Eligibility Criteria, Enrollment Practices and Trial Designs

NTRODUCTION 16 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 25

1 This guidance has been prepared by the Office of Medical Policy 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 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. Contains Nonbinding Recommendations Draft — Not for Implementation 2 26 FDA is issuing this guidance to satisfy the mandate under section 610(a)(3) of the FDA Reauthorization Act of 2017 (FDARA) (21 U.S.C. 360bbb note). 6 27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. 34 35 In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 36 Instead, guidances describe the Agency’s 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. 40 41 42 II. BROADENING ELIGIBILITY CRITERIA TO INCREASE DIVERSITY IN 43 ENROLLMENT 44 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. 52 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 drug’s 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

6 On April 16, 2018, as mandated by section 610(a)(1) of FDARA, 131 Stat. 1005, Public Law 115-52 (Aug. 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 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). Contains Nonbinding Recommendations Draft — Not for Implementation 3 60 to determine whether the adverse event is related to the investigational drug, to the medical 61 condition, or to a concomitant treatment. 62 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 therapy’s benefit-risk profile across the patient population likely to use the drug in clinical 71 practice, without jeopardizing patient safety. 72 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. 75 76 A. Broadening Eligibility Criteria in Enriched Clinical Trials 77 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. 9 79 80 Enrichment may increase the trial’s 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. 88 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. 93

9 See the draft guidance for industry Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs

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 FDA’s current thinking on this topic. 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 Draft — Not for Implementation 4 94 B. FDA Recommendations 95 96 1. Inclusive Trial Practices 97 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: 10 102 103 104 • 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). 113 114 • 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 population’s 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). 126 127 • 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. 11 130 131

10 See the following three draft guidances for industry regarding eligibility criteria of certain populations in oncology

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 FDA’s current thinking on these topics. 11 See 21 CFR 56.111(a)(2). Contains Nonbinding Recommendations Draft — Not for Implementation 5 132 • Consider including children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) in confirmatory clinical trials involving adults when appropriate.12, 13 133 134 135 2. Trial Design and Methodological Approaches 136 137 Sponsors may consider various trial design and methodological approaches to enrolling a broader 138 population. The following are examples of potential approaches to consider: 139 140 • 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).14 147 148 149 • 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. 157 158 • 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,

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 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 FDA’s 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 FDA’s 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 FDA’s current thinking on this topic. Contains Nonbinding Recommendations Draft — Not for Implementation 6 163 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).16 165 166 167 • 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. 177 178 • 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. 186 187 188 III. OTHER STUDY DESIGN AND CONDUCT CONSIDERATIONS FOR 189 IMPROVING ENROLLMENT 190 191 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

16 See the ICH guidance for industry E11(R1) Addendum: Clinical Investigation of Medicinal Products in the

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 https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDARA/u cm598050.htm. Contains Nonbinding Recommendations Draft — Not for Implementation 7 202 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) 204 205 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. 209 210 A. Make Trial Participation Less Burdensome for Participants 211 212 • 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. 19 218 219 220 • 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. 21 230 231

18 For the purposes of this guidance, a mobile 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. 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 https://www.fda.gov/RegulatoryInformation/Guidances/ucm126429.htm. See also 21 CFR 50.20. 21 Ibid. Contains Nonbinding Recommendations Draft — Not for Implementation 8 232 B. Adopt Enrollment and Retention Practices That Enhance Inclusiveness 233 234 • 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. 244 245 • 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. 23 248 249 250 • 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. 253 254 • 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. 259 260 • 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. 266

22 https://www.nimhd.nih.gov/programs/extramural/community-based-participatory.html.

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 https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM334959.pdf. Contains Nonbinding Recommendations Draft — Not for Implementation 9 267 C. Expanded Access 268 269 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. FDA’s 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 patient’s 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. 25 278 279 280 281 IV. BROADENING ELIGIBILITY CRITERIA AND ENCOURAGING 282 RECRUITMENT FOR CLINICAL TRIALS OF INVESTIGATIONAL DRUGS 283 INTENDED TO TREAT RARE DISEASES OR CONDITIONS 284 285 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. 295 296 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. 299 300 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: 303 304 • 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.

24 See 21 CFR part 312, subpart I, Expanded Access to Investigational Drugs for Treatment Use.

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). Contains Nonbinding Recommendations Draft — Not for Implementation 10 309 310 • 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. 321 322 • 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. 325 326 327 V. CONCLUSION 328 329 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.