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

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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

2

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 lifethreatening conditions or diseases for which there is an unmet medical need.
Contains Nonbinding Recommendations

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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, FDA’s guidance documents do not establish legally enforceable responsibilities. 

Instead, guidances describe the Agency’s 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 individual’s 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 FDA’s 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 
Contains Nonbinding Recommendations

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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 participant’s 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 therapy’s 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 FDA’s 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). 
Contains Nonbinding Recommendations

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• 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 population’s 

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). 
Contains Nonbinding Recommendations

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- 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 person’s self-representation as male or 

female or how that person is responded to by social institutions based on the individual’s gender presentation. 

Gender is rooted in biology and shaped by environment and experience. 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 FDA’s 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.
Contains Nonbinding Recommendations

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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):287–294.

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).
Contains Nonbinding Recommendations

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• 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 trial’s 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 markernegative 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.” 
Contains Nonbinding Recommendations

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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.
Contains Nonbinding Recommendations

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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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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 nonclinical 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.
Contains Nonbinding Recommendations

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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. FDA’s 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 patient’s 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/rwdrecommendations_final.pdf. For more information on FDA’s real-world data program, see Framework for FDA’s 

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). 
Contains Nonbinding Recommendations

13

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. Reenrollment 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, 
Contains Nonbinding Recommendations

14

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 therapy’s 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.
Contains Nonbinding Recommendations

15

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 

protocols for unwarranted exclusions.1 13

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 

(FDASIA).2 18 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 

Agency.3 27

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.
Contains Nonbinding Recommendations

16

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 

and those receiving concomitant medications, many of whom are often older adults.

4 39

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, 

especially patients 75 years or older.5 43

44

45 • In 2014 in the FDASIA Action Plan, FDA reiterated support for efforts to include 

older adult patients in clinical trials.6 46

47

48 3. Inclusion of Pregnant Women

49

• In 2016, section 20417 of the 21st Century Cures Act8 50 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 

and lactating women.

9 55 

56

57 • In April 2018, FDA published a draft guidance for industry on scientific and ethical 

considerations for inclusion of pregnant women in clinical trials.10 58

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 FDA’s current thinking on this topic.
Contains Nonbinding Recommendations

17

60 • In May 2019, FDA issued two draft guidances providing trial design 

recommendations for postapproval pregnancy safety studies11 61 and for clinical 

lactation studies.12 62

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 

designs.13 68

69

70

 11 See the draft guidance for industry Postapproval Pregnancy Safety Studies (May 2019). When final, this guidance 

will represent FDA’s 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 FDA’s 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 FDA’s current thinking on this topic.
Contains Nonbinding Recommendations

18

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 • FDA’s Office of Women’s Health provides information and resources for researchers 

79 on participation of women in clinical trials, including webinars, videos, scientific 

workshop proceedings, and links to other relevant resources.1 80 The Office of 

81 Women’s 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 

professionals to inform women about clinical trials.

2 84 NIH also provides resources to 

85 encourage the participation of women in clinical trials with its Office of Research on 

86 Women’s Health Inclusion Outreach Toolkit: How to Engage, Recruit, and Retain 

Women in Clinical Research.

3 87

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 

informed consent.4 91

92

93 • FDA’s 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 

resources.5 96

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/scienceresearch/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-clinicaltrials.

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.
Contains Nonbinding Recommendations

19

100 participation, including informational videos and links to other federal websites and 

media articles.6 101

102

103 • NIH informs the public about the availability of clinical trials and how to enroll

through its website “NIH Clinical Research Trials and You.”7 104

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 

studies that is accessible to the public and health care providers.8 108

109

110 • ResearchMatch, a public clinical research registry partially funded by NIH’s National 

111 Center for Advancing Translational Sciences, connects researchers with people who 

are interested in participating in clinical trials.9 112

113

114

 6 “About Research Participation,” available at https://www.hhs.gov/ohrp/education-and-outreach/about-researchparticipation/index.html.

7 “NIH Clinical Research Trials and You,” available at https://www.nih.gov/health-information/nih-clinicalresearch-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/wpcontent/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/