One of my mentors, Dr Robert N. Butler, conducted research at The National Institutes of Health (NIH) in the 1950s that established that “senility” was not an inevitable consequence of aging, but was the result of disease. Later, as the founding director of the National Institute of Aging, he helped to make Alzheimer’s disease research a national priority. In the decades that followed, researchers have added to the relevant bench science and explored the economic and social consequences of Alzheimer’s disease and other forms of dementia. Before his death in 2010, Dr Butler argued that the twenty-first century should be the “century of the brain,” and he emphasized the devastating consequences of Alzheimer’s disease and other forms of dementia for patients, families, and society.
During the past several decades, the US Congress has authorized billions of dollars for Alzheimer’s disease research, but this has not yet led to a major breakthrough in the treatment. It is therefore understandable why there was a great deal of excitement about a new drug being developed by Biogen for the treatment of Alzheimer’s disease, aducanumab (Aduhelm). Yet, when the drug was approved under the US Food and Drug Administration’s (FDA’s) accelerated approval pathway in June 2021, it generated more controversy than celebration. The FDA’s own advisory committee voiced strong objections to Adhuhelm’s approval and, after the FDA announced its decision, three members of the committee resigned in protest. Dr Aaron Kesseheim, one of the members, called the approval of Aduhelm “probably the worst drug approval decision in recent US history.”
Why did the approval of a drug designed to treat Alzheimer’s generate so much disagreement and controversy?
First, there were significant concerns about the amount and quality of evidence the FDA used to make its decision. Among other things, the FDA allowed Biogen to skip the Phase 2 trial, so there was limited evidence about dosing going into the Phase 3 trial. Beyond that, the results of the Phase 3 trials were mixed and critics do not believe that they provided sufficient evidence about benefits to justify approval.
A second issue was whether the definition of “benefit” adopted by Biogen and the FDA was sufficient. As with many clinical trials during the past few decades, Aduhelm was approved based on evidence about changes to a surrogate measure, rather than a clinical endpoint, like improvement in memory. In the case of Aduhelm, the FDA relied heavily on measures of amyloid-beta plaque in the brain as the surrogate outcome measure. This is controversial because a growing number of scientists have questioned whether amyloid-beta plaque, which is associated with Alzheimer’s, causes the disease.
Third, critics argued that the FDA failed to give appropriate weight to the side effects of the drug, which include headaches, delirium, falls, and swelling or bleeding in the brain. Furthermore, the use of Aduhelm requires patients to undergo regular MRIs, which led to concerns about fair access to the treatment.
In the months since the initial FDA decision, several health insurance companies have decided that they will not cover Aduhelm. After conducting a “coverage with evidence” determination, the Center for Medicare and Medicaid Services (CMS) concluded that it would only cover the drug in the context of clinical trials. This is consistent with the decision CMS made almost 10 years ago, in 2013, about whether to cover PET scans designed to detect the presence of amyloid-beta plaque in the living brain. As in its Aduhelm decision, CMS decided that FDA approval was not sufficient to justify coverage by Medicare for routine treatment. In the 2013 case, CMS decided that it needed more information about whether information about the presence of amyloid-beta plaque would change clinical treatment. In the case of Aduhelm, CMS decided that it needed more information about whether the benefits of the drug outweighed its harms.
The debate over Aduhelm is interesting, but as I argue in my article in Public Policy & Aging Report, this is not an isolated case. For decades, Congress, with encouragement from industry and many patient groups, has pushed the FDA to speed its approval process. The push for faster approval and changing evidentiary standards is often caught up in larger political disputes about the role of regulation and interest group power dynamics. The regulation of emerging technologies will never be a purely scientific matter because it reflects underlying values about the kind of society we hope to create. Studying the Aduhelm case, and others like it, provide insights into how our existing institutions are shaping these choices.