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With incomplete data to guide aducanumab (Aduhelm) prescribing, neurologists face ethical challenges and will be guided best by established principles to counsel people with Alzheimer's disease and their families, said a new position statement from the American Academy of Neurology (AAN).

"While neurologists have often depended upon the U.S. Food and Drug Administration's approval as a sign of a medication's safety and effectiveness, recent decisions indicate a lowering of the standards of scientific evidence used for drug approvals, which will require clinicians to scrutinize approved medications more carefully," wrote Winston Chiong, MD, PhD, of the University of California San Francisco, and co-authors in .

More pointedly, they specified: "One recent example is the approval of aducanumab, a monoclonal antibody directed at β-amyloid aggregates implicated in the pathogenesis of Alzheimer's disease."

Aducanumab was approved based on two phase III studies, EMERGE and ENGAGE, of people with mild cognitive impairment or very early Alzheimer's dementia. Both trials were stopped for futility. Subsequent analysis showed a small benefit in reduced clinical decline in one study but not the other.

"The clinical importance of the small statistical benefit in one trial for daily function is unclear," Chiong and co-authors noted in their AAN position statement.

The FDA used the accelerated approval pathway to approve aducanumab, basing its decision on the drug's effects on brain β-amyloid levels as a surrogate marker of likely clinical benefit.

"While surrogate markers may be useful when circumstances preclude measurement of clinical outcomes, insufficient reason was given by the agency for appealing to a surrogate marker for a case in which clinical outcomes were measured but insufficient for approval," the position statement authors observed. "Such additional explanation is crucial because the link between brain β-amyloid reduction and clinically meaningful outcomes in patients with symptomatic Alzheimer's disease remains unclear."

Ethical principles of beneficence indicate there are insufficient grounds to warrant offering aducanumab to patients with moderate or advanced Alzheimer's dementia or to patients without biomarker evidence of brain β-amyloid, they noted. Neurologists should inform patients that aducanumab will not cure Alzheimer's disease or restore cognitive function and should be aware of potential conflicts of interest that may compromise beneficence.

Amyloid-related imaging abnormalities (ARIA) -- brain edema, brain hemorrhage, or a combination of the two -- occurred in more than one-third of people receiving the approved dose of aducanumab, with higher risk in APOE4 allele carriers. In most cases, symptoms or imaging findings resolved or stabilized by stopping aducanumab temporarily, but one in 14 patients on full-dose treatment was removed from clinical trials permanently due to persistent ARIA. Monitoring for ARIA requires at least two MRIs after treatment is started, according to the aducanumab label.

The price of aducanumab treatment, including the cost of the drug, infusion charges, and MRIs, may cause financial harm to patients and families, the statement cautioned.

Ethical principles of nonmaleficence dictate that neurologists must communicate potential adverse effects like ARIA and its monitoring burdens, Chiong and co-authors said. "Neurologists have a responsibility to inform patients and families that the full costs of treatment may not be covered and about the financial ramifications of decisions to pursue treatment," they wrote.

Fewer than 1% of participants enrolled in the aducanumab trials were Black or Indigenous people, and fewer than 3% were Hispanic. "Informed consent conversations with patients of populations underrepresented in clinical trials should include disclosure about the absence of safety and efficacy data in these groups," Chiong and co-authors stated.

And while patients will undoubtedly ask about a drug that has garnered so much media attention, the statement added, neurologists should keep in mind that respect for patient autonomy is best demonstrated through shared decision-making, with clinicians playing an active role in interpreting patients' values and recommending care that promotes those values.

"Respect for patient autonomy does not require clinicians to offer treatments for which the potential harms, in their judgment, outweigh the anticipated benefits," the position statement authors wrote.

"It is understandable why a new drug for Alzheimer's disease generates so much interest, because while its approval has been controversial, it still offers a glimmer of hope to patients and their families," said AAN president Orly Avitzur, MD, MBA.

"By using ethical principles to create this position statement, the American Academy of Neurology aims to help neurologists and other physicians transparently counsel patients and their families with a goal of providing the highest quality patient-centered care."

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