Article In Brief
Recruitment of more diverse populations, including marginalized racial and ethnic groups, enables researchers to identify potential differences and targeted therapies for people with Alzheimer’s disease, Parkinson’s disease, epilepsy, and multiple sclerosis, researchers told Neurology Today. They also share strategies for achieving more diverse representation in clinical trials.
Researchers should design clinical trials to ensure that they include diverse populations of participants, investigators across a broad spectrum of neurologic disorders told Neurology Today in response to an editorial published Aug. 15 in JAMA Neurology.
The editorial focused on Alzheimer’s disease trials in the US, which it said has historically underrepresented populations. But those not involved with the editorial said the lack of diversity in clinical trials is problematic in other conditions as well—in Parkinson’s disease, epilepsy, and multiple sclerosis (MS)—and the dearth of representation could limit the applicability of findings from one trial to the next.
The JAMA Neurology editorial noted, for example, that the US Food and Drug Administration’s accelerated approval of the Alzheimer’s drug aducanumab was based on a study that only included six Black participants.
Lead author Joshua D. Grill, PhD, co-director of the Alzheimer’s Disease Research Center at the University of California, Irvine, and colleagues cited a systemic review of 101 trials published in 2021 in Alzheimer’s & Dementia that reported that a median 94.7 percent of AD trial participants were White. The review found that a median 1.2 percent of patients were Black or African American, 4.4 percent were Asian (when including three studies from Asia that had samples consisting of 100 percent Asian participants), and 5.6 percent were Hispanic. Yet African American and Hispanic people are disproportionately at risk for AD, according to the editorial.
“These and other minoritized racial groups, along with sexual and gender minority individuals and those of low socioeconomic status, low educational attainment, or residing in disadvantaged neighborhoods, all may be subjected to discrimination, reduced access to health care, and other social determinants of health that may ultimately affect brain resilience, risk of AD, and treatment safety and efficacy,” the authors wrote.
Focus on Eligibility Criteria, Funding
Critical to the effort to recruit more diverse participants is funding to pay for additional resources to achieve representation, the editorialists wrote. This includes “community-based researchers with established partnerships and trust in underrepresented communities,” they said, adding that each site involved in a trial should have specific goals aimed at achieving diverse recruitment.
Dr. Grill told Neurology Today that diversity should be considered throughout the spectrum of drug development, particularly for studies testing the safety and efficacy of a therapy in different populations, he explained.
“If you’re doing a first-in-human study of 10 people, diversity may be less key to answering the scientific question under study,” Dr. Grill said. “In large studies of safety and efficacy, this may represent the last opportunity to understand in a controlled setting potential differences among groups before a treatment becomes used in clinical practice, making diversity imperative.”
Dr. Grill pointed out that preliminary data suggest that the amount of phosphorylated tau in cerebrospinal fluid may differ by race and ethnicity, for example. One study published in JAMA Neurology in 2019 found lower concentrations of phosphorylated tau in African American people. Another study published in Alzheimer’s Research & Therapy in 2017 reported that cognitive impairment in African Americans is associated with smaller changes in cerebrospinal tau markers than in people who identify as White, and this may lead to missed diagnoses in African American populations.
“There may come a time when we need to do phase I studies in multiple populations rather than a single population,” he said.
Dr. Grill said he and his colleagues spent years putting together a team that could speak Spanish to recruit participants for the National Institutes of Health-funded AHEAD Study, which tests the efficacy of lecanemab (BAN2401) in people at increased risk of AD. The study now has 14 sites that can enroll Spanish speakers, he said.
But more research is needed to understand the challenges involved in recruiting populations from diverse communities. “What works in one diverse community may not work in another,” Dr. Grill said.
Diversity in Gene Studies
Diverse study populations are especially needed to help researchers find new genes associated with neurologic disease, said Andrew B. Singleton, PhD, a National Institutes of Health Distinguished Investigator and director of the Center for Alzheimer’s and Related Dementias. Dr. Singleton leads the Global Parkinson’s Genetic Program, a five-year study that aims to genotype more than 150,000 people around the world.
“We know the structure of the genome is subtly different between populations, and we can use that to our advantage to narrow down large regions that we know contain risk variants,” he said.
Parkinson’s disease needs to be understood in terms of how the genetic basis of disease differs between populations, according to Dr. Singleton.
“We know there are genetic influences that are more common in one population or absent in another population,” he said.
One example Dr. Singleton noted is the p.G2019S variant in found in the lrrk2 gene. The variant underlies about 20 percent of the Parkinson’s disease cases found in people of Ashkenazi Jewish descent and about 2 percent of cases in people of Northern European descent, but it essentially is absent in people of Asian descent, Dr. Singleton explained.
“At some point, we’re going get to a place where we routinely are trying to match the patient’s etiology and the mechanism driving disease in the patient to the therapeutic,” he said. “But you need to understand how that mechanism is different from population to population.”
Dr. Singleton advised researchers to specify in grant applications the funds needed to recruit diverse study participants.
“Most awarding agencies now have some kind of priority around diversity and diversification of the research endeavor, not only in the subjects you work with, but the models you work with,” he said. “I would not underestimate the power of answering that call.”
Epilepsy Trials
Increasing diversity for some trials is easier than for others, neurologists told Neurology Today. Kathryn A. Davis, MD, associate professor of neurology at the Perelman School of Medicine at the University of Pennsylvania, said the drug and device trials she is involved with recruit from clinics in and around Philadelphia that belong to the PennMedicine network. Patients evaluated for epilepsy surgery would all be considered as potential candidates for clinical trials, and this typically already is a diverse group, she said.
Recruiting for a study of new-onset epilepsy would be challenging because the patients would likely not have as much interaction with the medical system, said Dr. Davis. Researchers for such a study would need to conduct outreach to community clinics and other organizations, she said.
“You should be planning from the beginning of the study to ensure that you will have adequate representation in your cohort,” Dr. Davis said.
But Jacqueline A. French, MD, FAAN, professor of neurology at the NYU Langone School of Medicine and founder and director of the Epilepsy Study Consortium, said patients often feel reluctant to join a placebo-controlled intervention trial because they don’t want to be placed in the placebo group or they don’t want to change the medication they currently take. Other patients don’t want to be the first to try an experimental treatment. People from minority groups who have experienced mistreatment by the medical establishment, such as African Americans, also can be reluctant to participate in trials, she said.
“We have to rely on our academic medical centers to recruit because it’s such a very specific type of subject that we’re looking for,” Dr. French said. “The answer there would be to train as many investigators as possible in locations where a diverse population may be more likely to exist naturally.”
“If you’re doing a first-in-human study of 10 people, diversity may be less key to answering the scientific question under study. In large studies of safety and efficacy, this may represent the last opportunity to understand in a controlled setting potential differences among groups before a treatment becomes used in clinical practice, making diversity imperative.”—DR. JOSHUA D. GRILL
Dr. French and colleagues were able to do just that with an observational study called the Human Epilepsy Project 2 (HEP2), which recruited from 10 clinics in the US. The study observed people with treatment-resistant epilepsy and the treatments they received. They found that participants who identified as Black were much less likely than other populations to have been implanted with one of the devices used to treat this kind of epilepsy—a vagus nerve stimulator, a responsive neurostimulator, or a deep brain stimulator.
“We need to recruit from diverse populations so that we can identify these issues,” Dr. French said. “It might be that people who were not implanted weren’t offered the intervention or were and did not accept it. That work has to come next.”
Challenges in MS Trials
Mitzi Joi Williams, MD, FAAN, medical director and CEO of Joi Life Wellness Group, is working on research that she hopes will fill in gaps in knowledge about how MS affects different populations. This is especially an issue in the US, where researchers have found the incidence of MS in African American communities may be higher than previously thought, Dr. Williams noted.
“It’s difficult to generalize data when you only have, for example, 10 Black people in a phase 3 clinical trial,” she said.
Dr. Williams co-chairs the steering committee of the CHIMES trial, a phase 4 clinical trial that aims to understand the effects of ocrelizumab on people with MS who identify as Black or Hispanic.
“We partnered with patient advocacy organizations and patient influencers to create protocols and review materials,” she said. “Patient advocates were not asked specifically to share about the study, but they did participate in interviews/videos about the importance of diversity in research.”
“I also think it’s important to look at the diversity of your staff,” Dr. Williams said. “Those who are reaching their community should hopefully reflect the people they’re serving.”
Even general neurologists can help with recruitment by being aware of the higher burden of disease amongst Hispanic and Black Americans, Dr. Williams said. She recommends clinicians and researchers review a toolkit from the MS Minority Research Engagement Partnership Network, which includes patient education materials and a list of resources to help patients find a clinical trial.
“We should all look in our own spheres of influence to see what ways can we address this and increase diverse enrollment in clinical research,” she said.
Disclosures
Drs. Davis, Williams, and Singleton had no disclosures. Dr. Grill reports research funding from the National Institute on Aging, the Alzheimer’s Association, BrightFocus Foundation, Eisai, Eli Lilly, Genentech, and Biogen. He has consulted for SiteRx. Dr. French receives salary support from the Epilepsy Foundation and for consulting work and/or attending scientific advisory boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Alterity Therapeutics Limited, Anavex, Arkin Holdings, Angelini Pharma S.p.A, Arvelle Therapeutics Inc., Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Beacon Biosignals Inc., Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical Inc., BioXcel Therapeutics, Bloom Science Inc., BridgeBio Pharma Inc., Camp4 Therapeutics Corp., Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Coda Biotherapeutics, Corlieve Therapeutics, Crossject, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel Inc., Equilibre BioPharmaceuticals, Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Korro Bio Inc., Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte Inc., Neumirna Therapeutics, Neurocrine, Neuroelectrics USA Corp., Neuronetics Inc., Neuropace, NxGen Medicine Inc., Ono Pharmaceutical Co., Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Paladin Labs Inc., Passage Bio, Pfizer, Praxis, PureTech LTY Inc., Rafa Laboratories Ltd., Receptor Holdings Inc., SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, Third Rock Ventures LLC, UCB Inc., Ventus Therapeutics, Xenon, Xeris, Zogenix, and Zynerba. Dr. French also received research support from the Epilepsy Study Consortium (funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, and the Vogelstein Foundation), Epilepsy Study Consortium/Epilepsy Foundation (funded by UCB), GW/FACES, and NINDS. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Angelini Pharma S.p.A., Cerevel, Clinical Education Alliance, NeuCyte Inc., Neurocrine, Praxis, and Xenon. Dr. French serves on the editorial board of Lancet Neurology and Neurology Today. She is chief medical/innovation officer for the Epilepsy Foundation.
New Tool from NIA Promises to Aid Recruitment
A new tool from the National Institute on Aging aims to help Alzheimer’s disease researchers with recruitment strategies. OutreachPro lets users customize templates of educational materials, including handouts, fact sheets, radio scripts, videos, and social media posts, according to Melissa McGowan, MHS, program manager. The content can be about brain health in general or about what clinical trials are and why it’s important to participate in one.
“OutreachPro and its contents are systematically developed using literature reviews, environmental scans, listening sessions with stakeholders, focus groups with intended target audiences, national surveys, and user testing,” McGowan said in an email to Neurology Today. The tool was extensively tested with people representing diverse and under-resourced populations, she added.
OutreachPro has a library of content developed for African American, Hispanic/Latino, Asian American, and Pacific Islander populations and is available in English, Spanish, Chinese, Tagalog, and Hindi. Users can customize content by choosing the language and health status of the people who will read it. For example, the materials can be customized for a caregiver, a person at risk for dementia, a person within the early stages of the disease, or a person with Alzheimer’s.
Since the site is still in the beta stage, McGowan explained, the NIA has not yet assessed its impact on recruitment.
