Clinical trials are the final bridge to cross before a new treatment can reach patients. Though Alzheimer's disease affects individuals across cultural, ethnic, racial, and socioeconomic lines, today’s clinical studies do not reflect the non-discriminatory nature of the disease.
While issues of trial diversity have been discussed at length, this challenge recently came up when a US Food and Drug Administration (FDA) Advisory Committee (AdCom) discussed the potential of Eli Lilly's Alzheimer’s drug Kisunla (donanemab). At the time, the committee highlighted the lack of diversity in the enrollment population of the Phase III TRAILBLAZER-ALZ 2 study (NCT04437511). More specifically, they emphasized deficiencies in the trial with respect to racial diversity, genotypic diversity (ApoE4 homozygotes), and the trial’s exclusion of patients with underlying comorbidities like Down syndrome, who are also at risk of developing Alzheimer’s. Still, given the drug’s efficacy, Kisunla was later approved, in July of this year.
The challenge of diverse enrollment is two-pronged, says Dr. Jorge Llibre, assistant professor of neurology at the Washington University School of Medicine in St. Louis. Minority populations are at greater risk for Alzheimer’s, but the absence of adequate data describing these subgroups makes it difficult to enroll a diverse patient population, he says. Nevertheless, it is critical to characterize the treatment effect within diverse populations to ensure that a given medication is effective for all patients who receive it.
Enrollment built on exclusion
The norm in Alzheimer’s clinical trials has been to enroll primarily white patient populations, says Llibre. In Lilly’s TRAILBLAZER, 90.9% of the patients included in the treatment group were white. Similarly, in Eisai's confirmatory Phase III CLARITY AD study (NCT03887455) of Leqembi (lecanemab), another Alzheimer’s disease drug, 76.3% of patients in the lecanemab group were white.
While the field can assume that medications will be effective in most populations, there is no definitive demonstration of efficacy in minority populations, says Dr. Joy Snider, director of the Knight Alzheimer Disease Research Center (ADRC) Clinical Trials Unit at the Washington University School of Medicine in St. Louis.
“The question is, how were those [eligibility] cutoffs defined? The cutoffs we use for Alzheimer's disease are defined in a 95% non-Hispanic population. So when a patient does not meet a cutoff, my question is, which cutoff?” says Llibre.
A recent analysis of plasma-based biomarkers for a Phase III AHEAD trial (NCT04468659) showed that participants from underrepresented groups are often ineligible based on existing amyloid plasma Aβ42/40 results, despite having a higher risk for dementia (Molina-Henry et al., Alzheimers Dementia. 2024 Jun;20(6):3827-3838). Despite designing “liberal” eligibility criteria to “favor sensitivity over specificity,” the plasma screening algorithm remained biased against underrepresented racial and ethnic groups.
It is therefore important to consider the limitation of the existing screening criteria used to determine eligibility for a study, says Llibre. The first step would be to validate an acceptable cutoff in a more diverse population to design the much-needed evolved cutoffs, Llibre explains. Therein lies the challenge: Data is needed to design a cutoff, but the field does not have the data in diverse populations.
Existing eligibility cutoffs are also designed to exclusively evaluate patients with Alzheimer’s disease, says Llibre. However, patients are often affected by related neurological diseases, comorbidities, and mixed pathologies of Alzheimer’s, which necessitates contextual use of these cutoffs, he adds.
Apart from racial diversity, the recent advisory committee hearing also highlighted the lack of representation from individuals with Down syndrome.
As individuals who live with Down syndrome are often diagnosed with dementia earlier than the general population, that itself is a factor that must be considered when designing and funding trials in the space, explains Joy Balls-Berry, Core Leader of the Health Disparities and Equity Core in the Knight ADRC. Because clinical trials exclude individuals with vascular comorbidities and Down syndrome due to safety concerns, the challenge with this is that the field does not know the risk profile of enrolling Down syndrome patients, adds Llibre.
Having a plan to enroll a diverse group of patients directly influences how a treatment may eventually be used in the clinic. “When we go to treat people in the clinic and are counseling patients who are going to get these medications, we can't say a lot of people like you have gotten this drug [in trials], because they haven’t. So it also impacts patient care for people trying to decide whether they want to try the medication,” says Snider.
Knowledge, resource, and service gaps
Regardless of the design, a clinical trial requires a time and financial commitment from a participant. If an individual needs to come in for a full day of procedures and an infusion every two to four weeks, mostly those who have transportation, childcare, and can afford to get off work will enroll, says Snider.
Snider adds that adequate compensation for these efforts is also necessary. In one instance, she recollects how a participant decided not to enroll in the AHEAD clinical study due to deficient compensation. “If we're going to get more people from different socioeconomic levels, we have to have a way to support them as they participate in the trial,” explains Snider.
Aside from access, patients who belong to certain educational or socioeconomic classes are more likely to know about a study. If a subpopulation is not able to get that information for themselves, they will be underrepresented in these studies, says Dr. Mary Sano, Director of the Alzheimer's Disease Research at the Icahn School of Medicine at Mount Sinai in New York.
“The reality is that when it comes later in your life, you already have a history of care and service, you know what is available to you and you know how hard it is to get anything,” adds Sano.
There is less awareness about the disease and clinical trials within certain populations, especially the Hispanic and African American populations, says Dr. Marc Agronin, the CMO at Frank C. and Lynn Scaduto MIND Institute at Miami Jewish Health. Education programs on the condition in communities of color can close this knowledge gap between the patient and research communities, he explains.
Furthermore, with the availability of approved disease modifying therapies like Eisai’s Leqembi and Lilly’s Kisunla, it is more important than ever to explain the benefit of enrolling in clinical trials, says Agronin.
A disconnect between intent and action
While there have been increased outreach efforts across minority communities, a lack of understanding of the factors that drive the socioeconomic status of patients has opened a gap between outreach and translated action, says Llibre.
The “overwhelming majority” of research centers are not prepared to enroll diverse communities despite verbalizing their goals of diverse recruitment, explains Llibre. “In order to be diverse, you have to have centers that are able to fully enroll and follow people that speak a different language. And that's not universal. You need the researchers that are leading some of these initiatives to look like the community they are trying to reach to build more trust in that community,” he says.
It is the responsibility of the sponsor to have the materials ready at trial initiation, and that is not always the case, says Agronin. The onus on clinical trial centers is not where it needs to be. “If you do not have the tools to recruit, you will recruit whoever comes in the door,” explains Agronin.
