suggests a trend that patients of [age] years of age have a higher [study 
outcome] in comparison to patients of [age] years of age, but these differences were not 
found statistically significant by [x] statistical analysis. 
 
Tables or Forest plots showing outcomes by demographic subgroups are potential options 
for reporting outcomes. 
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Sample forest plots of hazard ratios by race- and ethnicity-specific subgroups 
 
Per FDA guidance, FDA recommends the two-question format to collect data about race and 
ethnicity. These sample plots were generated for illustrative purposes and do not reflect actual 
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clinical data. If the number of subjects is very small, a confidence interval may be too wide to be 
meaningful.46 
 
(1)  Premarket Submission Stage 
 
There may be two objectives for pre-specified age-, race-, and ethnicity-specific 
subgroup analysis: (1) for subgroup-specific labeling information and (2) for 
reporting purposes as recommended for all submissions. When submitting or 
publicly reporting results of pre-specified age-, race-, and ethnicity-specific 
subgroup analyses to support subgroup-specific labeling, we recommend the 
following: 
 
  Clearly state which analyses were conducted. 
  Specify statistical methods used to assess for heterogeneity of treatment 
differences by age, race, and ethnicity (as described above). 
  You may include inferential statistics, including p-values and/or 
confidence intervals, if there is pre-specified statistical hypothesis testing 
for a subgroup with multiplicity adjustment.  To provide appropriate 
context, describe prior scientific evidence suggesting that clinically 
meaningful differences by subgroup are expected, or describe statistical 
limitations of analyses. 
 
Sponsors should consider the following when submitting or publicly reporting 
results of exploratory age-, race-, and ethnicity-specific subgroup analyses: 
 
  Clearly state which analyses were conducted. 
  Specify statistical methods used to assess for heterogeneity of treatment 
differences by age, race, and ethnicity (as described above). 
  Use descriptive statistics only (mean, standard deviation, etc.). 
 
If clinically meaningful age-, race-, and ethnicity-specific differences in safety or 
effectiveness (or probable benefit for HDEs) are observed, or if there are potential 
differences that might require follow-up studies, you should include in publicly 
reported labeling and review summaries a discussion on whether or how this affects 
the overall benefit-risk profile for different subgroups.   
(2)  Postmarket Submission Stage  
 
When presenting results of age, racial, and ethnic subgroup analyses of any 
mandated postmarket study(ies), the recommendations above also apply. 
 
                                                           
46 See FDAs guidance Collection of Race and Ethnicity Data in Clinical Trials http://www.fda.gov/ucm/groups/fdagov-
public/@fdagov-afda-gen/documents/document/ucm126396.pdf. 
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If a clinically meaningful signal is detected in your final analysis, FDA may 
recommend changes to your approved labeling documents.  
Appendix 1  Decision Framework 
 
We encourage the use of existing scientific data (e.g. recent previous studies, disease natural 
history studies) to determine whether there is a hypothesis for a clinically meaningful 
demographic subgroup-specific difference for your device.  When there is a hypothesis for a 
clinically meaningful difference, the following decision trees provide a framework in deciding 
when various age-, race-, or ethnicity-specific statistical recommendations apply for different 
clinical study designs.  Sponsors should also describe how any clinically meaningful differences 
across subgroups may contribute to differences in benefit-risk profile in certain subpopulations.  
 
Figures 1-4 include flowchart summaries of the recommendations provided in Sections V and 
VI. Please refer back to these sections for a detailed explanation of the recommendations. 
 
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Figure 1: Recommendations for Demographic Subgroup-Specific 
Statistical Study Design 
 
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Figure 2: Recommendations for Demographic Subgroup-Specific 
Statistical Analysis for One-Arm Studies (Objective Performance 
Criterion, Performance Goal, Observational Study) 
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Figure 3: Recommendations for Demographic Subgroup-Specific 
Statistical Analysis for Comparative Studies 
 
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Figure 4: Recommendations for Submitting and Reporting 
Subgroup-Specific Participation and Outcome Information 
 
36