Eligibility Criteria, Enrollment Practices and Trial Designs
NTRODUCTION
17 Over the past few decades, FDA policy initiatives have focused on promoting enrollment
18 practices that lead to clinical trials better reflecting the population most likely to use the drug if
the drug is approved, primarily through broadening eligibility criteria.
2 19 Despite these efforts,
20 challenges to participation in clinical trials remain, and certain groups continue to be
21 unnecessarily underrepresented in many clinical trials. This guidance recommends approaches
that sponsors of clinical trials to support a new drug application3 22 or a biologics license
23 application can take to broaden eligibility criteria, when scientifically and clinically appropriate,
and increase enrollment of underrepresented populations4 in their clinical trials.5 24
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
that describe the characteristics the participants must or must not have to be able to participate in the study (i.e.,
inclusion and exclusion criteria). Eligibility criteria are determined for each study and may include, for example,
characteristics such as age, gender, medical history, current health status, presence or absence of certain genotypes,
blood pressure, heart rate, and absence of certain diseases.
3 This guidance applies to drugs, including biological drug 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 to both demographic populations (e.g., sex, race, ethnicity, age) and non-demographic
populations (e.g., patients with organ dysfunction, comorbid conditions, and those at the extremes of the weight
range).
5 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.
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26 FDA is issuing this guidance to satisfy the mandate under section 610(a)(3) of the FDA
Reauthorization Act of 2017 (FDARA) (21 U.S.C. 360bbb note).
6 27 In accordance with the
28 FDARA mandate, this guidance discusses (1) broadening eligibility criteria and avoiding
29 unnecessary exclusions for clinical trials; (2) developing eligibility criteria and improving trial
recruitment so that the participants7 30 enrolled in trials will better reflect the population most likely
31 to use the drug, if the drug is approved, while maintaining safety and effectiveness standards;
32 and (3) applying the recommendations for broadening eligibility criteria to clinical trials for
33 drugs intended to treat rare diseases or conditions.
35 In general, FDAs guidance documents do not establish legally enforceable responsibilities.
36 Instead, guidances describe the Agencys current thinking on a topic and should be viewed only
37 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
38 the word should in Agency guidances means that something is suggested or recommended, but
39 not required.
42 II. BROADENING ELIGIBILITY CRITERIA TO INCREASE DIVERSITY IN
43 ENROLLMENT
45 One objective of eligibility criteria is to help protect participants by excluding people for whom
46 the risk of an adverse event from participation is not likely to be reasonable in relation to any
potential benefit and the importance of the knowledge that may be expected to result.8 47 For
48 example, patients with decreased renal function or certain concomitant illnesses are often
49 excluded because of concerns that they may be more susceptible to the adverse effects of an
50 investigational drug because it is metabolized by the kidney or interacts with other medications
51 the patient takes.
53 In addition, participants with multiple concomitant illnesses and those receiving other drugs are
54 often excluded because of concerns that such conditions or other drugs could affect a
55 determination of the investigational drugs safety or effectiveness. Pregnant women are also
56 frequently excluded out of concern for fetal health. In addition to protecting participant safety,
57 the exclusion of certain patients on multiple medications or with multiple comorbidities is
58 sometimes intended to avoid noise in the safety data. Medically complex patients often have
59 adverse clinical events that are related to their underlying conditions, which may make it difficult
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 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.
8 See 21 CFR 56.111(a)(2).
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60 to determine whether the adverse event is related to the investigational drug, to the medical
61 condition, or to a concomitant treatment.
63 At the same time, certain populations are often excluded from trials without strong clinical or
64 scientific justification (e.g., the elderly, those at the extremes of the weight range, individuals
65 with organ dysfunction, those with malignancies or certain infections such as HIV, and children).
66 Additionally, failure to include complex participants in a development program may lead to a
67 failure to discover important safety information about use of the investigational drug in patients
68 who will take the drug after approval. Therefore, broadening eligibility criteria, when
69 appropriate, maximizes the generalizability of trial results and the ability to understand the
70 therapys benefit-risk profile across the patient population likely to use the drug in clinical
71 practice, without jeopardizing patient safety.
73 For more information on current FDA and International Conference on Harmonisation (ICH)
74 policy initiatives on broadening eligibility criteria in clinical trials, see Appendix A.
76 A. Broadening Eligibility Criteria in Enriched Clinical Trials
78 Enrichment is a trial design strategy in which a there is a targeted inclusion of certain
populations, with the goal of more readily demonstrating the effect of the drug, if there is one.
80 Enrichment may increase the trials potential to show an effect, if one exists, by ensuring that
81 participants have a particular severity of a disease, a particular subset of a disease, or particular
82 genetic markers. Prognostic enrichment enrolls participants who are more likely to reach study
83 endpoints (e.g., participants with risk factors for cardiovascular disease in a cardiovascular
84 outcome trial) or to have a disease of greater severity, reducing the size of a trial necessary to
85 show an effect. Predictive enrichment includes participants with a specific characteristic (e.g.,
86 genetic, pathophysiologic) who may be more likely to respond to an intervention. Enrichment
87 does not usually exclude demographic groups.
89 FDA encourages the use of enrichment strategies to increase the potential of a trial to detect an
90 effect of the investigational drug, although it is often advisable to include a reasonable sample of
91 participants who have the disease but do not meet the prognostic or predictive enrichment
92 characteristics prespecified in the clinical trial.
and Biological Products (December 2012). 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. When final, this guidance will represent FDAs current thinking on
this topic. For the most recent version of a guidance, check the FDA guidance web page at
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94 B. FDA Recommendations
96 1. Inclusive Trial Practices
98 Sponsors should adopt practices for determining eligibility criteria that will allow the clinical
99 trial population to reflect the diversity of the patients who will be using the drug if the drug is
100 approved. Although there are many approaches a sponsor can take to broaden eligibility criteria
101 in clinical trials, FDA provides the following recommendations and encourages the use of others
as appropriate:
104 - Examine each exclusion criterion to determine if it is needed to help assure the safety
105 of trial participants or to achieve the study objectives when developing clinical trial
106 protocols. If not, consider eliminating or modifying the criteria to expand the study
107 population as well as tailoring the exclusion criteria as narrowly as possible to avoid
108 unnecessary limits to the study population. For example, if there are unreasonable
109 risks to participants with advanced heart failure, but enrollment of those with milder
110 disease would be appropriate, the exclusion criteria should specifically define the
111 population of heart failure participants that should be excluded (e.g., New York Heart
112 Association (NYHA) stage III and IV).
114 - Consider whether criteria from phase 2 studies  which may be more restrictive and
115 are often transferred to phase 3 protocols  can be eliminated or modified to avoid
116 unnecessary limits on the study population. Although excluding certain participants
117 may be scientifically or clinically justified under specific circumstances (e.g., certain
118 drug-drug or drug-disease interactions or concerns regarding a populations
119 vulnerability to a particular toxicity), such criteria may be removed or modified
120 during study conduct based upon data available from the completion of other relevant
121 studies (e.g., drug-drug or drug-disease interaction studies). It may be possible in
122 some cases to have the development program include specific studies in higher risk
123 populations conducted at sites with expertise in working with such participants
124 (although in such a case the consent form should identify this increased risk among
125 certain participants).
127 - Base exclusions on an appropriate measure of organ dysfunction that does not lead to
128 the unnecessary exclusion of certain populations when such exclusions are necessary
129 because participants with impaired organ function would be placed at unreasonable
risk.
trials: (1) Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, and Hepatitis C Virus
Infections (March 2019); (2) Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or
Concurrent Malignancies (March 2019); and (3) Cancer Clinical Trial Eligibility Criteria: Brain Metastases
(March 2019). When final, these guidances will represent FDAs current thinking on these topics.
11 See 21 CFR 56.111(a)(2).
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132 - Consider including children (ages 2 to 11 years) and adolescents (ages 12 to 17 years)
in confirmatory clinical trials involving adults when appropriate.12, 13 133
135 2. Trial Design and Methodological Approaches
137 Sponsors may consider various trial design and methodological approaches to enrolling a broader
138 population. The following are examples of potential approaches to consider:
140 - Consider characterizing  in early clinical development  drug metabolism and
141 clearance across populations that may metabolize or clear the drug differently (e.g.,
142 the elderly and patients with liver or kidney dysfunction). Early characterization of
143 drug metabolism and clearance across groups will help avoid later exclusions.
144 Alternatively, an expansion cohort may also allow dose modification and may be
145 used to assess a reasonably safe dose in specific populations in which there may be
146 significant differences in the systemic exposure to the investigational drug (e.g.,
pediatric or elderly participants or participants with organ impairment).14 147
149 - Consider using adaptive clinical trials, which allow for pre-specified trial design
changes during the trial, including altering the trial population.15 150 An adaptive design
151 can start with a narrow population if there are concerns about safety and can expand
152 to a broader population based on interim data from the trial as well as external data.
153 Adaptive trials may also provide for broader enrollment when there is uncertainty
154 regarding whether the drug will be effective in certain populations, with an interim
155 analysis that will enable adjustment of future enrollment based on pre-specified
156 criteria regarding response.
158 - Consider a pediatric development program early (although enrollment of children and
159 adolescents in development programs is a complex subject that is beyond the scope of
160 this guidance). For pediatric trials with potential safety concerns, consider staggering
161 enrollment based on age (i.e., enrollment of older pediatric participants first, then
162 younger pediatric participants). Because this approach may not always be warranted,
industry Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials (March 2019).
13 For considerations regarding the inclusion of pediatrics in adult oncology clinical trials, see the draft guidance for
industry Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients (March 2019). When final,
this guidance will represent FDAs current thinking on this topic.
14 See the draft guidance for industry Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite
Development of Oncology Drugs and Biologics (August 2018). This draft guidance defines a first-in-human (FIH)
multiple expansion cohort trial as an FIH trial with a single protocol with an initial dose-escalation phase that also
contains three or more additional patient cohorts with cohort-specific objectives. When final, this guidance will
represent FDAs current thinking on this topic.
15 See the draft guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (September 2018).
When final, this guidance will represent FDAs current thinking on this topic. 
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163 such enrollment should be justified with a clear scientific rationale (e.g., juvenile
164 toxicity studies have not yet been completed to support studies in younger pediatric
participants).16 165
167 - Consider including a broader participant group in the trial as part of the secondary
168 efficacy and safety analyses, even when the primary analysis population is narrowed
169 (e.g., when using enrichment designs). Consider enrolling participants across the full
170 spectrum of disease severity, and structure eligibility criteria to include participants
171 from all disease stages or syndrome presentations, while assessing efficacy and safety
172 for the larger population, even if the primary endpoint is based on a population with a
173 particular stage of the disease. This approach allows the study to utilize enrichment
174 to help demonstrate effectiveness while also providing information on effectiveness
175 and safety in a broader population and not decreasing the chances of achieving
176 success on the primary clinical endpoint.
178 - Consider including pharmacokinetic sampling when appropriate and when it is
179 possible for continued participation with sufficient assurances of safety during
180 pregnancy to establish dosing in women who become pregnant during a trial and in
181 whom the risks of continued trial participation are reasonable in relation to the
182 anticipated benefits and the importance of the knowledge that may be expected to
183 result. This may provide important information regarding drug metabolism during
184 pregnancy and across the trimesters, a time when physiology can change
185 significantly.
188 III. OTHER STUDY DESIGN AND CONDUCT CONSIDERATIONS FOR
189 IMPROVING ENROLLMENT
191 Beyond the limitations in participation imposed by narrow eligibility criteria, potential
192 participants may face additional challenges to enrolling in clinical trials. A trial requiring
193 participants to make frequent visits to specific sites may result in added burden for participants,
194 especially the elderly, children, disabled and cognitively impaired individuals who require
195 transportation or caregiver assistance, or participants who live far from research facilities, such
196 as those in rural or remote locations. Burdensome financial costs (e.g., travel, missing work)
197 may also impede participation, and study visits may interfere with jobs and/or family and
198 community obligations. Moreover, for individuals under current clinical care on a regularly
199 scheduled basis (e.g., individuals with multiple chronic conditions), additional clinical trial study
200 visits may be burdensome and a disincentive for enrollment in clinical trials. A mistrust of
clinical research among certain populations also impacts enrollment.
17 201 FDA, the National
Pediatric Population (April 2018).
17 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
cm598050.htm. 
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202 Institutes of Health (NIH), and HHS have a number of resources that serve to further the goal of
203 improving enrollment practices and broadening inclusion criteria. (See Appendix B)
205 As part of the overall study design, sponsors can improve the diversity of enrolled participants by
206 accounting for logistical and other participant-related factors that could limit participation in
207 clinical trials. The following are a few examples of potential approaches, and FDA encourages
208 the development of other approaches.
210 A. Make Trial Participation Less Burdensome for Participants
212 - During the study design phase, consider the recruitment challenges that may occur
213 because of the planned visit schedule: reduce the frequency of study visits to
214 those needed to appropriately monitor safety and efficacy and consider whether
215 flexibility in visit windows is possible and whether electronic communication
216 (e.g., telephone/mobile telephone, secured electronic mail, social media
platforms) or mobile technology tools18 217 can be used to replace site visits and
provide investigators with real-time data. 19 218
220 - During recruitment, offer and make participants aware of financial
221 reimbursements for expenses associated with costs incurred by participation in
222 clinical trials (e.g., travel and lodging expenses). FDA does not consider
223 reimbursement for reasonable travel expenses to and from the clinical trial site
224 and associated costs such as airfare, parking, and lodging to raise issues regarding
undue influence.20 225 Similarly, consideration may be given to paying participants
226 in exchange for their participation in the research; however, FDA recognizes that
227 payment for participation may raise difficult questions that should be addressed
228 by the IRB, such as how much money should participants receive, and for what
229 should participants receive payment, such as their time, inconvenience,
discomfort, or some other consideration.
detects and measures a physical or chemical characteristic and translates this into an electrical signal. Mobile
technology tools and are generally capable of transmitting the information they record from study participants to
remote databases (e.g., ambulatory blood pressure monitor).
19 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.
20 See the guidance for institutional review boards and clinical investigators Payment and Reimbursement to
Research Subjects  Information Sheet (January 2019), available at
. See also 21 CFR 50.20.
21 Ibid.
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232 B. Adopt Enrollment and Retention Practices That Enhance Inclusiveness
234 - Work directly with communities to address participant needs and to involve
235 patients, patient advocates, and caregivers in the design of clinical trial protocols.
236 Patients may provide valuable insight into challenges and burdens and may be
237 more willing to accept risk for a potential benefit as long as the risks are clearly
238 communicated in the informed consent and the research team explains the risks.
239 Community-based participatory research promotes the design of clinical research
240 with the assistance of community members and leaders to more effectively meet
the needs of potential participants.22 241 Understanding how participants choose
242 whether to participate in a clinical trial allows sponsors to more effectively recruit
243 participants who may be reluctant to enroll.
245 - Ensure that clinical trial sites include geographic locations with a higher
246 concentration of racial and ethnic minority patients to recruit a more diverse study
247 population. Consider diversity when selecting health care providers to assist with
clinical trial recruitment because this may promote diversity among participants.
250 - Incorporate strategies for public outreach and education. Industry, patient
251 advocacy groups, medical associations, and other stakeholders can consider
252 collaborating to educate participants about clinical trial participation.
254 - Make recruitment events accessible by holding them often, as well as offering
255 them during evening and weekend hours. Consider holding the events in non256
clinical but trusted locations (such as houses of worship) and social commercial
257 venues (such as barbershops and beauty salons) as a means of connecting with
258 diverse populations.
260 - Explore agreements to foster the exchange of medical records between clinical
261 trial sites in order to promote participant retention by obtaining participant
262 consent for clinical trial investigators to transfer medical records, including
263 electronic medical records, when participants move from one location to another,
264 because participants often struggle to navigate the gathering and transfer of
265 records between sites.
23 Racial and ethnic minorities currently comprise 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
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267 C. Expanded Access
269 Despite efforts to broaden inclusion criteria, there may be patients who do not meet the eligibility
270 criteria or for other reasons cannot participate in the clinical trial. FDAs expanded access
271 regulations provide a pathway to potentially offer such patients, when they have a serious or
272 immediately life-threatening disease or condition, treatment with an investigational drug,
273 provided certain criteria are met, including that there is no comparable or satisfactory alternative
therapy.
24 274 Expanded access refers to the use of an investigational drug when the primary
275 purpose is to diagnose, monitor, or treat a patients disease or condition rather than to obtain the
276 kind of information about the drug that is generally derived from clinical trials. However, in
277 certain limited circumstances, data from expanded access use may inform clinical
development.
281 IV. BROADENING ELIGIBILITY CRITERIA AND ENCOURAGING
282 RECRUITMENT FOR CLINICAL TRIALS OF INVESTIGATIONAL DRUGS
283 INTENDED TO TREAT RARE DISEASES OR CONDITIONS
285 Clinical trials of investigational drugs intended to treat rare diseases or conditions present a
286 unique set of challenges. Because of limited numbers of patients, maximum participation in
287 clinical trials is essential for successful trial completion and interpretation. Subsets of potential
288 participants are sometimes excluded from clinical trials because of narrow eligibility criteria,
289 including (1) those with advanced disease or without narrowly defined symptoms in a
290 heterogenous disorder, (2) age, (3) duration of disease, (4) severity of symptoms, (5)
291 concomitant medication, or (6) disability. Because rare diseases often affect small,
292 geographically dispersed patient populations with disease-related travel limitations, special
293 efforts may be necessary to enroll and retain these participants to ensure that a broad spectrum of
294 the patient population is represented.
296 Although certain strategies, including predictive and prognostic enrichment, are used to increase
297 the efficiency of clinical trials for rare diseases, the effects in the broader population remain of
298 interest.
300 Sponsors should therefore consider the following approaches (and others as appropriate) to
301 broadening clinical trial eligibility criteria for clinical trials of investigational drugs intended to
302 treat rare diseases and improve the enrollment and retention of participants with rare diseases:
304 - Engage early in the drug development process with patient advocacy groups that are
305 strongly committed to finding new therapies, to elicit their suggestions for the design
306 of trials, including trial protocols, that participants will be willing to enroll in and
307 support. For a number of rare diseases, there are active patient advocacy groups that
308 are strongly committed to finding new therapies and supporting clinical trials.
25 See question 26 in the guidance for industry Expanded Access to Investigational Drugs for Treatment Use 
Questions and Answers (June 2016; updated October 2017). 
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310 - Plan to re-enroll participants from early-phase trials into later-phase trials when
311 studying the effectiveness of treatments for rare diseases  in limited circumstances,
312 if medically appropriate, and if there is no unreasonable anticipated safety issue.
313 Traditionally, participants are often ineligible for a phase 3 trial if they had been
314 previously exposed to the drug in an earlier-phase trial; however, with so few
315 participants in rare disease trials, re-enrolling participants may facilitate the analysis
316 of safety and efficacy in the broadest possible population. Caution should be
317 exercised to avoid selection bias, as the participants who better tolerated the drug and
318 experienced more effectiveness in early phases may be disproportionally selected for
319 a phase 3 trial, which may contribute to efficacy findings that are not representative
320 of the larger population that will use the drug if the drug is approved.
322 - Make available an open-label extension study after early-phase studies to encourage
323 participation by ensuring that all study participants, including those who received
324 placebo, will ultimately have access to the investigational treatment.
327 V. CONCLUSION
329 Broadening eligibility criteria and adopting more inclusive enrollment practices will open
330 clinical trials to a diverse participant population reflective of the population that will use the drug
331 if the drug is approved. To avoid unnecessary exclusions and obtain critical safety and
332 effectiveness data applicable to a more representative patient population, sponsors should
333 consider the recommendations in this guidance when designing and conducting clinical trials.
334 FDA also encourages sponsors to consider and develop other approaches as appropriate.