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Biogen’s Next Alzheimer Drug Feeds Push for FDA Approval Revamp

Sept. 30, 2022, 9:45 AM

Promising trial results on Eisai Co. and Biogen Inc.‘s Alzheimer’s drug don’t discount the need for changes to the fast-track approval pathway the FDA is using to review the product, doctors and health policy analysts say.

The companies said this week their experimental lecanemab significantly slowed the progression of Alzheimer’s disease among participants in a global Phase 3 confirmatory trial. They said they plan to use the findings in an application for full approval in the US by March 2023, as they await a decision on accelerated approval.

Lawmakers are pushing for changes to the accelerated approval pathway amid criticisms that many fast-track drugs have remained on the market without completing studies showing a clinical benefit. Analysts say that despite lecanemab’s promise, better oversight of the pathway is critical amid lingering uncertainty around amyloid-targeting drugs and the number of other treatments on the market without a confirmed benefit.

“A promising drug still comes with uncertainty of whether or not it works for our patients,” said Reshma Ramachandran, a Yale School of Medicine family physician and the FDA task force chair for Doctors for America.

“We need safeguards in place for the FDA to require manufacturers fulfill their end of the bargain with accelerated approval,” she said.

Lecanemab, like Biogen’s other drug Aduhelm, targets amyloid plaque in the brain that’s often associated with Alzheimer’s. Alzheimer’s patient advocacy groups said the results provide support for the long-debated theory that the buildup of amyloid is one of the main causes of the disease.

But policy analysts caution that the latest results haven’t yet been released in a peer-reviewed publication or FDA-briefing documents. They say more research is needed to make this conclusion, and that issues with the FDA’s fast-track pathway extend beyond any single treatment under review.

A decision on accelerated approval for lecanemab is expected by Jan. 6, 2023.

‘Huge Grain of Salt’

The accelerated approval program allows faster approval of drugs that treat serious conditions and fill an unmet medical need. To speed the review process, the approvals can be based on surrogate endpoints, or factors like tumor shrinkage that signal a treatment works but don’t show direct clinical benefit the way criteria like an overall survival rate does.

As a condition of accelerated approval, the FDA requires that drug sponsors complete confirmatory trials to “verify the clinical benefit of the drug or demonstrate an effect on irreversible morbidity or mortality.”

The confirmatory trial for lecanemab used clinical cognitive decline as its primary endpoint. Data from earlier trials submitted to FDA for lecanemab’s accelerated approval application used amyloid plaques as a predictor of slowed cognitive decline among Alzheimer’s patients. This surrogate endpoint was also used in trials on Aduhelm (aducanumab).

Aduhelm was granted approval by the FDA through the accelerated approval pathway in 2021 despite recommendations against doing so from an independent panel of advisers.

Biogen and Eisai said in their press release that lecanemab reduced the pace of cognitive decline in people with early Alzheimer’s disease by 27% over 18 months when compared with a placebo.

But this should be viewed “with a huge grain of salt,” Ramachandran said.

“It’s unclear whether a statistically significant decline among those with early stages of Alzheimer’s disease is clinically meaningful,” she said.

The findings are “very encouraging,” but analysts need to ask “whether the statistically significant finding” will be “meaningful to patients and their families, Emily Largent, an assistant professor of medical ethics and health policy at the University of Pennsylvania’s medical school, said.

Ramachandran also said that using amyloid as a surrogate endpoint still has an “unproven association” with a clinical benefit."We have over two dozen studies that have failed to show an association between beta amyloid and clinical improvement of Alzheimer’s disease,” she said.

Ramachandran also expressed concerns over the reports of side effects associated with lecanemab, including brain swelling and bleeding, even though the companies said severe cases were rare.

“As we saw with aducanumab, initially this was presented as not a significant finding, but further details from the FDA briefing documents said otherwise,” she said.

Post-Market Delays

The need for change to accelerated approval “stems from decades of experience and observed challenges with this regulatory pathway, and do not turn on any single product or biological mechanism,” said Thomas J. Hwang, a physician at the Dana Farber Cancer Institute in Boston whose work focuses on pharmaceutical regulation and reimbursements. The institute is a principal teaching affiliate of Harvard Medical School.

Proponents of changes have cited delays in some companies meeting post-market requirements to confirm whether their drug actually offers a clinical benefit.

In a report released Thursday, the Health and Human Services Office of Inspector General analyzed all 278 drug applications granted accelerated approval since the FDA initiated the program in 1992. The watchdog found 104 of them have incomplete confirmatory trials, and more than a third of those studies—35 of the 104—have at least one that’s past the date they were scheduled to be completed.

“Ensuring that FDA has the tools to effectively administer the accelerated approval pathway is crucial to FDA’s mission to protect the public health by ensuring the safety, efficacy, and security of human drugs and biologics,” the OIG said.

Yet Medicare and Medicaid spend billions on drugs that have yet to demonstrate a proven clinical benefit, the OIG found. The two public payers spent more than $18 billion between 2018 to 2021 on 18 drugs with incomplete confirmatory trials past their original planned completion dates.”

Legislative Push

Holly Fernandez Lynch, a bioethicist at the University of Pennsylvania, said in remarks at an event hosted by the Greenwall Foundation Thursday that accelerated approval is “based on the idea that you can get post-market trials done.” She called on the FDA to ensure that companies already have post-approval trials underway before their products are cleared under this pathway.

A House-passed version of a package to reauthorize industry user fees to the FDA would have given the agency the authority to withdraw approval of drugs that don’t show a clinical benefit or if a company fails to meet its post-market requirements. The bill would have also required updated guidance on using novel surrogate endpoints to predict a clinical endpoint.

The user fee reauthorization set to be passed along with a stopgap funding measure this week omits these measures.

House Energy and Commerce Chairman Frank Pallone, Jr. (D-N.J.) said in a statement Sept. 26 that he and other key lawmakers are “committed to returning to the negotiating table ahead of the December government funding deadline to revisit these key priorities” and would “continue pushing to advance as much of the House-passed legislation as possible.”

Largent said the accelerated approval pathway “requires us to make a tradeoff between speed and certainty.”

“Ideally, the pathway gets drugs to patients who lack meaningful options faster,” she said. “But before post-approval trials are completed, we are prescribing—and paying—for drugs while uncertainty remains about clinical benefits.”

To contact the reporters on this story: Celine Castronuovo at; Jeannie Baumann in Washington at

To contact the editors responsible for this story: Alexis Kramer at; Cheryl Saenz at