The National Institutes of Health (NIH) is the world's largest public funder of medical research.
For decades, NIH funding has improved scientific understanding of diseases like cancer and HIV/AIDS -- and led to lifesaving and life-enhancing discoveries. More recently, thanks to targeted Congressional increases for Alzheimer's since 2015, the NIH's spending on research into the disease has risen nearly six-fold, reaching $3.5 billion in 2023.
The growth in federal research investment has been game changing for the National Institute on Aging (NIA), which manages more than 90 percent of NIH's Alzheimer's funding. When positive clinical trial results on lecanemab (sold under the brand name Leqembi) were released over a year ago, NIA Director Dr. Richard Hodes claimed partial credit for the basic research behind it, stating, "Although NIA did not fund the lecanemab study, our decades of research paved the way for this Alzheimer's trial that notably met its primary and secondary endpoints."
In early January 2023, the FDA granted accelerated approval to lecanemab, after published data in the New England Journal of Medicine showed the monoclonal antibody therapy slowed progression of early Alzheimer's by 27 percent over an 18-month trial. In his updated statement, Dr. Hodes explained, "The results showed lecanemab produced a clear yet modest clinical benefit in people who were in the early stages of Alzheimer's."
Six months later, the FDA granted traditional approval to lecanemab after another positive clinical trial confirmed its medical benefit to people living with early Alzheimer's. Lecanemab had met the FDA's standard of review, and its effectiveness was further validated by a unanimous vote of the FDA's Advisory Committee.
It was the first-ever FDA traditional approval of a disease-modifying therapy for Alzheimer's disease. Dr. Hodes celebrated the moment, stating, "This occasion -- combined with ongoing scientific pursuits and advances in Alzheimer's and related dementia research -- helps mark decades of scientific progress toward effectively treating and preventing these diseases."
Dr. Hodes' optimism is justified. But we are concerned about whether a $300 million Alzheimer's real-world data (RWD) platform, that requires substantial NIA staff involvement, is being funded to help the Medicare program ration beneficiary access.
The first sign came in April 2022, when officials from the Centers for Medicare & Medicaid Services (CMS) announced a restrictive "coverage with evidence development" (CED) Medicare policy for FDA-approved Alzheimer's monoclonal antibody therapies. Under a CED policy, Medicare will only cover a treatment or procedure when eligible health care providers and beneficiaries volunteer to participate in CMS-approved clinical studies. Beneficiaries who cannot access the clinical study sites or are reluctant to be required to enroll in a clinical study to receive access are left without coverage. Typically, CED studies are run and funded by one or more non-governmental organizations. However, Medicare Alzheimer’s CED policy uniquely references NIH-supported studies in all of its sections on coverage.
The decision was unprecedented, and not only for its mention of NIH-supported studies. Never before had CMS applied CED to an on-label use of FDA-approved medications. There are strong signals that this won't be the last time, as gene and stem cell therapies for cancer and rare diseases continue to progress through clinical development.
Once CMS locks an FDA-approved treatment in CED, it's extraordinarily difficult to reverse the decision. A published analysis found that several of the current 22 CEDs have been ongoing for more than 15 years. And a report on CED called Façade of Evidence: How Medicare's Coverage with Evidence Development Rations Care and Exacerbates Inequity, issued by the Alliance for Aging Research, found that Medicare beneficiaries of color and those living in rural areas are more likely to be denied access under CEDs because the rigid conditions of coverage primarily direct care to urban medical centers in wealthier areas.
Worse, CMS has exploited inequitable participation in existing CED clinical studies as justification to keep CED going -- creating an endless loop of inequity and restricted access.
The next concerning sign appeared in May 2022, when the NIA held the workshop, "Gaps and Opportunities for Real-World Data." At the workshop, the CMS Chief Strategy Officer for Coverage and Deputy Medical Director spoke about the importance of studies that are “fit-for-purpose,” a presumed euphemism for CED. Five months later, CMS leaders published their vision on markedly expanding use of CED for FDA-approved breakthrough medical devices and therapeutics.
The next sign was more like a flashing neon billboard. In June 2022, in a funding bill that included appropriations for the NIA's RWD platform, Congress encouraged the NIA to support "a patient-based national registry of regulatory grade, longitudinal evidence for patients receiving any FDA-approved disease modifying therapies for Alzheimer’s disease in real-world clinical practice" [emphasis added]. This was quickly followed by approval of the award concept in September 2022 and the NIA's March 2023 Request for Applications (RFA).
An April 2023 Reuters article covering the NIA's grant announcement interviewed Dr. Nina Silverberg, director of the NIA's Alzheimer's Disease Research Centers program. In response to the reporter's inquiry about whether the RWD platform would be used to track Alzheimer's patients after they receive treatments such as lecanemab, Dr. Silverberg said, "We didn't design it for that purpose, but it might be possible [to use it for that purpose]." The article notes that CMS did not respond to a request for comment.
When the FDA granted lecanemab traditional approval in early July 2023, Medicare officials proclaimed they would provide broader coverage for beneficiaries who have "a physician who participates in a qualifying registry with an appropriate clinical team and follow-up care," which are requirements but no specific definitions for them are provided. The CMS CED data submission portal consists of a step-by-step form where each next step is unknown, leaving providers wondering whether they will be permitted to proceed, even as they enter sensitive patient data.
The July 2023 CMS announcement included a first-ever, agency-run CED study, which estimates 8,680 patients for enrollment, and allows other studies. So far, only two additional registry-based clinical studies are listed: one is through Beth Israel Deaconess Medical Center, which estimates 500 patients for enrollment; and the other is through Emory University, which estimates 735 patients.
Next, in late July, a group of health policy analysts sent a sign-on letter to CMS calling for one publicly available, population-level CED data registry, with additional elements strikingly similar to those required in the NIA RWD platform RFA. Several of the letter signers leveraged previous roles as former MEDCAC chairs, former FDA employees, former HHS employees, and former Congressional staff. Policymakers ought to take note, especially if one or more of the signers or their affiliated institutions end up being awarded the NIA grant.
It is unclear exactly how many Leqembi Medicare claims CMS has processed or paid since it started accepting them in late July. An August 30 article in the Boston Globe outlined workforce and capacity constraints due to CMS CED registry implementation requirements. We hope that policymakers ask CMS for a claims report at the sixth-month mark in January 2024.
There are timing and access concerns at play if CMS plans to approve the NIA's RWD platform as its patient registry for lecanemab and other monoclonal antibodies, such as donanemab, which could receive FDA traditional approval by the first quarter of 2024.
According to the NIA's RFA, the earliest start date is April 2024 for the grantee to work on the project, a full two years after CMS' original Medicare coverage determination for this class of therapies. The registry is not required to be open to submission by researchers until two years from that, by April 2026, with broad access to submitters a year later in 2027. If CMS is counting on the NIA registry to be their source for answering CED questions it will take years to start collecting data, with patients facing restrictions on coverage due to CED for a longer period of time due to the extended timeline.
We are very supportive of real-world data collection, and of the NIA working cooperatively with whichever group of academic centers or advocacy groups win the award. However, the NIA Alzheimer's RWD platform -- while worthwhile as a broad research effort -- should in no way be tied to Medicare CED coverage policy.
Leading patient advocacy groups like the Alzheimer's Association, which Reuters reports is applying for the NIA RWD platform grant award, ought to oppose tying the NIA RWD platform to Medicare CED data collection. The association has spent the last year publicly advocating for CMS to reverse its CED coverage policy and provide "full and unrestricted coverage" to FDA-approved Alzheimer's treatments.
The NIA has paved the way for a new generation of Alzheimer's treatments through groundbreaking research supported by Congress. But for the NIA to keep pushing new frontiers, it needs to ensure its real-world, data-collection platform isn't used as a CMS utilization management tool to ration patient access.
Sue Peschin, MHS, is president and CEO at the Alliance for Aging Research in Washington, D.C.
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