Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am excited to be talking with Jamie Gamerman, who serves as regulatory counsel in CDER’s Office of Medical Policy. She will be sharing some thoughts with us on the newly published final guidance titled, “Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs.” Our discussion today will focus on important points about this guidance document for the drug development community. Welcome, Jamie! Thank you for speaking with us today.

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Can you provide us with a brief background on the importance of clinical trial diversity?

Yes. Enrolling participants with a wide range of baseline characteristics may create a study population that more accurately reflects the patients likely to take the drug, if approved. It also may uncover differences by demographic and non-demographic characteristics that may be important for safe and effective use of the investigational drug. Therefore, enrolling underrepresented populations in clinical research is important.

The guidance focuses on both demographic and non-demographic characteristics of trial participants. Race is the most common characteristic people think of when they hear diversity. While racial diversity is incredibly important, when developing drugs, it is also important to consider the broad array of characteristics so that the people participating in the clinical trials will be representative of the people who will be taking the drug, if approved. This includes other demographic characteristics such as age, ethnicity, sex, and gender, and non-demographic characteristics such as patients at an extreme of a weight range, patients with comorbid conditions, and patients with disabilities.

Although some progress has been made to improve clinical trial diversity, more work is needed. This guidance provides recommendations for industry to continue to increase enrollment of underrepresented populations in their clinical trials.

What are some challenges that limit the diversity of clinical trial populations?

Challenges that limit diversity in clinical trials include the use of narrow eligibility criteria, the fact that participation in clinical trials can be burdensome, and that the established practices used to recruit and retain volunteers in clinical trials may not effectively enroll underrepresented participants.

How does the guidance recommend addressing these challenges? How should drug developers broaden eligibility practices?

In general, eligibility criteria are established to help protect individuals. FDA recognizes that certain exclusions are appropriate when necessary to help protect individuals for whom the risk of an adverse event outweighs both the individual’s potential benefit from participating in the trial and the importance of the knowledge that could result from the trial. For example, patients with varying degrees of kidney or liver impairment are often excluded early in drug development programs. This may lead to inadequate information for these patients on how to adjust doses of the drug, if approved, and questions on whether they could be more vulnerable to certain risks. Another example is pregnant and lactating participants, who are frequently excluded when there is inadequate information to assess the risk to the fetus or infant.

However, some eligibility criteria have become commonly accepted over time, and eligibility criteria templates are sometimes used across trials, excluding certain populations from trials without clinical or scientific justification. This guidance encourages sponsors not to use rote eligibility criteria, but instead to evaluate eligibility criteria specific to the benefits and risks of each trial and to ensure that there is strong clinical or scientific justification for excluding populations from a trial.

Sponsors also can consider broadening eligibility criteria in the later stages of drug development when more information about the benefit-risk profile of the investigational drug is known across the patient population likely to use the drug after approval.

Moving on to the next challenge you mentioned. What does the guidance recommend for making clinical trials less burdensome?

Participants often have busy schedules. Sponsors should consider challenges due to planned visit schedules and accessibility to the clinical trial sites. For example, sponsors should consider the use of electronic informed consent. This would allow participants to read and sign necessary forms remotely instead of traveling to a clinical trial site for that purpose. Another suggestion is, when possible, sponsors should consider reducing the frequency of visits and adding flexibility in visit windows. Telemedicine also offers an option for those who have Internet access or who are Internet savvy; however, not everyone relies on the Internet, so sponsors should make alternative study sites available that are closer to where participants live.

Another consideration is the financial impact of clinical trials on participants, who may have to travel to distant clinical trial sites. Sponsors may offer financial reimbursements for expenses incurred by participants in clinical trials, such as for travel and lodging, because such expenses do not raise issues regarding undue influence.

And for the last challenge. What enrollment and retention practices are recommended in the guidance that enhance inclusiveness?

One suggestion is to implement more inclusive strategies for public outreach and education, including incorporating patient-focused research into clinical trial design. This research incorporates what matters most to patients in their treatment and may improve retention in clinical trials. Also consider fostering community engagement through medical societies, focus groups, community advisory boards, disease registries, and community-based participatory research.

In addition, it is helpful to 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.

Another option is making recruitment events accessible by holding them often and offering them during evening and weekend hours. Events can be held at trusted, popular places, such as places of worship, barbershops, and beauty salons, as well as at public events, including cultural festivals and parades. This guidance also recommends exploring agreements to facilitate the exchange of medical records between clinical trial sites.

Another consideration is providing trial resources and documents in multiple languages and hiring multilingual research staff and/or interpreters to encourage the participation and retention of individuals with limited English comprehension. Finally, the use of digital health technologies, claims data electronic health records, and real-world data could promote more efficient recruitment of a diverse population. Online and social media recruitment strategies may also be used to identify participants for whom a traditional referral center is not accessible.

There are unique challenges around clinical trial enrollment for rare diseases because of the smaller size of the patient populations. Can the strategies provided in this guidance apply to clinical trials for rare diseases?

All recommendations mentioned in the guidance apply to rare diseases, but there are specific recommendations for participants affected by these conditions. Rare diseases often affect small, geographically dispersed patient populations; special efforts may be necessary to enroll and retain these participants to ensure that a broad spectrum of the patient population is represented.

Sponsors should consider engaging early in the drug development process with patient advocacy groups, experts, patients with the disease, and FDA to get their recommendations. Sponsors should also consider re-enrolling participants from early-phase trials into later-phase randomized trials when studying the effectiveness of treatments for rare diseases. In addition, it may be helpful for sponsors to make available an open-label extension study with broader inclusion criteria after their preceding studies to encourage participation and to allow study participants, including those who received a placebo, to have access to the investigational treatment.

We recommend that sponsors also review a draft guidance published by FDA in 2019 on rare diseases entitled Rare Diseases: Common Issues in Drug Development. In that draft guidance, we

• provide updates to the Natural History Studies section;
• discuss considerations regarding the evaluation and validation of surrogate biomarkers;
• describe nonclinical flexibility;
• and provide additional information on external controls and early randomization.

What is the evolution of this guidance?

This is part of a congressional mandate that required draft and final guidance under the FDA Reauthorization Act of 2017. In April 2018, FDA held a public meeting to discuss topics related to eligibility criteria in clinical trials. Discussions at the public meeting informed this guidance, the draft version of which was published in 2019. Stakeholders submitted about 90 comments to the docket after publication of the draft guidance, most of which were positive and praised FDA’s efforts in improving clinical trial diversity, including FDA’s women’s health initiatives and the transparency FDA provides with its Drug Trials Snapshots. Comments came from members of Congress, industry groups and individual companies, associations, citizens, and patient advocates.

We reviewed and addressed each comment. While most of the changes to the draft version were editorial changes to improve clarity, FDA included a few additional recommendations in the final version. With regard to broadening eligibility criteria and trial inclusivity, FDA recommended the use of real-world data to find trial participants and the use of mobile medical professionals, such as nurses and phlebotomists, to visit participants at or near their residences instead of requiring participants to visit distant clinical trial sites. As another example, based on a comment received, we added language on improving accessibility to clinical trial sites for patients with disabilities.

Can you talk about some FDA policies that led to this guidance?

We wrote this guidance to enhance diversity, building on the work of previous FDA guidance documents and policies. Examples of such efforts include the guidance documents Collection of Race and Ethnicity in Clinical Trials, which was published in 2016 and Pediatrics E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population, which was published in 2018.

FDA and HHS have done a lot of work in this area in a host of patient populations, including older adults¹, pediatric patients with cancer², oncology patients with other diseases,³ and pregnant women.⁴

We also want to highlight the FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, also known as the FDASIA Action Plan, that published in 2014. The plan proposed strategies to encourage greater clinical trial participation, including collaborating with industry, federal agencies, and interested stakeholders to improve clinical trial diversity.

In addition, it is important to underscore the other HHS initiatives that are listed in the guidance, such as NIH’s ResearchMatch Program that connects researchers with trial participants, the website Clinicaltrials.gov, a searchable database of clinical trials, and the HHS Office for Human Research Protections website on clinical trial participation.

For our final question, can you give the audience a brief overview of where are we going in this area?

Last year, FDA Commissioner Califf published a paper on key FDA priorities, with one being health equity. We have a few tools to advance this topic moving forward, including FDA Drug Trials Snapshots, which helps the public to access trial demographics for approved New Molecular Entities and original biologics. The Office of Minority Health and Health Equity and the Office of Women’s Health also have initiatives in this space. In addition, FDA is working on finalizing the draft guidance Diversity Plans to Improve Enrollment of Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials and later this year FDA will be conducting public workshops on clinical trial diversity in response to the Food and Drug Omnibus Reform Act of 2022.

I think it’s important to note that we’ve made some progress in this area, and we continue to do so. This guidance is just the beginning of the conversation and one piece in a much larger puzzle.

Jamie, thank you for speaking with us today about the final guidance on enhancing the diversity of clinical trial populations. We have learned so much from your informative discussion on the document. We would also like to thank the guidance working group for writing and publishing this guidance.

To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.

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¹Examples of documents related to the older populations include Guideline for the Study of Drugs Likely to be Used in the Elderly (1989) and Studies in Support of Special Populations: Geriatrics E7 June 1993. In 2012, FDA adopted another ICH guidance to emphasize inclusion of people 75 and older.
²For 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). 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).
³Examples of documents related to the older populations include Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections (July 2020); Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies (July 2020), and Cancer Clinical Trial Eligibility Criteria: Brain Metastases (July 2020)
⁴Examples of documents related to the older populations include the draft guidance Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials (April 2018). 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. Other specific draft guidances are Postapproval Pregnancy Safety Studies (May 2019) and Clinical Lactation Studies: Considerations for Study Design (May 2019).