Diversity Challenges in Clinical Trials of Alzheimer Disease and Related Dementias

Diversity, equity, and inclusion (DEI) initiatives have increasingly become a focus across businesses, educational institutions, and health care organizations, sparking important conversations and encouraging the passage of laws that mandate efforts be made for more representation, especially in clinical trials of Alzheimer disease and related dementias (ADRD).

Federal Regulations Aimed at Diversifying Clinical Research

In December 2022, the Food and Drug Omnibus Report Act of 2022 (FDORA) was enacted as an amendment to the Federal Food, Drug, and Cosmetic (FDC) Act and the Public Health Service (PHS) Act.¹ Its passage mandated the US Food and Drug Administration (FDA) draft certain informational documents, such as public reports and strategic plans,² as well as industry guidance designed to increase the enrollment of ethnoracially diverse populations in clinical trials and studies.¹

By January 2024, the FDA published draft guidance regarding the collection of race and ethnicity data in clinical trials and studies for FDA-regulated medical products. The guidance recommended that sponsors of investigational drugs and devices enroll participants that reflect the target population most likely to use the FDA-approved product,³ encouraging the enrollment of underrepresented populations.

Lack of Diversity in ADRD Trials

According to research, individuals of Hispanic/Latino or African descent vs White individuals are at a higher risk for developing ADRD.^4,5 However, they are routinely underrepresented in clinical trials.

In 2021, the FDA fast-tracked aducanumab (Aduhelm^®) for approval as a treatment for AD.⁶ Aducanumab became the first new FDA-approved treatment for AD in over 20 years of research and development. The multinational clinical trials (ENGAGE and EMERGE) were designed to evaluate the efficacy and safety of aducanumab, however, the population included extraordinarily low proportions of patients with African (0.6%) or Hispanic/Latino (3.2%) ancestry.⁷

Researchers published a systematic review of the literature in 2022 and included 101 clinical trials for AD in their final analysis. They reported that AD trial participants consisted predominantly White individuals (median percentage, 94.7%). When analyzing temporal trends, this percentage did not increase or decrease significantly between 2001 and 2019.⁸

Clinical investigators continue to struggle with increasing diversity in AD clinical trials, begging the question of why?

We spoke with 3 clinical trial investigators with expertise in AD who revealed that the existing barriers to diversity and equity in AD clinical trials are multilayered and complex.

Barriers to ADRD Trial Diversity

The very nature of AD poses a challenge to patient recruitment for clinical trials. Compared with people with conditions that do not impact cognitive functioning, those with ADRD have more difficulties independently researching treatment options and making decisions about participating in clinical trials.

Under-referrals, Cultural Perspectives, and The Nature of AD

Marissa Natelson Love, MD, a neurologist at the University of Alabama at Birmingham who specializes in behavioral medicine and memory and cognitive disorders at a tertiary referral center, expounded upon several key issues that have affected diversity in her AD clinical trials.

“A big issue is under-referral of at-risk ethnoracially diverse populations to our center,” Dr Love explained. “This may be due to lack of recognition by or referral from primary care physicians (PCPs) or other neurologists who send patients to us for a second opinion. It is also possible that caregivers and family members are simply not bringing their concerns of dementia to the attention of their loved one’s doctor or not requesting a referral to dementia specialists.”

Dr Love also shared that she has encountered differences in cultural perspectives on aging. “Western cultures value independent living whereas other cultures value communal living, such that several generations of family members live in the same household, providing older adults with the care and support that people of Western cultures may not always have.”

She also acknowledged that the nature of AD may be a barrier to recruitment due to the cognitive impairment experienced and the greater social support needed for participants in AD trials compared with other clinical trials.

“Study partners can more accurately report participant medical histories, current symptoms, and any noticeable symptom improvements while the participants undergo ADRD-related treatment. But not everyone with ADRD has this type of strong social support network,” Dr Love noted.

Financial Disincentives, Insurance Barriers, and Lack of Resources

Norman Foster, MD, a geriatric neurologist and professor emeritus from the University of Utah in Salt Lake City, has specialized in brain imaging and neurodegenerative diseases and dementia for more than 30 years. Dr Foster explained how financial disincentives, insurance barriers, and lack of resources can impact diversity and equity in clinical trials, as well as in clinical care.

“There is always this tension between profit motive and philanthropic motive in medicine, and it is an increasingly difficult tension … There is the issue of whether aducanumab is cost-effective, but also the issue of whether the medication itself is truly effective,” he said.

Dr Foster emphasized that although that aducanumab for AD received FDA approval, Medicare decided not to reimburse the treatment because the clinical trials were conducted in populations that were not reflective of the diversity of the general Medicare population. “Historically, justification to deny treatment reimbursement based on lack of clinical trial diversity has affected treatment only for those with AD and not for people with other conditions, despite the same lack of clinical trial diversity. Additionally, Medicare does not reimburse intravenous infusions [like aducanumab] to the same extent as private insurers,” he noted.⁹

These financial and insurance disincentives result in barriers to treatment accessibility and willingness to administer or even fund the research and development of these types of treatments. As such, Biogen, the manufacturer of aducanumab, has announced that it is discontinuing production of the drug to “reprioritize its resources” in AD, but for reasons not attributable to safety or efficacy.⁶

“Quality care of AD requires a multidisciplinary team approach, but those teams are difficult to construct. New treatments really require a change in paradigm, logistics, and infrastructure to meet the needs of high-quality dementia care,” Dr Foster said.

Structural Barriers and Social Determinants of Health

Ganesh Babulal, PhD, an associate professor of neurology in the division of aging and dementia at the Washington University School of Medicine in St. Louis, has authored several articles related to diversity in AD drug trials.^8,10-12 Dr Babulal has frequently discussed the structural barriers and social determinants of health (SDOH) that not only influence health care equity, affordability of treatment, and treatment response, but also deter socioeconomic, racial, and ethnic diversity in ADRD clinical trials.

“Life expectancy is increasing on a large scale globally. We will inevitably see increases in cases of dementia and AD. Researchers have investigated the increased risk for ADRD and its particularly high prevalence in low- and middle-income countries (LMICs),” Dr Babulal said.

“The Lancet Commission’s piece on dementia prevention, intervention, and care stated that 40% of worldwide dementias are explained by 12 modifiable risk factors.¹³ The first on the list of 12 is childhood education, followed by air pollution, depression, hypertension, and smoking. Each modifiable risk factor is related to lifestyle and an understanding of brain health.”

Dr Babulal explained that approximately 11% to 12% of clinical trials for ADRDs have been conducted in LMICs “due to the larger up-front investment needed from pharmaceutical companies and the industry as a whole.” He believes that increased representation from LMICs, who are more at-risk for developing these conditions, can help clinicians determine exactly why there is an increased risk among certain ethnoracial groups for ADRD.

“It is really not just due to genetics. We are finding out more and more that there are SDOH that contribute to this higher risk. Access to quality health care, healthy foods, and resources would benefit brain health. These lifestyle and environmental factors play a role in the development and progression of ADRD,” Dr Babulal said.

He added, “Lack of diversity in clinical trials can lead to treatments that are less effective or even harmful for individuals in certain groups. It widens the gap by perpetuating a new source of health disparity. A treatment that is effective for one group is not necessarily effective for others.”

Researchers who conducted a cross-sectional study of 568,368 community-based Medicare beneficiaries aged 65 and older found that SDOH explained between 10% and 13% of ethnic and racial disparities in ADRD care.¹⁴

“One of the most prominent factors leading to overrepresentation of non-Hispanic White patients in clinical trials is the pervasive mistrust of clinical research and health care systems among minoritized communities stemming from past unethical practices, as well as systemic inequalities and racism,” Dr Babulal continued.

“Cultural differences, misconceptions, and stigma surrounding ADRD may also contribute to low participation rates in clinical trials among many communities … Addressing concerns well before enrollment and providing a certain level of transparency is critical.”

Effective Strategies to Increase AD Clinical Trial Diversity

The barriers that make it difficult to recruit diverse patients for AD clinical trials are complex and multifaceted, requiring significant efforts be made in the hopes of achieving well-balanced representation.

Dr Foster and his AD clinical trial teams tried to improve diversity by establishing outreach clinics in predominately African American and rural communities and by engaging with underserved populations, including Native American, Hispanic, and Polynesian patient populations. Efforts such as educating Spanish-speaking providers and social workers were particularly effective.

Similarly, Dr Babulal found that establishing a knowledgeable clinical trial team reflective of the community was another effective means of recruiting diverse patients.

“There is a science of recruitment and community engagement that must be funded,” he explained. “The trial team must tailor the message to the community, carefully considering the culture, language, and geography when developing educational materials.”

His clinical trial team provides free educational sessions in the community to address concerns, answer questions, and spread awareness. His organization has also participated in community health fairs and screenings.

All 3 clinical trial investigators emphasized the importance of engaging and educating trusted individuals, leaders, and organizations within these specific communities, including religious organizations and federally qualified health centers that provide services to underserved populations.