FDA’s approval of the drug comes with strings: Biogen must conduct a new clinical trial, and the agency could rescind its approval if the study does not show the drug is effective. Still, the FDA’s decision raises new questions about whether the agency is lowering its burden of proof for drugmakers. FDA normally requires “substantial evidence” for approval in the form of two large clinical trials demonstrating efficacy. That aducanumab fell short suggests to some health care providers and industry watchdogs that FDA is bowing to political and industry pressure rather than basing its decision on scientific evidence.
“I’m quite disappointed in the decision by the FDA. It’s not in the best interest of patients and not in the best interest of our health care system,” said Joseph Ross, a physician at Yale University and co-director of the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation.
The agency acknowledged the “considerable public debate” over aducanumab in a statement announcing the approval.
“At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward,” said Patrizia Cavazzoni, the FDA’s top drug regulator. “We ultimately decided to use the Accelerated Approval pathway — a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit.”
Ultimately, Cavazzoni said, FDA determined that the drug’s benefits outweighed the risks to patients.
“This historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease,” Michel Vounatsos, Biogen’s chief executive officer, said in a statement. “We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.”
The demand for Alzheimer’s treatments is strong. The disease, which affects roughly 5.8 million Americans, is the most common form of dementia. It is progressive and ultimately fatal.
Aducanumab, a monoclonal antibody administered via a monthly infusion, is the first Alzheimer’s treatment to target the amyloid protein that collects in patients’ brains and is thought to cause their progressive dementia. Analysts have predicted that aducanumab could earn billions of dollars given the large patient population and lack of competitor therapies.
But its path to market has been rocky. Biogen began two Phase III clinical trials in 2015, collectively enrolling nearly 2,000 participants with evidence of early disease. After an interim data analysis in March 2019 of both trials revealed that aducanumab wasn’t likely to be beneficial, the company said it would discontinue the trials.
Biogen reversed course in October 2019 after analyzing three more months of data that researchers had collected while the interim analysis was in progress. The company said the new data showed that the drug succeeded in one trial and would likely do so in the second if the study had been able to continue. Biogen applied to FDA for approval in June 2020.
Patient advocates argue that the approval of aducanumab paves the way for new and better therapies down the line. “We all know and recognize that it would not be a cure, but it would be the beginning of a new era of treatment,” Maria Carrillo, the chief science officer of the Alzheimer’s Association, told POLITICO.
In her statement, Cavazzoni said that while pre-approval clinical trials split on whether the drug reduced symptoms of Alzheimer’s disease, all of those studies showed the drug “consistently and very convincingly reduce the level of amlyoid plaques in the brain in a dose- and time-dependent fashion.”
The agency is betting that the reduction in amyloid plaque signals that the drug will ultimately be proven effective, she added.
But some neurologists are not convinced that the data available demonstrate the drug’s efficacy.
“I’m worried about the inconclusiveness of the current data and the possibility that the effect the drug showed in those two trials was no better than no treatment,” said David Knopman, a clinical neurologist at the Mayo Clinic.
Those skeptical of the drug include the independent FDA advisory committee charged with reviewing the data Biogen submitted with its approval application. During a heated meeting in November 2020, the committee concluded that there was not enough evidence to show the drug was effective — contradicting an internal FDA analysis that concluded the same evidence was “extraordinarily persuasive.”
More recently, the Institute for Clinical and Economic Review — a nonprofit group that evaluates medical treatments — said last month that “the evidence is insufficient to conclude that the clinical benefits of aducanumab outweigh its harms or, indeed, that it reduces progression” of Alzheimer’s disease.
And last week, the American Geriatrics Society wrote to FDA urging it to reject the drug. Approval “is premature given the lack of sufficient evidence to support that aducanumab reduces progression of Alzheimer’s disease and that the potential benefits as a treatment for patients could outweigh the potential harms,” the society wrote.
There are also questions about the drug’s safety. About 35 percent of clinical trial participants who received the treatment developed a form of brain swelling that can be fatal if not properly mitigated. These cases were particularly common in participants with a genetic mutation called APOE4, which puts them at a greater risk for Alzheimer’s disease in general.
Regulatory watchdogs say the approval sends the wrong kind of signal to the pharmaceutical industry and continues a pattern of recent FDA drug approvals that appear to be influenced by industry or politics.
“Such a reckless action irreparably damage[s] the FDA’s credibility, which has already been damaged because of various decisions it’s made during the Covid-19 pandemic,” says Michael Carome, a physician and director of the health research group at Public Citizen, a liberal advocacy organization.
He compared the FDA’s approval aducanumab to its decisions to issue emergency-use authorizations last year for a pair of unproven Covid-19 treatments — the malaria drug hydroxychloroquine and convalescent plasma from pandemic survivors — under strong pressure from former President Donald Trump.
The agency has since revoked the hydroxychloroquine authorization and placed limits on which patients can receive convalescent plasma, based on data collected after the treatments were put into wide use.