FDA says Aduhelm approval fit accelerated pathway to a T, as families begged for a shot to halt Alzheimer's decline

Had the FDA delayed the approval of Biogen's Aduhelm, Alzheimer's disease patients and their families would have been left behind as the regulatory machine churned slowly toward a decision, agency officials argue in a new defense of the decision. 

In a scientific journal posting, FDA leaders acknowledged the complexity of the data surrounding the Alzheimer’s drug and defended the agency’s use of the accelerated approval pathway.

The FDA faces criticism from all sides over its decision to approve the therapy that has yet to be proven effective in clinical trials. The agency endorsed the drug based on a surrogate endpoint that suggests it may provide clinical benefit, but controlled studies have so far produced contradictory results.

Usually for the FDA, mum’s the word after a drug is approved. Sometimes, for high-profile or new drugs, the agency issues a press release describing the action and the benefit to patients. But in the case of Aduhelm, the agency has been forced to defend against a wave of criticism by issuing statements and releasing behind-the-scenes documents.

“In weighing the benefits vs the risks of aducanumab, we considered that Alzheimer disease leads to irreversible loss of memory, cognition, and ability to function in daily activities,” FDA officials Billy Dunn, M.D., Peter Stein, M.D., and Patrizia Cavazzoni, M.D., wrote in a Tuesday post for the American Medical Association’s JAMA Network.

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The officials highlighted the unmet need for treatments that can alter the course of Alzheimer's disease rather than treating symptoms. No drugs have been approved for the condition in nearly two decades.

Aduhlem scored its FDA nod through the agency's accelerated approval lane, allowing Biogen to market the drug while it conducts research to confirm the benefit. The company has nine years to do that work, and some experts have questioned how the trial will be possible when the therapy is already on the market.

"Aducanumab fits into this regulatory paradigm," the officials explained, noting that completed studies showed the drug can reduce the amyloid plaques in the brain. While the drug lacks evidence to demonstrate it can improve Alzheimer's symptoms, this reduction is thought to alter the course of the disease, the FDA officials said.  

Biogen and its partner Eisai presented data to support the approval from three clinical trials, two of which failed. The available evidence was "complicated and in some respects contradictory," the agency experts acknowledged.

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But the data still provided a “strong suggestion” that Aduhelm can reduce the plaques and provide a clinical benefit, they argued.

During the review process, the FDA heard from families who wanted a treatment that could slow or halt the devastating consequences of Alzheimer’s disease, the officials said.

“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,” the officials said. “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.”

Meanwhile, another major criticism of the FDA’s decision is that the drug—which may or may not provide a small benefit to patients—is not a harmless placebo. A pooled analysis of two phase 3 studies showed that 41% of patients who took it later had an abnormality in MRI imaging, which means swelling or bleeding in the brain. This is compared to just 10% of placebo patients who had the same concerns raised in imaging. These adverse events were asymptomatic in 76% of cases and only 0.3% were reported as serious.

RELATED: New FDA papers reveal internal split over Biogen's Aduhelm approval

“The safety profile of aducanumab was well characterized in the development program and did not preclude approval,” the officials said.

In documents released in late June, the FDA revealed a rift among staffers over the drug’s approval. Stein, who attached his name to the most recent post and serves as director of the FDA’s Office of New Drugs, admitted that the approval of Aduhelm “veers” from the typical accelerated review pathway. Previously, these approvals were for therapies that would take years to generate evidence of effect, allowing patients to take them in the meantime.

With Aduhelm, Biogen was unable to prove clinical benefit and failed to meet the bar for a traditional approval.

Since the approval, Congress has launched a probe into the cozy relationship between the FDA and Biogen during the approval process. The agency’s own interim commissioner, Janet Woodcock, M.D., has called for an investigation from the Office of Inspector General.