The FDA’s controversial approval of Aduhelm, the drug intended to treat Alzheimer’s Disease, has resulted in resignations from their advisory committee and now investigations, both internal and Congressional. The FDA and editors of JAMA Internal Medicine are speaking out before the investigational circus comes to town.
The FDA perspective
If you need to get up to speed on the controversy, look here. The approval was based on three studies.
- 197 patients in a double-blind cohort study looking at increasing doses of aducanumab (Aduhlem). There was a dose-related improvement in both patients’ clinical improvement and reduction in visible Aβplaque (the anatomic biomarker of Alzheimer’s Disease found within the brain). These findings were statistically significant only at the highest dose, 10mg/kg monthly.
- Two Phase III studies, involving roughly 1650 patients each, both double-blind, placebo-controlled. The first of these showed the same clinical improvement as the previous smaller study and improvement in tests that use other measures of cognitive function, memory, and activities of daily living. The authors write that the “P values …were impressively significant.” The second of the two phase III studies did not replicate the first.
Both Phase III studies were stopped for “futility” – because statistically, they would have been unable to achieve their objectives – in this instance, showing a clinical benefit in Alzheimer’s Disease patients. The measure of futility was determined before these studies began to reduce bias once the investigations were underway.
“We [FDA] concluded, as did the FDA’s Peripheral and Central Nervous System Advisory Committee, that the clinical trial data were not adequate on their own to convincingly demonstrate a clinical benefit in reducing clinical decline in patients with Alzheimer disease.”
The “accelerated approval” regulatory path offered an opportunity to provide the medication to patients despite scientific uncertainty. Aduhelm easily met two of the four criteria, a treatment for a disease with unmet medical need and a demonstration of efficacy against a surrogate endpoint, the Aβplaque. The third criteria asks, can we expect the medication “to provide meaningful clinical advantage over available therapy?” There is no alternative, and hope springs eternal – this is a moot point. Finally, and critically, is the medication’s surrogate end, the reduction in Aβplaque, “reasonably likely” to predict a clinical benefit – in other words, do we believe the decline in plaque will positively affect the course of the disease.
"Reasonably likely" is the wording of the regulation, but as the authors take pains to point out – the statute doesn’t require certainty. There is little doubt that Aduhelm reduces plaque; the uncertainty, scientifically, is whether plaque is the cause or just an effect. In the end, the FDA factored in the wishes of the patients and their families, critical stakeholders in this decision.
“Many [families] made it clear that they are willing to accept the tradeoff of some uncertainty about clinical benefit in exchange for earlier access to a potentially effective drug, which is the exact premise and intent of accelerated approval.”
The FDA approval became even more controversial because the clinical evidence of benefit only accrued to those early in the course of the disease, and they placed no limits or guidance on whom might be given the drug. We might argue about restricting use to specific patient groups, but the reality is that physicians can prescribe a medication off-label; no one checks whether the drug is being prescribed for an approved purpose (Echoes of any of the anti-viral off label therapies for COVID-19).
There is a critical caveat to off-label use, to any use actually. Who foots the bill? With a price tag of $56,000 annually, Aduhelm is very expensive. Few families will pick up the tab, and many articles have explained that the cost would bankrupt Medicare. But while Medicare routinely pays for FDA-approved medications, those decisions are not a given. Medicare must make a coverage decision.
Medicare’s National Coverage Decision
This is not Medicare’s first rodeo when approving and paying for treatments – coverage. It has its own advisory committees to determine which group of patients and treatments may be eligible. For example, one intervention for repairing the carotid artery, carotid stenting, was restricted to patients who were too “high risk” for conventional surgery. A physician might still perform carotid stenting in a low-risk patient, but Medicare would not cover any of the expenses; they would fall on the patient. And it is essential to realize that Medicare is the “bell weather standard”; few private insurers cover treatments that Medicare does not – private coverage follows Medicare, not the other way around.
Given the economic consequences of Aduhelm’s approval, it is exceedingly unlikely that Medicare will not place restrictions on its use. The program has two options. First, it could ask for additional evaluation. There is a Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) for just that purpose, and it is often called to weigh in on coverage decisions.
Alternatively, Medicare might restrict the use of Aduhelm to beneficiaries participating in ongoing clinical trials. That shifts the cost of research to taxpayers; Biogen will continue to be paid while the studies are conducted. The authors, both editors of JAMA Internal Medicine, have been members of Medicare’s payment advisor board and, perhaps unsurprisingly, suggested referring the decision to MEDCAC. I am not sure that a second committee will arrive at a different conclusion.
They also recommended, and I would agree, that coverage should be limited to those patients with early Alzheimer’s Disease and those involved in a clinical trial. I believe that those restrictions are the best tradeoff. It restricts use to those who may benefit, and it collects more data to help us determine if Aduhelm is effective. This approach, unfortunately, shifts the cost of that research to taxpayers.
Still, financing a well-designed study will be far less costly than approving the medication with fewer restrictions, and would demonstrate our empathy for those patients and families afflicted by a progressive neurologic disease, a disease that robs us of our “selfhood” while leaving our corporal presence as a reminder of who we once were.
Sources: Approval of Aducanumab for Alzheimer Disease— the FDA’s Perspective JAMA Internal Medicine DOI: 10.1001/jamainternmed.2021.4607
Medicare and the Shocking US Food and Drug Administration Approval of Aducanumab JAMA Internal Medicine DOI: 10.1001/jamainternmed.2021.4610