Enhancing the Diversity of 
Clinical Trial Populations  
Eligibility Criteria, 
Enrollment Practices, and 
Trial Designs 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
 
November 2020 
Clinical/Medical 
 
 
    
Enhancing the Diversity of 
Clinical Trial Populations  
Eligibility Criteria, 
Enrollment Practices, and 
Trial Designs 
Guidance for Industry 
 
Additional copies are available from: 
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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and/or 
 
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances     
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
November 2020 
Clinical/Medical 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 2 
II.  BROADENING ELIGIBILITY CRITERIA TO INCREASE DIVERSITY IN 
ENROLLMENT ............................................................................................................................ 3 
A.  Inclusive Trial Practices ................................................................................................................ 4 
B.  Trial Design and Methodological Approaches ............................................................................ 7 
C.  Broadening Eligibility Criteria in Trials Using Enrichment Strategies ................................... 8 
III.  OTHER STUDY DESIGN AND CONDUCT CONSIDERATIONS FOR 
IMPROVING ENROLLMENT .................................................................................................. 9 
A.  Make Trial Participation Less Burdensome for Participants .................................................... 9 
B.  Adopt Enrollment and Retention Practices That Enhance Inclusiveness .............................. 10 
C.  Expanded Access .......................................................................................................................... 12 
IV.  BROADENING ELIGIBILITY CRITERIA AND ENCOURAGING 
RECRUITMENT FOR CLINICAL TRIALS OF INVESTIGATIONAL DRUGS 
INTENDED TO TREAT RARE DISEASES OR CONDITIONS ......................................... 13 
V.  CONCLUSION ............................................................................................................... 14 
APPENDIX A:  CURRENT EFFORTS TO BROADEN ELIGIBILITY CRITERIA IN 
CLINICAL TRIALS ................................................................................................................... 15 
APPENDIX B:  CURRENT EFFORTS TO IMPROVE ENROLLMENT IN CLINICAL 
TRIALS ........................................................................................................................................ 18 
  Contains Nonbinding Recommendations 
 
Enhancing the Diversity of Clinical Trial Populations  Eligibility 
Criteria, Enrollment Practices, and Trial Designs 
Guidance for Industry1 
 
 
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 office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
Over the past few decades, FDA has promoted enrollment practices that would lead to clinical 
trials that better reflect the population most likely to use the drug if the drug is approved, 
primarily through broadening eligibility criteria.2  Despite these efforts, challenges to 
participation in clinical trials remain, and certain groups continue to be underrepresented in many 
clinical trials.  This guidance recommends approaches that sponsors of clinical trials intended to 
support a new drug application3 or a biologics license application can take to increase enrollment 
of underrepresented populations in their clinical trials.4  
 
This guidance considers both demographic characteristics of study populations (e.g., sex, race, 
ethnicity, age, location of residency) and non-demographic characteristics of populations (e.g., 
patients with organ dysfunction, comorbid conditions, disabilities, those at the extremes of the 
weight range, and populations with diseases or conditions with low prevalence). Enrolling 
                                                 
1 This guidance has been prepared by the Office of Medical Policy and the Office of New Drugs in the Center for 
Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and 
Drug Administration.  
 
2 For the purposes of this guidance, the term eligibility criteria refers to the requirements for entry into a clinical 
trial, i.e., the characteristics the participants must or must not have to be able to participate in the study (often 
referred to as inclusion and exclusion criteria).  Eligibility criteria are determined for each study and generally 
include evidence that a participant has the disease or condition being treated, often for a defined minimum duration, 
defined severity, and with particular symptoms or signs, and may also include characteristics such as age, sex, 
medical history, current health status, presence or absence of certain genotypes, blood pressure or other physiologic 
parameter, and absence of certain diseases.  
 
3 This guidance applies to drugs, including biological products.  For the purposes of this guidance, drug or drug 
product is used to refer to human drugs and human biological products that are regulated as drugs. 
 
4 This guidance applies broadly to all types of drug products, including drugs for the treatment of serious and life-
threatening conditions or diseases for which there is an unmet medical need. 
 
 
  2 
  Contains Nonbinding Recommendations 
 
participants5 with a wide range of baseline characteristics may create a study population that 
more accurately reflects the patients likely to take the drug if it is approved and allow assessment 
of the impact of those characteristics on the safety and effectiveness of the study drug.   
 
In issuing this guidance, FDA is satisfying the mandate under section 610(a)(3) of the FDA 
Reauthorization Act of 2017 (FDARA) (21 U.S.C. 360bbb note).6  Consistent with the FDARA 
mandate, this guidance discusses (1) broadening eligibility criteria and avoiding unnecessary 
exclusions for clinical trials; (2) developing eligibility criteria and improving trial recruitment so 
that the participants enrolled in trials will better reflect the population most likely to use the drug, 
if the drug is approved, while maintaining safety and effectiveness standards; and (3) applying 
the recommendations for broadening eligibility criteria to clinical trials of drugs intended to treat 
rare diseases or conditions. 
 
In general, FDAs guidance documents 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.  
 
 
II.  BROADENING ELIGIBILITY CRITERIA TO INCREASE DIVERSITY IN 
ENROLLMENT 
 
One objective of eligibility criteria is to exclude people from participating in a trial for whom the 
risk of an adverse event outweighs both that individuals potential benefit from participating and 
the importance of the knowledge that may be expected to result.7  FDA recognizes that certain 
exclusions are appropriate when necessary to help protect such individuals.  For example, 
patients with varying degrees of kidney or liver impairment are often excluded early in drug 
development programs because adequate information is not available on how to adjust doses of 
the investigational drug for such patients or whether such patients could be more vulnerable to 
certain risks.  Pregnant and lactating women are also frequently excluded when there is 
inadequate information to assess the risk to the fetus or infant.8   
                                                 
5 For the purposes of this guidance, the term participant refers to either an individual currently enrolled in a clinical 
trial or an individual who may potentially enroll in a clinical trial. 
 
6 On April 16, 2018, as mandated by section 610(a)(1) of FDARA, 131 Stat. 1005, Public Law 115-52 (August 18, 
2017), FDA held a public meeting to discuss topics related to eligibility criteria in clinical trials, including (1) the 
rationale for, and potential barriers created by, inclusion and exclusion criteria; (2) the benefit to appropriate study 
populations from trials with alternative designs; (3) barriers to clinical trial participation; (4) clinical trial designs 
that increase trial population diversity; (5) how changes to trial inclusion and exclusion criteria could impact clinical 
trials; and (6) how changes to eligibility criteria may impact the complexity and length of clinical trials.  Discussions 
at the public meeting informed this guidance. 
 
7 See 21 CFR 56.111(a)(2). 
 
8 For FDAs draft considerations on how and when to include pregnant women in clinical trials, see the draft 
guidance for industry Pregnant Women:  Scientific and Ethical Considerations for Inclusion in Clinical Trials 
 
  3 
  Contains Nonbinding Recommendations 
 
 
Medically complex patients with certain concomitant illnesses or those taking particular drugs 
may also be excluded in drug development programs.  Such patients may be more susceptible to 
a potential toxicity of the investigational drug and can experience adverse events that are related 
to their underlying conditions or concomitant treatments (i.e., a participants current medications 
interact with the investigational drug), which may impact their ability to complete the trial or 
meet all of the trial obligations. 
 
As data on excretory and metabolic pathways and drug-drug interactions become available 
during the drug development program, allowing appropriate dose adjustments, there should be 
fewer exclusions related to concomitant medications or comorbidities.  Similarly, as the safety 
experience with a product increases, eligibility criteria should be broadened to include more 
medically complex participants; any remaining exclusions should be justified.   
 
FDA also recognizes that some eligibility criteria have become commonly accepted over time or 
used as a template across trials, sometimes excluding certain populations from trials without 
strong clinical or scientific justification (e.g., older adults, those at the extremes of the weight 
range, those with malignancies or certain infections such as HIV, and children).  Some patients 
may be unable to participate without reasonable accommodations (e.g., patients with physical 
and/or mental disabilities, non-English speakers, patients who work and require evening or 
weekend hours, and some older adult patients with limited access to transportation).  
Unnecessary exclusion of such participants may lead to a failure to discover important safety 
information about use of the investigational drug in patients who will take the drug after 
approval.  Therefore, broadening eligibility criteria in later stages of drug development for the 
phase 3 population increases the ability to understand the therapys benefit-risk profile across the 
patient population likely to use the drug in clinical practice.   
  
For more information on current FDA and International Council for Harmonisation (ICH) policy 
initiatives on broadening eligibility criteria in clinical trials, see Appendix A. 
 
A.  Inclusive Trial Practices 
 
There are many approaches a sponsor should take to broaden eligibility criteria in clinical trials 
to ensure that the study population better reflects the patient population likely to use the drug in 
clinical practice.  FDA provides the following recommendations and encourages sponsors to 
consider other FDA recommendations as appropriate:9    
                                                 
(April 2018).  When final, this guidance will represent FDAs current thinking on this topic.  We update guidances 
periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
9 See the following three guidances for industry regarding eligibility criteria of certain populations in oncology 
trials:  (1) Cancer Clinical Trial Eligibility Criteria:  Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus 
Infections (July 2020); (2) Cancer Clinical Trial Eligibility Criteria:  Patients with Organ Dysfunction or Prior or 
Concurrent Malignancies (July 2020); and (3) Cancer Clinical Trial Eligibility Criteria:  Brain Metastases (July 
2020).   
 
 
  4 
  Contains Nonbinding Recommendations 
 
 
  When developing clinical trial protocols, work to ensure that eligibility criteria serve 
the goal of having a representative sample of the population for whom the drug has 
been developed and examine each exclusion criterion to determine if it is needed to 
help assure the safety of trial participants or to achieve the study objectives.  If it is 
not needed, consider eliminating or modifying the criterion to expand the study 
population.  For example, when exclusions are necessary because participants with 
impaired organ function would be placed at unreasonable risk, base the exclusions on 
an appropriately specific measure of organ dysfunction that does not lead to the 
unnecessary exclusion of participants with milder dysfunction.10  For example, if 
there are unreasonable risks to participants with advanced heart failure, but 
enrollment of those with milder disease would be appropriate, the exclusion criteria 
should specifically define the population of heart failure participants that should be 
excluded (e.g., New York Heart Association (NYHA) stage III and IV). 
   
  Consider whether exclusion criteria from phase 2 studies  which may be very 
restrictive and are often transferred to phase 3 protocols  can be eliminated or 
modified for phase 3 trials, which have a different objective than phase 2 studies, to 
avoid unnecessary limits on the study population.  Although excluding certain 
patients may be scientifically or clinically justified under specific circumstances (e.g., 
certain drug-drug or drug-disease interactions or concerns regarding a populations 
vulnerability to a particular toxicity), such criteria may be removed or modified 
during study conduct based upon data available from the completion of other relevant 
studies (e.g., in vitro or in vivo drug-drug or drug-disease interaction studies).  It may 
also be possible in some cases to have the development program include specific 
studies in higher risk populations conducted at sites with expertise in working with 
such participants (although in such a case the consent form should identify this 
increased risk among certain participants and the trial should be designed with the 
needs of the higher risk populations in mind, if the drug is intended for that 
population). 
 
  Sponsors should enroll participants who reflect the characteristics of clinically 
relevant populations with regard to age, sex, race, and ethnicity.11  Inadequate 
participation and/or data analyses from clinically relevant populations can lead to 
insufficient information pertaining to medical product safety and effectiveness for 
product labeling.  This objective can be met through: 
 
                                                 
10 See 21 CFR 56.111(a)(2). 
 
11 See the guidance for industry Collection of Race and Ethnicity Data in Clinical Trials (October 2016).   
 
 
  5 
  Contains Nonbinding Recommendations 
 
-  Inclusion of children and adolescents in confirmatory clinical trials involving 
adults when appropriate12, 13 
 
  Inclusion of women14 in clinical trials in adequate numbers to allow for analysis 
-
by sex,15 for example, by avoiding unjustified exclusion based on sex and taking 
other actions to promote inclusion.16  For most drugs, representatives of both 
sexes should be included in clinical trials in numbers adequate to allow detection 
of clinically significant sex-related differences in drug response.17   
 
  Inclusion of racial and ethnic minorities in clinical trials and the analysis of 
-
clinical trial data by race and ethnicity.  Differences in response to medical 
products (e.g., pharmacokinetics, efficacy, or safety) have been observed in 
racially and ethnically distinct subgroups of the U.S. population.18  These 
differences may be attributable to intrinsic factors (e.g., genetics, metabolism, 
elimination), extrinsic factors (e.g., diet, environmental exposure, sociocultural 
                                                 
12 For considerations regarding the inclusion of adolescents in adult oncology clinical trials, see the guidance for 
industry Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials (March 2019). 
 
13 For considerations regarding the inclusion of pediatric patients in adult oncology clinical trials, see the guidance 
for industry Cancer Clinical Trial Eligibility Criteria:  Minimum Age Considerations for Inclusion of Pediatric 
Patients (July 2020).   
 
14 For the purposes of this guidance, the term women refers to participants biological construct.  
 
15 FDA recognizes that sex and gender are distinct terms, with sex defined as a biological construct and gender as a 
social construct. Sex is the classification of living things, generally as male or female according to their reproductive 
organs and functions assigned by chromosomal complement.  Gender is 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.  See Wizeman, TM and Pardue, M, editors, 
2001, Exploring the Biological Contributions to Human Health:  Does Sex Matter?  National Academies Press.  
FDA understands that the majority of clinical trial participants enroll by self-identified gender and for many 
participants, gender and sex are concordant; for the purposes of this guidance, FDA is assuming that sex and gender 
are concordant.  FDA also recognizes that for some clinical trial participants, gender and sex may not be concordant.  
Discussion of this topic falls outside the scope of this guidance. 
 
16 See the guidance for industry Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs 
(July 1993).  
 
17 Ibid.  For more information regarding FDAs policy on understanding sex differences and the inclusion of women 
in clinical trials, see Understanding Sex Differences at FDA, available at 
https://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm131182.htm, and FDA 
Research, Policy, and Workshops on Women in Clinical Trials, available at 
https://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm131731.htm. 
 
18 See the guidance for industry Collection of Race and Ethnicity Data in Clinical Trials (October 2016).  In fact, in 
June of 2005, FDA approved BiDil, the first drug approved by the Agency to treat a disease in patients identified by 
race. The drug was approved for the treatment of heart failure in Black patients. The sponsor conducted two trials in 
the general population that failed to show a benefit, but suggested a benefit of BiDil in Black patients. The company 
then studied the drug in 1,050 self-identified Black patients, and it was shown to be safe and effective. 
 
 
  6 
  Contains Nonbinding Recommendations 
 
issues), or interactions between these factors.19  Analyzing data on race and 
ethnicity may assist in identifying population-specific signals.20  Therefore, FDA 
recommends that for drugs and biologics, sponsors include a plan for inclusion of 
clinically relevant populations no later than the end of the Phase 2 meeting.21   
 
B.  Trial Design and Methodological Approaches  
 
Sponsors should consider various trial design and methodological approaches that will facilitate 
enrollment of a broader population.  The following are examples of approaches to consider: 
 
  Consider characterizing  in early clinical development  drug metabolism and 
clearance across populations that may metabolize or clear the drug differently (e.g., 
older adults and participants with liver or kidney dysfunction).  Early characterization 
of drug metabolism and clearance across groups will help avoid later exclusions and, 
more generally, will allow dose adjustment to optimize effectiveness and safety 
across different populations.    
 
  Using an adaptive clinical trial design would allow for pre-specified trial design 
changes during the trial when data become available, including altering the trial 
population.22  An adaptive design can start with a narrow population if there are 
concerns about safety and can expand to a broader population based on interim safety 
data from the trial that provide support for doing so.  Adaptive trials may also provide 
for broader enrollment when there is uncertainty regarding whether the drug will be 
safe and effective in certain populations, with an interim analysis that will enable 
adjustment of future enrollment based on pre-specified criteria regarding response.  
 
  Consider a broader pediatric development program early.  The arbitrary sequential 
enrollment of pediatric subgroups by chronological age for some conditions could 
unnecessarily delay development of medicines for children by limiting the population 
for study.  Therefore, staggering enrollment in pediatric studies based on 
chronological age (i.e., enrollment of older pediatric participants first, then younger 
pediatric participants) should be justified with a clear scientific rationale (e.g., a 
known or potential developmental safety concern).23    
 
                                                 
19 Ibid.  See Huang SM and Temple R, 2008, Is this the drug or dose for you?  Impact and consideration of ethnic 
factors in global drug development, regulatory review, and clinical practice, Clin Pharmacol Ther, 84(3):287294. 
 
20 Ibid. 
 
21 See the guidance for industry Collection of Race and Ethnicity Data in Clinical Trials (October 2016). 
 
22 See the guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics (November 2019).   
 
23 For more information on the inclusion of pediatric subpopulations, see the ICH guidance for industry E11(R1) 
Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population (April 2018). 
 
 
  7 
  Contains Nonbinding Recommendations 
 
  Consider including pharmacokinetic sampling to establish dosing in women who 
become pregnant during a trial when it is possible for continued participation with 
sufficient assurances of safety, and if the risks to the participant and fetus of 
continued trial participation are reasonable in relation to the anticipated benefits and 
the importance of the knowledge that may be expected to result.  This may provide 
important information regarding drug metabolism during pregnancy and across the 
trimesters, a time when physiology can change significantly. 
 
C.  Broadening Eligibility Criteria in Trials Using Enrichment Strategies 
 
Enrichment is a trial design strategy in which there is a targeted inclusion of certain populations, 
with the goal of more readily demonstrating the effect, if any, of the drug.24  Enrichment may 
increase the trials potential to show an effect, if one exists, by ensuring that participants have a 
particular severity of a disease, subset of a disease, or genetic marker.  Prognostic enrichment 
enrolls participants who are more likely to reach study endpoints (e.g., participants with risk 
factors for cardiovascular disease in a cardiovascular outcome trial) or who have a disease of 
greater severity, reducing the size of a trial necessary to show an effect.  Predictive enrichment 
enrolls participants with a specific characteristic (e.g., genetic, pathophysiologic) that makes 
them more likely to respond to an intervention.  In general, enrichment should not lead to the 
exclusion of demographic groups; even with enrichment, efforts to maintain enrollment criteria 
that are as broad and representative as possible are important.  
 
Enrichment strategies can increase the ability of a trial to detect an effect of the investigational 
drug; however, it is sometimes advisable to include a reasonable sample of marker-negative 
participants who have the disease but do not meet the enrichment criteria, particularly when (1) 
there is uncertainty about the sensitivity of the measurement for the enrichment marker and the 
responsiveness of marker-negative patients and (2) substantial use is anticipated in the marker-
negative population (e.g., for serious diseases with few alternative therapies).  Apart from 
enrichment-based selection criteria, the unnecessary use of exclusions described previously 
should be avoided. 
 
As noted, even in an enriched trial, it may be useful to include a broader participant group.  
These participants could be part of a secondary analysis of efficacy, perhaps with a different 
efficacy endpoint (e.g. a surrogate marker).  Enrolling participants across the full spectrum of 
disease severity should be considered, even if the primary endpoint is based on a population with 
a particular stage of the disease.  This approach allows the study to utilize enrichment to help 
demonstrate effectiveness and may also, if adequately designed, provide some efficacy 
information on the broader population. 
 
 
                                                 
24 See the guidance for industry Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and 
Biological Products (March 2019).  This guidance defines enrichment as the prospective use of any patient 
characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely 
than it would be in an unselected population.     
 
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  Contains Nonbinding Recommendations 
 
III.  OTHER STUDY DESIGN AND CONDUCT CONSIDERATIONS FOR 
IMPROVING ENROLLMENT 
 
As noted previously, beyond the limitations in participation imposed by narrow eligibility 
criteria, potential participants may face additional challenges to enrolling in clinical trials.  A 
trial requiring participants to make frequent visits to specific sites may result in added burden for 
participants, especially older adults, children, disabled and cognitively impaired individuals who 
require transportation or caregiver assistance, or participants who live far from research facilities, 
such as those in rural or remote locations.  Financial costs (e.g., travel, missing work, dependent 
care) may also impede participation, and study visits may interfere with jobs and/or family and 
community obligations.  Moreover, for individuals under current clinical care on a regularly 
scheduled basis (e.g., individuals with multiple chronic conditions), additional clinical trial study 
visits may be psychologically, physically, and financially burdensome, and a disincentive for 
enrollment.  A mistrust of clinical research among certain populations also impacts enrollment.25  
FDA, the National Institutes of Health, and HHS have a number of resources that serve to further 
the goal of improving enrollment practices and broadening inclusion criteria.  (See Appendix B.) 
 
As part of the overall study design, sponsors can improve the diversity of enrolled participants by 
accounting for logistical and other participant-related factors that could limit participation in 
clinical trials.  The following are a few examples of potential approaches, and FDA encourages 
the development of other approaches. 
 
A.  Make Trial Participation Less Burdensome for Participants 
 
  During the study design phase, consider the recruitment challenges that may occur 
because of the planned visit schedule and difficulties with accessibility (including 
for individuals with disabilities) to trial sites: reduce the frequency of study visits 
to those needed to appropriately monitor safety and efficacy, and consider 
whether flexibility in visit windows is possible and whether electronic 
communication (e.g., telephone/mobile telephone, secured electronic mail, social 
media platforms) or digital health technology tools26 can be used to replace site 
visits and provide investigators with adequate real-time data.27  Consider the use 
of mobile medical professionals, such as nurses and phlebotomists, to visit 
                                                 
25 For more discussion on barriers to clinical trial enrollment, see the Public Workshop:  Evaluating Inclusion and 
Exclusion Criteria in Clinical Trials, held April 16, 2018, available at 
https://www.fda.gov/media/134754/download.  
 
26 For the purposes of this guidance, a digital health technology tool is a sensor, a device, or a device component that 
detects and measures a physical or chemical characteristic and translates this into an electrical signal.  Digital health 
technology tools are generally capable of transmitting the information they record from study participants to remote 
databases (e.g., ambulatory blood pressure monitor). 
 
27 See the guidance for industry Use of Electronic Health Record Data in Clinical Investigations (July 2018), which 
provides recommendations on the use of electronic health record data in FDA-regulated clinical investigations. 
 
 
  9 
  Contains Nonbinding Recommendations 
 
participants at their locations instead of requiring participants to visit distant 
clinical trial sites.  
 
  During recruitment, offer and make participants aware of financial 
reimbursements for expenses associated with costs incurred by participation in 
clinical trials (e.g., travel and lodging expenses).  FDA does not consider 
reimbursement for reasonable travel expenses to and from the clinical trial site 
and associated costs such as airfare, parking, and lodging to raise issues regarding 
undue influence.28  Similarly, consideration may be given to paying participants 
in exchange for their participation in research  FDA recognizes, however, that 
payment for participation may raise difficult questions that should be addressed 
by the IRB, such as how much money participants should receive, and for what 
participants should receive payment, such as their time, inconvenience, 
discomfort, or some other consideration.29 
 
B.  Adopt Enrollment and Retention Practices That Enhance Inclusiveness  
 
  Implement more inclusive strategies for public outreach and education, including 
incorporating patient-focused research into clinical trial design.30  Industry, 
patient advocacy groups, medical associations, and other stakeholders can 
consider collaborating to educate participants about clinical trial participation.  
Work directly with communities to address participant needs and involve site 
coordinators, patients, patient advocates, and caregivers in the design of clinical 
trial protocols in order to determine which elements of the protocol may 
discourage participation and how the study can be optimally designed to enhance 
recruitment.  Patients may provide valuable insight into challenges and burdens 
and may be more willing to accept risk for a potential benefit from participation 
or to further knowledge about their disease; however, reasonably foreseeable risks 
must be communicated to participants in the documents provided as part of 
obtaining informed consent.  See 21 CFR 50.25(a)(2).   
 
  Consider fostering community engagement through medical societies, focus 
groups, community advisory boards, disease registries, and community-based 
participatory research, the latter of which promotes the design of clinical research 
with the assistance of community members and leaders to more effectively meet 
the needs of potential participants.31  Remain engaged with communities after the 
conclusion of the clinical research and share trial updates to continue to 
                                                 
28 See the information sheet guidance for institutional review boards and clinical investigators Payment and 
Reimbursement to Research Subjects (January 2018).  See also 21 CFR 50.20.  
 
29 Ibid. 
 
30 See the guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development: Collective 
Comprehensive and Representative Input (June 2020).   
 
31 https://www.nimhd.nih.gov/programs/extramural/community-based-participatory.html.  
 
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  Contains Nonbinding Recommendations 
 
strengthen bi-directional relationships with communities.  Providing cultural 
competency and proficiency training for clinical investigators and research staff 
may help facilitate the building of a trusting relationship with participants, 
provide a helpful resource for investigators and research staff on how to engage 
with participants with different backgrounds, help decrease biased communication 
and behavioral practices, and help avoid the use of cultural generalizations and 
stereotypes in interactions with participants.  Understanding how participants 
choose whether to participate in a clinical trial allows sponsors to more effectively 
recruit participants who may be reluctant to enroll. 
 
  Ensure that clinical trial sites include geographic locations with a higher 
concentration of racial and ethnic minority patients and indigenous populations, 
as well as locations within the neighborhoods where these populations receive 
their health care, because restricting clinical trial sites to selected geographic 
locations may limit the ability to enroll a diverse trial population.  Consider 
diversity when selecting health care providers and study coordinators to assist 
with clinical trial recruitment, because participants may prefer a health care 
provider of their same cultural background.32  
 
  Make recruitment events accessible by holding them often, as well as offering 
them during evening and weekend hours.  Consider holding the events in non-
clinical but trusted locations (such as places of worship or community centers), 
social commercial venues (such as barbershops and beauty salons), and public 
events (such as cultural festivals, carnivals, and parades) as a means of connecting 
with diverse populations and populations that may have limited or no internet 
access.  
 
  Explore agreements to facilitate the exchange of medical records between clinical 
trial sites in order to promote participant retention by obtaining participant 
consent for clinical trial investigators to transfer medical records, including 
electronic medical records, when participants move from one location to another, 
because participants often struggle to navigate the gathering and transfer of 
records between sites. 
 
  Consider providing trial resources and documents in multiple languages and  
multilingual research staff and/or interpreters in order to encourage the 
participation and retention of individuals with limited English comprehension.  
 
                                                 
32 Racial and ethnic minorities currently compose a small percentage of clinical trial participants relative to the 
prevalence of disease in these populations.  According to the Zip Code Analysis Project, 80 percent of minorities 
live in only 20 percent of the zip codes in the United States.  See Dialogues on Diversifying Clinical Trials:  
Successful Strategies for Engaging Women and Minorities in Clinical Trials, available at 
https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM334959.pdf. 
 
 
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  Consider using real-world data to promote more efficient recruitment of a diverse 
population by using, for example, claims data and electronic health records (while 
maintaining patient privacy and ensuring that patient permissions/consent for the 
sharing/access of identifiable data from electronic health records is obtained and 
maintained) to identify potential sites and participants.33  
 
  Consider use of online/social media recruitment strategies to identify participants 
for whom a traditional referral center is not accessible.  
 
  Consider using electronic informed consent to allow participants to read and 
sign necessary forms remotely instead of traveling to a clinical trial site, while 
ensuring that all potential participants, including those with literacy issues, 
understand all necessary information.34  Underrepresented populations with 
limited or no internet access, however, may benefit from personal interactions 
with investigators to better understand the risks and benefits of trial participation; 
for these populations, consider holding consenting processes and interventions in 
locations that are more accessible to the participant.  
 
C.  Expanded Access 
 
Despite efforts to broaden inclusion criteria, there may be patients who do not meet the eligibility 
criteria or for other reasons cannot participate in the clinical trial.  FDAs expanded access 
regulations provide a pathway to potentially offer such patients, when they have a serious or 
immediately life-threatening disease or condition, treatment with an investigational drug, 
provided certain criteria are met, including that there is no comparable or satisfactory alternative 
therapy.35  Expanded access refers to the use of an investigational drug when the primary 
purpose is to diagnose, monitor, or treat a patients disease or condition rather than to obtain the 
kind of information about the drug that is generally derived from clinical trials.  However, in 
certain limited circumstances, data from expanded access use may inform clinical development 
(e.g., by identifying patients for subsequent studies).36 
 
                                                 
33 For additional discussion on the use of real-world data in study planning and recruitment, see Clinical Trials 
Transformation Initiative (CTTI) Recommendations: Use of Real-World Data to Plan Eligibility Criteria and 
Enhance Recruitment, available at https://www.ctti-clinicaltrials.org/sites/www.ctti-clinicaltrials.org/files/rwd-
recommendations_final.pdf.  For more information on FDAs real-world data program, see Framework for FDAs 
Real-World Evidence Program, available at https://www.fda.gov/media/120060/download. 
  
34 See the guidance for institutional review boards, investigators, and sponsors Use of Electronic Informed Consent 
in Clinical Investigations  Questions and Answers (December 2016).  As used in that guidance document, 
electronic informed consent refers to the use of electronic systems and processes that may employ multiple 
electronic media, including text, graphics, audio, video, podcasts, passive and interactive websites, biological 
recognition devices, and card readers to convey information related to the study and to obtain and document 
informed consent. 
 
35 See 21 CFR part 312, subpart I, Expanded Access to Investigational Drugs for Treatment Use. 
 
36 See question 26 in the guidance for industry Expanded Access to Investigational Drugs for Treatment Use 
Questions and Answers (October 2017).  
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  Contains Nonbinding Recommendations 
 
 
IV.  BROADENING ELIGIBILITY CRITERIA AND ENCOURAGING 
RECRUITMENT FOR CLINICAL TRIALS OF INVESTIGATIONAL DRUGS 
INTENDED TO TREAT RARE DISEASES OR CONDITIONS 
 
Clinical trials of investigational drugs intended to treat rare diseases or conditions present a 
unique set of challenges.  Because of limited numbers of patients, maximum participation in 
clinical trials is essential for successful trial completion and interpretation.  Because rare diseases 
often affect small, geographically dispersed patient populations with disease-related travel 
limitations, special efforts may be necessary to enroll and retain these participants to ensure that 
a broad spectrum of the patient population is represented. 
 
Although certain strategies, including predictive and prognostic enrichment, are used to increase 
the efficiency of clinical trials for rare diseases, the effects in the broader population remain of 
interest.  Sponsors should therefore consider the following additional approaches (and others as 
appropriate) to broadening clinical trial eligibility criteria for clinical trials of investigational 
drugs intended to treat rare diseases and improve the enrollment and retention of participants 
with rare diseases: 
 
  Engage early in the drug development process with patient advocacy groups, experts, 
and patients with the disease, and elicit their suggestions for the design of trials, 
including trial protocols, that participants will be willing to enroll in and support.  For 
a number of rare diseases, there are active patient advocacy groups that are strongly 
committed to finding new therapies and supporting clinical trials.   
 
  Consider re-enrollment of participants in early-phase trials into later-phase 
randomized trials when studying the effectiveness of treatments for rare diseases.  Re-
enrollment should be done in limited circumstances, when medically appropriate and 
scientifically sound, if there is no unreasonable anticipated safety issue, and as long 
as the therapy received in phase 1 is not expected to change the course of the disease.  
Traditionally, participants are often considered ineligible for a phase 3 trial if they 
had been previously exposed to the drug in the earlier-phase trial; however, with so 
few patients available for rare disease trials, re-enrolling participants may be 
reasonable and may facilitate the analysis of safety and efficacy in the broadest 
possible population.  Sponsors considering this approach should examine the 
potential for selection bias as the participants who better tolerated the drug and 
experienced more effectiveness in early phases may be disproportionally selected for 
a phase 3 trial, which may contribute to safety findings that are not representative of 
the population of patients who will use the drug if it is approved.  The safety and 
tolerability profile observed in the entire study population and the percent of 
reenrolled subjects in the phase 3 trial, taken together, can help to inform the degree 
to which selection bias would likely contribute to the overall assessment of safety and 
tolerability.  
 
  Make available an open-label extension study with broader inclusion criteria after 
early-phase studies to encourage participation by ensuring that all study participants, 
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  Contains Nonbinding Recommendations 
 
including those who received placebo, will ultimately have access to the 
investigational treatment. 
 
 
V.  CONCLUSION  
 
Broadening eligibility criteria and adopting more-inclusive enrollment practices should improve 
the quality of studies by ensuring that the study population is more representative of the 
population that will use the drug if the drug is approved; by facilitating the discovery of 
important safety information about use of the investigational drug in patients who will take the 
drug after approval; and by increasing the ability to understand the therapys benefit-risk profile 
in later stages of drug development for the phase 3 population across the patient population 
likely to use the drug in clinical practice.  FDA encourages sponsors to consider the approaches 
outlined in this guidance and develop other approaches as appropriate. 
 
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  Contains Nonbinding Recommendations 
 
1  APPENDIX A:  CURRENT EFFORTS TO BROADEN ELIGIBILITY CRITERIA IN 
2  CLINICAL TRIALS 
3   
4  The Food and Drug Administration (FDA) and the International Council for Harmonisation 
5  (ICH) have issued a number of population-specific guidances to address the importance of 
6  including a broad population in clinical trials and avoiding unnecessary exclusions: 
7   
8  1.  Inclusion of Clinically Relevant Populations 
9   
10    In 2013, FDA broadly addressed inclusion criteria with its good review practice 
11  document titled Good Review Practice:  Clinical Review of Investigational New Drug 
12  Applications that guides its clinical reviewers to examine investigational new drug 
13  protocols for unwarranted exclusions.1 
14   
15    In 2014, FDA published an action plan titled FDA Action Plan to Enhance the 
16  Collection and Availability of Demographic Subgroup Data (FDASIA Action Plan) 
17  in response to the 2012 Food and Drug Administration Safety and Innovation Act 
18  (FDASIA).2  The FDASIA Action Plan proposes strategies to encourage greater 
19  clinical trial participation, including collaborating with industry, other federal 
20  agencies, and interested stakeholders to improve clinical trial diversity. 
21   
22    In 2016, prompted by the FDASIA Action Plan, FDA published the guidance titled 
23  Collection of Race and Ethnicity Data in Clinical Trials, which encourages sponsors 
24  to enroll participants who reflect the demographics of clinically relevant populations 
25  with regard to age, gender, sex, race, and ethnicity and recommends that sponsors 
26  submit a plan to address the inclusion of clinically relevant populations to the 
27  Agency.3 
28   
29  2.  Inclusion of Older Adult Populations 
30   
31    In November 1989, FDA articulated its support for the inclusion of older adult 
32  participants in clinical trials with the release of a guidance for industry titled 
33  Guideline for the Study of Drugs Likely to be Used in the Elderly.   
34   
                                                 
1 See Good Review Practice:  Clinical Review of Investigational New Drug Applications, available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM377108.pdf.  
 
2 See the FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, available 
at 
https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAc
t/FDASIA/UCM410474.pdf. 
 
3 See the guidance for industry Collection of Race and Ethnicity Data in Clinical Trials (October 2016).  We update 
guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
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  Contains Nonbinding Recommendations 
 
35    In June 1993, within the global pharmaceutical regulatory community, ICH (of which 
36  FDA is a member) issued a guideline titled Studies in Support of Special Populations: 
37  Geriatrics E7, which discourages arbitrary maximum age requirements in clinical 
38  trial protocols and encourages the inclusion of participants with concomitant illness 
39  and those receiving concomitant medications, many of whom are often older adults.4 
40   
41    In February 2012, an ICH guidance for industry, adopted by FDA, clarifies ICH E7 
42  and emphasizes the importance of including older adult patients in clinical trials, 
43  especially patients 75 years or older.5 
44   
45    In 2014 in the FDASIA Action Plan, FDA reiterated support for efforts to include 
46  older adult patients in clinical trials.6 
47   
48  3.  Inclusion of Pregnant Women 
49   
50    In 2016, section 20417 of the 21st Century Cures Act8 required the establishment of a 
51  Task Force on Research Specific to Pregnant Women and Lactating Women.  The 
52  task force was charged with providing advice and guidance to the Secretary of Health 
53  and Human Services on Federal activities related to identifying and addressing gaps 
54  in knowledge and research regarding safe and effective therapies for pregnant women 
55  and lactating women.9     
56   
57    In April 2018, FDA published a draft guidance for industry on scientific and ethical 
58  considerations for inclusion of pregnant women in clinical trials.10 
59   
                                                 
4 The 1993 ICH guideline is available at https://database.ich.org/sites/default/files/E7_Guideline.pdf.  See also the 
ICH guidances for industry E7 Studies in Support of Special Populations: Geriatrics (August 1994) and E7 Studies 
in Support of Special Populations:  Geriatrics  Questions & Answers (February 2012). 
 
5 See ICH E7 Studies in Support of Special Populations:  Geriatrics  Questions and Answers.  
 
6 Ibid. 
 
7 42 U.S.C. 289a-2, 130 Stat. 1033, 1070. 
 
8 130 Stat. 1033, Pub. L. 114-255 (January 6, 2016). 
 
9 See 42 U.S.C. 289a-2; see also  https://www.nichd.nih.gov/about/advisory/PRGLAC.  The task force developed 
recommendations to address areas such as overcoming participation barriers for pregnant women and lactating 
women and integrating them into the research agenda.  See the task force final report to the HHS Secretary and 
Congress, September 2018, available at https://www.nichd.nih.gov/sites/default/files/2018-09/PRGLAC_Report.pdf. 
 
10 See the draft guidance for industry Pregnant Women:  Scientific and Ethical Considerations for Inclusion in 
Clinical Trials (April 2018).  When final, this guidance will represent FDAs current thinking on this topic. 
 
 
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  Contains Nonbinding Recommendations 
 
60    In May 2019, FDA issued two draft guidances providing trial design 
61  recommendations for postapproval pregnancy safety studies11 and for clinical 
62  lactation studies.12  
63   
64  4.  Inclusion of Participants with Rare Diseases 
65   
66    In January 2019, FDA reissued a draft guidance on scientific considerations on drug 
67  development for rare diseases that includes suggestions for inclusion criteria and trial 
68  designs.13 
69   
70     
                                                 
11 See the draft guidance for industry Postapproval Pregnancy Safety Studies (May 2019).  When final, this guidance 
will represent FDAs current thinking on this topic. 
 
12 See the draft guidance for industry Clinical Lactation Studies:  Considerations for Study Design (May 2019).  
When final, this guidance will represent FDAs current thinking on this topic. 
 
13 See the draft guidance for industry Rare Diseases:  Common Issues in Drug Development (January 2019).  When 
final, this guidance will represent FDAs current thinking on this topic. 
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  Contains Nonbinding Recommendations 
 
71  APPENDIX B:  CURRENT EFFORTS TO IMPROVE ENROLLMENT IN CLINICAL 
72  TRIALS 
73   
74  The following is a sampling of efforts by the Food and Drug Administration (FDA), the 
75  Department of Health and Human Services, and the National Institutes of Health (NIH) to 
76  improve enrollment practices in clinical trials: 
77   
78    FDAs Office of Womens Health provides information and resources for researchers 
79  on participation of women in clinical trials, including webinars, videos, scientific 
80  workshop proceedings, and links to other relevant resources.1  The Office of 
81  Womens Health also provides the Diverse Women in Clinical Trials Campaign 
82  Partner Toolkit, which contains multilingual fact sheets, posters, and social media and 
83  email messages that can be used by healthcare providers or other outreach 
84  professionals to inform women about clinical trials.2  NIH also provides resources to 
85  encourage the participation of women in clinical trials with its Office of Research on 
86  Womens Health Inclusion Outreach Toolkit:  How to Engage, Recruit, and Retain 
87  Women in Clinical Research.3  
88   
89    FDA maintains a Consumer Update web page that provides general information on 
90  clinical trials for consumers, including information on clinical trial participation and 
91  informed consent.4  
92   
93    FDAs Office of Minority Health and Health Equity provides a web page for racial 
94  and ethnic minority and underrepresented consumers that contains a clinical trial 
95  diversity tool kit, a webinar, multilingual fact sheets, videos, and links to relevant 
96  resources.5  
97   
98    The Office for Human Research Protections at the Department of Health and Human 
99  Services provides resources and information for the public on clinical trial 
                                                 
1 FDA Research, Policy and Workshops on Women in Clinical Trials, available at https://www.fda.gov/science-
research/womens-health-research/fda-research-policy-and-workshops-women-clinical-trials#Tools_for_Researchers. 
 
2 Women in Clinical Trials available at https://www.fda.gov/consumers/womens-health-topics/women-clinical-
trials. 
  
3 NIH Inclusion Outreach Toolkit: How to Engage, Recruit, and Retain Women in Clinical Research, available at 
https://orwh.od.nih.gov/toolkit. 
   
4 Inside Clinical Trials:  Testing Medical Products in People, available at 
https://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143531.htm.  
 
5 Minorities in Clinical Trials, available at 
https://www.fda.gov/ForConsumers/ByAudience/MinorityHealth/ucm472295.htm.  
 
 
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  Contains Nonbinding Recommendations 
 
100  participation, including informational videos and links to other federal websites and 
101  media articles.6 
102   
103    NIH informs the public about the availability of clinical trials and how to enroll 
104  through its website NIH Clinical Research Trials and You.7  
105   
106    The website clinicaltrials.gov, maintained by the NIH National Library of Medicine, 
107  provides a database with information on publicly and privately supported clinical 
108  studies that is accessible to the public and health care providers.8   
109   
110    ResearchMatch, a public clinical research registry partially funded by NIHs National 
111  Center for Advancing Translational Sciences, connects researchers with people who 
112  are interested in participating in clinical trials.9  
113   
114   
                                                 
6 About Research Participation, available at https://www.hhs.gov/ohrp/education-and-outreach/about-research-
participation/index.html.  
 
7 NIH Clinical Research Trials and You, available at https://www.nih.gov/health-information/nih-clinical-
research-trials-you.  For more information on NIH efforts to improve clinical trial enrollment, see Proceedings of 
the NIH Workshop on the Enrollment and Retention of Participants in NIH-funded Clinical Trials, available at 
https://osp.od.nih.gov/wp-
content/uploads/2015/04/Proceedings%20of%20the%202014%20NIH%20Workshop%20on%20Enrollment%20in
%20NIH%20Funded%20Clinical%20Trials%20(2)_UPDATED_2015%20(2).pdf.  
 
8 https://clinicaltrials.gov/ct2/home   
 
9 https://www.researchmatch.org/  
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