Anti-dementia bias and Medicare regulation of Alzheimer's disease care.

Abstract

The Center for Medicare and Medicaid Services (CMS) asserted a new role as a drug regulator in April 2022. The Food and Drug Administration (FDA) had approved aducanumab (Aduhelm) through accelerated approval based on its reduction of a biomarker of Alzheimer's disease pathology, amyloid positron emission tomography (PET). The FDA has used accelerated approval to approve other drugs without confirmatory data, usually in oncology, and each time, CMS has paid for them. For the first time for any FDA-approved drug, CMS issued a national coverage determination (NCD) for aducanumab using the coverage with evidence development (CED) mechanism to restrict reimbursement to research participants.1 Going a step further, CMS extended the NCD beyond aducanumab to any future drug in the class of anti-amyloid monoclonal antibodies to which aducanumab belongs. At the time, aducanumab clinical efficacy was questionable because of conflicting, truncated, phase 3 trials. However, by including future drugs in its NCD, CMS set up the predictable scenario2 in which a new anti-amyloid antibody would show clear efficacy and yet its coverage would still be restricted by the NCD. In December 2022, the results of the phase 3 trial of lecanemab (Leqembi) were published, showing both amyloid PET clearance and clinical benefit.3 Any reasonable regulatory standard for broad approval and coverage had been met. Asked by the Alzheimer's Association to reconsider its NCD, CMS replied, “there is not yet evidence meeting the criteria for reconsideration.”4 If an 1800-patient trial with positive cognitive and functional endpoints does not meet criteria for even reconsidering coverage denial, then what will? CMS did promise: If the FDA gives lecanemab traditional approval rather than accelerated approval in July 2023, CMS will expand coverage from randomized clinical trial participants to participants in other prospective research studies “on the same day.” But CMS must approve these new prospective studies, and there is no mechanism for registering them; establishing a new regulatory infrastructure may take years. Patients and physicians worry that CMS cannot keep its same-day promise, and a beneficial FDA-approved medication for a terminal disease will sit unused. “Amyloid [β] is associated with normal physiologic processes.” “Immunoglobulin light chains (which cause AL amyloidosis) are associated with normal immunity.” “Amyloid plaques can be detected in cognitively normal older adults.” “Atherosclerosis can be detected in older adults without heart failure.” “The number one risk factor [for AD] is age itself.” “The number one risk factor for kidney cancer is age itself.” “The number one risk factor for prostate cancer is male sex itself.” These statements only seem reasonable for AD because it is not given the full status of a disease, as though the underlying biology of AD is somehow normal. The NCD authors also worry about harms by anti-amyloid therapy to patients who have “early or mild disease and are relatively high functioning.” This portrays a plausibly admirable desire to protect patients without severe memory loss who should be less willing to accept a risky treatment. CMS does not add, “but they will probably decline inexorably to dementia and then death.” The logic is akin to restricting chemotherapy for patients with “cancer that has not yet metastasized and caused debilitating pain and weakness.” CMS, patients, and physicians all correctly worry about side effects, but only CMS paints AD pathology and dementia as natural parts of getting old, unworthy of a new and risky therapy. The bias may be unintentional, but CMS perpetuates a stigma from which patients have long suffered discrimination. The Veterans’ Health Administration (VA) will cover lecanemab without a research restriction, exposing the shaky rationale on which the CMS NCD is based. Unlike CMS, the VA may negotiate discounts. CMS could recognize this distinction and start a candid discussion about drug prices and cost efficiency. Lecanemab could be a catalyst for congressional drug pricing reform. But first CMS must regulate fairly and treat AD patients with equal respect. The authors have nothing to report. The author declares no conflicts of interest. The author receives grant funding from the National Institutes of Health and the Alzheimer's Association. The work in this manuscript received no funding. Author disclosures are available in the supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.