By Beatrice Brown
On June 7, 2021, the U.S. Food and Drug Administration (FDA) announced the accelerated approval of aducanumab (Aduhelm), a biologic manufactured by Biogen for the treatment of Alzheimer’s disease.
The FDA’s decision, which went against the near-unanimous opinion of its own advisory committee following its meeting in November 2020, has been embroiled in controversy over whether the available evidence demonstrated benefits that outweigh the risks of the drug. Namely, questions remain whether: 1) the conflicting evidence from the two pivotal trials is sufficient to suggest clinical benefit worthy of approval; and 2) the surrogate measure used to justify its accelerated approval is actually correlated with clinical benefit.
The FDA reviewed data from two pivotal trials — ENGAGE and EMERGE — both of which were terminated about halfway through on the basis of futility. However, on the basis of additional data that came in after the termination point, Biogen claims that EMERGE showed a 22% relative reduction in the clinical dementia score in the high dose treatment group. (ENGAGE still failed to meet its primary endpoint.)
Post-hoc analyses were conducted by Biogen to explain the difference in findings, but, while useful for creating future hypotheses, post-hoc analyses are not sufficient for deciding the benefit of a drug and forming the basis of FDA approval.
The FDA ultimately approved aducanumab through its Accelerated Approval pathway on the basis of a surrogate measure: the effect of the drug in reducing levels of amyloid beta plaque. Although it has been hypothesized that amyloid reduction may be correlated with slowing the symptoms of dementia, substantial clinical trial data from the past two decades have cast doubt on this idea. And, though the FDA will require Phase 4 confirmatory trials as a condition of Accelerated Approval, these take years to complete and are often delayed.
Ethical Issues in the Decision
Several considerations surrounding the approval of aducanumab suggest that the FDA’s decision contradicts the agency’s goals and raise ethical issues about how the decision was made.
FDA’s approval of aducanumab may run against the bioethical principles of beneficence and non-maleficence.
The data from the two pivotal trials for aducanumab identified definitive harms to the drug. The data demonstrated that amyloid-related imaging abnormalities (ARIA) affecting the brain, including vasogenic brain edema (ARIA-E), occurred in higher rates among those treated with aducanumab versus those who received placebo (35% vs. 3% in the high-dose groups). Although ARIA-E can be asymptomatic and rather harmless when treated early, imaging and dosing management is critical — which may be difficult to implement in routine practice — and the brain swelling and bleeding that result can prove dangerous. And while we are aware of known safety concerns, we are uncertain of the magnitude of benefit that patients will derive.
Complicating this calculus is the FDA approved the drug for all patients with Alzheimer’s, rather than restricting the recommended patient population to those studied within the clinical trials (those with early Alzheimer’s, defined as those with mild cognitive impairment or mild dementia due to Alzheimer’s). This means that patients with advanced Alzheimer’s disease could be prescribed the drug despite the possibility that these patients may derive even less benefit and face even more risk than those in clinical trials.
While it is certainly important to prioritize drugs that may improve the condition of those with Alzheimer’s disease, since there are no good treatments for it, FDA’s approval of aducanumab may result in fewer drugs for Alzheimer’s disease being successfully developed and approved.
Once a drug for a given condition is approved, it becomes more complicated to enroll patients in subsequent clinical trials testing the efficacy and safety of new experimental therapies. Rather than face the risk of being randomized to the placebo group, patients are likely to opt for the approved drug on the market. Future therapies may focus on a different target that would have a greater benefit and more certain effect than amyloid beta plaque reduction, yet clinical trials to bring such a drug to market may be hampered by the availability of aducanumab.
Although FDA is requiring post-marketing studies to confirm aducanumab’s benefit, such trials often take years, in part because of difficulty reaching target enrollment. Previous experience also shows that the FDA does not consistently remove accelerated approval drugs from the market even if the so-called confirmatory trials are negative. If the drug is not pulled from the market following negative post-marketing studies, irreparable harm may be done to the public’s trust in the FDA due to approving what was supposed to be a blockbuster drug in the face of uncertain evidence, which would have downstream effects on all of patient care.
Finally, although this is outside the FDA’s purview, Biogen announced that the price of aducanumab will be $56,000 for a year of treatment. By contrast, a recent analysis by the Institute for Clinical and Economic Review determined that for aducanumab to be cost-effective, a reasonable price per year could be around $8,000. Aducanumab’s exorbitant price will have two concerning effects. First, it will greatly increase spending for Medicare Part B, since many patients using the drug will be covered by Medicare. This price tag will likely make aducanumab Medicare Part B’s most expensive medication over the course of the next few years. Second, those with Medicare who do not also qualify for Medicaid and those with private insurance will likely have to pay out-of-pocket for at least a portion of the cost. It is possible that insurance companies will not cover the drug given its uncertain benefit-risk profile. And when private companies do decide to cover the drug, premiums will increase for everyone on those plans.
In all, some patients will not be able to afford the drug, despite their desire for it, and other patients’ premiums will go up as a result of wide use of a drug for which there is currently no clear evidence of efficacy. There is also likely to be a demand that outpaces supply in terms of what is needed to support patients who receive the drug, like machines for imaging requirements and infusion chairs — all of which add more costs to the system.
Trust in the FDA is already fragile, and has been stretched further by the FDA’s decision to approve aducanumab. To regain the public’s trust, the FDA must uphold a key fundamental purpose: ensuring that data supporting new drugs are collected from well-designed trials and interpreted fairly and consistently with broad scientific opinion.