Racial minorities and others disproportionately affected by Alzheimer’s disease could continue facing barriers to treatment unless Medicare does more to facilitate access to research and safety studies, policy watchers say.
The Centers for Medicare & Medicaid Services’ finalized plan for
These vulnerable patients are “the ones that are going to experience the brunt of a bad decision first,” when you don’t have an agency ensuring the drug actually works for them, said Reshma Ramachandran, a fellow at Yale University’s National Clinician Scholars Program.
The CMS made multiple changes to its initial coverage determination in response to trial access concerns from advocacy groups. The agency removed the requirement that approved clinical trials take place at hospital-based outpatient centers, as well as exclusion criteria that would have prevented patients with Down syndrome from participating.
But hospital-based centers may be the only locations with the medical research teams needed to carry out these trials, even though some minority and rural populations may not live near these sites or have the resources to travel. The coverage plan also doesn’t push researchers to conduct preliminary safety studies for patients with Down syndrome—which is needed before including them in larger efficacy trials.
Policy watchers say the CMS could reimburse patients for the time and travel needed to participate in these trials, and also clarify to trial sponsors when additional safety data is needed on specific populations. The agency could also require that CMS-approved comparative studies using patient health databases meet certain diversity benchmarks.
Tamara Syrek Jensen, director of the coverage and analysis group in the CMS Centers for Clinical Standards and Quality, said in a public stakeholder call April 11 that “diversity is extremely important in any CMS approved trial, and it is a criterion, in any protocol or any study that is submitted to CMS for approval.”
CMS Administrator Chiquita Brooks-LaSure said in an emailed statement that the agency is “creating a pathway for people with Medicare to quickly access drugs the FDA determines have shown a clinical benefit.” She added that the pathway “encourages manufacturers and trial administrators to ensure that the clinical trials recruit racially diverse participants.”
Trial Center Access
Biogen’s Aduhelm won FDA accelerated approval in June 2021 even though a panel of outside scientific advisers recommended against it, citing mixed evidence on the drug’s efficacy. Researchers have identified several potential side effects from the treatment, including headaches, dizziness, falls, and brain bleeds.
The CMS’s coverage determination would apply to all antibody-based drugs that target amyloid plaques—the sheets of abnormal protein that accumulate in patients’ brains—in qualified clinical trials. The agency said manufacturers and study sponsors conducting approved trials must submit plans showing how they intend to include patients representative of the Medicare population, accounting for geographic, racial, and ethnic diversity.
Patient groups had expressed concerns that the initial determination’s hospital outpatient center requirement would have restricted access for certain minority and rural populations. While the CMS removed that requirement, policy watchers say larger hospitals and research sites may end up being the only locations with the capacity to conduct these studies.
Approved trials for treatments targeting amyloid must include a “multidisciplinary dementia team and optimal medical management,” and be carried out at study sites “with clinical expertise and infrastructure to provide treatments consistent with the safety monitoring outlined in the FDA-approved label,” according to the final coverage decision.
“It sounds like that is just a lot of words said in a different way to mean hospital outpatient setting,” said Sue Peschin, president and CEO of the Alliance for Aging Research.
Ramachandran, who has repeatedly expressed concerns with Aduhelm’s accelerated approval, defended the importance of having requirements for study sites with clinical expertise and treatment infrastructure in place. “We want to be able to collect robust data on whether or not the drug actually works and is safe for patients,” she said.
She added, though, that combating traditional access barriers to these research centers is critical to getting more adequate and representative findings.
Trial sponsors need to ensure participants “are aware of these trials and can access them or be provided means to make accessibility easier to medical centers,” Esther Krofah, executive director of FasterCures and the Center for Public Health at the Milken Institute, said in an email.
Reimbursements to trial participants for costs associated with travel, child care, and time taken off from work can help attract a more diverse group of trial participants, Ramachandran said. “That would be at least like a short-term fix,” until the CMS is “able to make investments in terms of increasing the infrastructure for rural hospitals or rural clinics, or other places where they could be able to dispense the drug.”
Patient advocacy groups like the Alliance for Aging Research and UsAgainstAlzheimer’s, which both receive funding from Biogen, urged the CMS to remove trial criteria that would have restricted access for those with Down syndrome or other medical conditions that are “likely to increase significant adverse events” after taking the drug.
But policy watchers argue that the Medicare agency should explicitly notify researchers that they must carry out safety studies on Alzheimer’s patients with Down syndrome and from minority groups before they are included in larger-scale clinical trials. Safety is an important factor measured in Phase 1 clinical trials, before studying a treatment’s efficacy, side effects, and adverse reactions.
The CMS should inform sponsors of amyloid-targeting treatments with clinical trials already past Phase 1 if they now have to go back and do safety studies on patients who weren’t previously included, Peschin said.
“There’s just going to be kind of confusion over what type of evidence for that particular community is going to meet CMS’ standard,” she said.
At least half of people with Down syndrome will develop dementia due to Alzheimer’s disease as they get older, according to estimates from the National Institute on Aging. That’s because Down syndrome patients contain an extra copy of chromosome 21, which carries a gene that produces the amyloid.
Safety data is just as essential for other segments of the Alzheimer’s patient population, including Black and Hispanic Americans, Ramachandran said.
In a letter to the CMS, she noted that the initial trials on Aduhelm only included 0.6% of participants who identify as Black, and 3% Hispanic. Approximately 18.6% of Black Americans and 14% of Hispanic citizens age 65 and older have Alzheimer’s disease, compared with 10% of White adults in this age group, according to advocacy group UsAgainstAlzheimer’s.
Biogen announced in March that it would be recruiting at least 18% of patients in the U.S. from Black and Latino communities in its Phase 4 confirmatory trial for Aduhelm.
The CMS decision also allows researchers to conduct prospective comparative studies using patient registries—or databases collecting clinical or medical data— in lieu of randomized controlled trials if a treatment is approved by the FDA, or if the drug shows clinical benefits prior to approval.
Patient registries for certain amyloid-targeting drugs could be effective for analyzing a large swath of patient data, but only if they are representative of the true national Alzheimer population, policy analysts say.
“While the idea of a patient registry sounds good on paper, they have a record of exacerbating health disparities,” Peschin said. “It takes patients a long time for the evaluation and to kind of fill out everything in the registry, and that’s not available to everybody depending on their lifestyle and their resources.”
The best way for the CMS to ensure adequate representation is to work with the FDA to establish specific diversity benchmarks for patient registries as conditions for Medicare coverage, Ramachandran said, adding that explicit requirements could better incentivize researchers to incorporate these diversity principles early in trial development.
“When there’s only just encouragement, we only hear promises really from companies that they will actually enroll patients adequately into these trials,” she said.