Leaders of the US Food and Drug Administration (FDA) are defending the approval of the controversial Alzheimer’s disease (AD) drug aducanumab (Aduhelm), describing the decision as “appropriate and warranted.”
In a viewpoint article published online July 13 in JAMA Internal Medicine, Billy Dunn, MD, Peter Stein, MD, and Patrizia Cavazzoni, MD, leaders of the Center for Drug Evaluation and Research, outline the complexities of the data supporting the new drug application and the rationale for approving the drug against the advice of the FDA’s own advisory panel.
However, other experts are pushing back, calling for reform of the FDA’s approval process and pointing out that aducanumab’s approval could well be a disaster for Medicare.
As reported by Medscape Medical News, early in the drug’s path to approval, the FDA’s Peripheral and Central Nervous System Advisory Committee rejected aducanumab because the clinical trial data did not convincingly demonstrate a clinical benefit in reducing cognitive decline.
This posed a challenge for FDA. The available evidence was “strongly suggestive of a benefit from aducanumab but was complicated and in some respects contradictory,” Dunn and colleagues acknowledge.
Such situations are addressed in the accelerated approval pathway, by which the FDA has authority to approve a drug like aducanumab, they note.
“Accelerated approval is intended to provide earlier access to drugs for serious diseases when there is residual uncertainty at the time of approval regarding the drug’s ultimate clinical benefit,” the authors write.
Accelerated approval is permitted when four criteria are met:
The drug must be for treatment of a serious disease with unmet medical needs.
The drug must be expected to provide meaningful clinical advantage over available therapy.
There must be a demonstration of an effect of the drug on a surrogate endpoint (typically, one that reflects the underlying pathology of the disease).
There must be a determination that it is reasonably likely that the effect on the surrogate endpoint predicts clinical benefit of the drug.
Aducanumab fits into this regulatory paradigm, Dunn and colleagues note.
They point out that AD is a serious disease for which there are only symptomatic treatments that do not delay cognitive decline. In addition, they assert that by targeting a key underlying pathologic process, accumulation of amyloid-beta, the drug is expected to provide meaningful benefit over available therapy.
In both phase 3 trials and an earlier-phase clinical trial, aducanumab clearly and convincingly reduced amyloid-beta plaque ― a key pathologic hallmark and a defining characteristic of the disease, they note.
In weighing the benefits against the risks of aducanumab, Dunn, Stein, and Cavazzoni state that the FDA considered that AD leads to irreversible loss of memory, cognition, and the ability to function in daily life.
The FDA also heard from patients and their families about the “devastating toll” the disease has taken and their desire for a treatment to stop or delay functional losses.
“Many made it clear that they are willing to accept the trade-off 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. If instead, approval had been delayed, the loss of brain function in these patients over this time—which might have been lessened by earlier initiation of treatment—would not be regained,” Dunn and colleagues write.
Call for Approval Process Reform
The approval of aducanumab shows that the accelerated approval pathway needs to be reformed, write the authors of a companion viewpoint article in the same issue JAMA Internal Medicine.
The aducanumab decision demonstrates the need for “better consensus regarding the use of biomarkers in any type of drug approval, including how biomarkers are chosen and what features allow them to serve as the basis for accelerated or regular approval,” write Bishal Gyawali, MD, PhD, Queen’s University, Kingston, Ontario, Canada, and co-authors.
“The current practice of accepting similar surrogate markers for accelerated approval as for confirmation of clinical benefit for regular approval should be curtailed,” they write.
For the public and physicians to trust the accelerated approval pathway and the clinical value of drugs that have received accelerated approval, “reforms as well as the timely completion of post approval trials are needed.
“The demonstration of clinical benefit should be based on clinical end points, and the approved indication should be promptly and automatically withdrawn if the confirmatory trial is negative,” Gyawali and colleagues say.
A “9/11″ Moment” for Medicare
The co-authors of a separate viewpoint article say the decision to approve aducanumab poses a problem for Medicare.
Aducanumab, which costs $56,000 per patient per year and needs to be taken indefinitely, could very well threaten the financial viability of the program, write Francis Crosson, MD, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California, Kenneth Covinsky, MD, associate editor, JAMA Internal Medicine, and Rita Redberg, MD, editor, JAMA Internal Medicine.
“Meanwhile, there are effective care management programs available for persons with dementia that have been shown to improve quality of life at a fraction of the cost of aducanumab,” they write.
“The FDA’s shocking and nearly unprecedented decision to override its own expert panel and approve aducanumab for wide use in patients with Alzheimer disease may prove to be a ‘9/11 moment’ for Medicare,” Crosson, Covinsky, and Redberg note.
“That is, there may be permanent changes that dramatically alter the program, for better or for worse. Either Medicare Part B expenditures are on a path to skyrocket in the future, especially if marginally effective drugs are introduced at very high costs, or Congress could seriously consider and enact legislation to lower the costs of prescription drugs,” they point out.
Disclosures for all authors are listed with the original articles.