Biogen will have until the end of the decade to complete another clinical trial confirming its newly approved Alzheimer's treatment can actually benefit patients.
The Food and Drug Administration mandated the follow-up study as a requirement of the conditional clearance it granted Biogen's drug, called Aduhelm, on Monday. According to an approval letter from the regulator, the biotech company has until next August to finalize a plan for the study, until 2029 to finish testing and until 2030 to submit a final report to regulators.
If Biogen fails to complete the study, or results are negative, FDA officials said the agency would pull Aduhelm from market. In the meantime, however, Biogen will be able to sell the drug widely, potentially generating tens of billions of dollars in revenue without convincing proof of clinical effectiveness.
"We believe that the data supports accelerated approval while holding the company accountable for conducting an additional study to confirm the benefits observed in one of the trials, which we fully intend to do," Patrizia Cavazzoni, head of the FDA's main drug review office, told reporters Monday. "We acknowledge that it will take some time to conduct a confirmatory trial."
The agency hopes to accelerate testing, however, by incorporating "opportunities" for earlier study results while the overall trial continues, an FDA spokesperson told BioPharma Dive in a statement after this story was published.
"We consider the nine-year timeline a conservative estimate, which is an appropriate starting point for development of the draft protocol from the sponsor for its global confirmatory study," the spokesperson wrote in an email. STAT News previously reported the FDA viewed the trial timeline as conservative, citing an unnamed official.
Yet, in a Monday interview with CNBC, Biogen CEO Michel Vounatsos emphasized that nine-year timeline, although he acknowledged the specific trial plans were not yet set.
As things stand now, Aduhelm is backed by two nearly identical Phase 3 studies as well as an earlier Phase 1 trial. But the results are highly controversial, as data from those two late-stage studies were conflicting. In one, treatment appeared to modestly slow cognitive and functional decline among patients given a high dose of Aduhelm. In the other, treatment had no effect. Patients on the high dose even seemed to decline slightly faster than those given placebo.
The discordant data has stirred significant doubts among experts whether Aduhelm truly slows disease progression, and whether data from the one successful trial was a false positive. Both questions are made more complicated by Biogen's March 2019 decision to halt the trials early, thinking then that the drug was unlikely to succeed. The company's subsequent reversal was highly unorthodox and muddied the statistics used to determine treatment benefit.
Accordingly, in the run-up to Monday's decision, many experts had urged the FDA to reject Aduhelm and ask Biogen to complete a third large, well-controlled study before granting approval.
"No number of post hoc analyses of these two trials can substitute for the value that could be generated by a new trial," said Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, in an April interview. Alexander was a member of an FDA advisory committee that rejected Biogen and the agency's case for Aduhelm in a contentious November meeting.
The FDA dismissed the committee's advice, choosing after a long review a middle-ground approach that it hadn't discussed at the meeting. Even though Biogen requested a full approval for Aduhelm, based on the signs of clinical benefit in the one trial, the agency instead granted an accelerated approval, based on the drug's effect in reducing a toxic plaque found in the brains of Alzheimer's patients.
Aduhelm does that very well, but it's not clear whether plaque reductions directly correlate to slower cognitive and functional declines. At the November meeting, even the head of the FDA's neuroscience division said the agency was not using amyloid reduction as a surrogate of efficacy — a position the regulator seemingly reversed.
Unlike full approvals, accelerated approvals require a confirmatory study, which Biogen will now have to complete in order to keep its drug on the market. But the long timeline allowed by the FDA gives the company more than eight years to do so, even if opportunities for interim results are built in. Aduhelm's two Phase 3 trials ran for about four years to complete, although they were stopped early.
"We expect the sponsor to commit all resources needed to move this trial forward as effectively as possible, with the aim of completing the trial as soon as is feasible, while assuring the quality of the data and the robustness of the results," the FDA spokesperson told BioPharma Dive.
In its letter, the agency didn't specify whether the study must use a placebo as a comparison, asking instead for "an appropriate control for the treatment of Alzheimer's disease."
Experts previously questioned whether an approval of Aduhelm would make other clinical trials testing Alzheimer's drugs much harder, as patients would be less willing to receive a placebo.
"There have been concerns that the availability of an approved drug like this might make it more difficult to recruit for other drug trials," said David Knopman, a neurologist and Alzheimer's specialist at the Mayo Clinic, in an interview ahead of the FDA's decision. "I think that's true."
Biogen has not yet proposed a study plan for the required third trial, and has until October to submit a draft. The company could set up study sites in other countries where Aduhelm is not approved and patients might be more willing to accept being randomized to receive a placebo.
The FDA, however, thinks trials in the U.S. will still be feasible. "I expect there will be patients, sites within the U.S. that will be interested in participating in a clinical trial," said Peter Stein, head of the FDA's Office of New Drugs. "Again, there remains some uncertainty with regard to ultimate clinical benefit. There will be patients who are able to participate knowing that."
In a Tuesday interview, a Biogen executive indicated to BioPharma Dive they planned to run the study as placebo-controlled.
The yearslong timeline, said Biogen's chief medical officer Maha Radhakrishnan, gives the company "time to think through what are the parameters we need to consider, what will it take to really be able to enroll the patients based on inclusion and exclusion criteria for that study."
Radhakrishnan also noted Biogen plans to collect "real-world" data outside of clinical trials.
To date, the vast majority of the roughly 250 accelerated approvals granted by the FDA have gone to drugs for cancer or HIV, the disease which catalyzed the program's creation in the 1990s. A handful are for other diseases but only a few, including Biogen's multiple sclerosis drug Tysabri, are for neurological diseases.
Aduhelm's approval may set a precedent for more to follow. "The accelerated approval pathway has been an incredibly useful tool in oncology," said the FDA's Cavazzoni. "For those of who have followed the dramatic leaps forward in the cancer space in the last 20 years, we believe it serves as a model that we hope can be replicated with neurodegenerative diseases."
While the FDA highlights the accelerated approval program as a success, drugmakers don't always follow-up quickly with the required confirmatory evidence. Thirteen percent of the 145 accelerated approvals granted before 2016 have not yet been converted to a full approval, according to a recent analysis by the Institute for Clinical and Economic Review.
And withdrawing a drug that's failed in confirmatory testing isn't always easy to do. The FDA in April convened an advisory meeting to consider whether to withdraw six cancer immunotherapy approvals for which the confirmatory data was negative. Experts on the panel recommended upholding four of them.
Jacob Bell contributed reporting.
Note: This story has been updated to include references to an FDA statement given to BioPharma Dive after publication.