Accelerated approval reforms need meaningful confirmatory trial improvements, professors write in Science
Outside of Covid-19, 2021 has been the year of the accelerated approval.
Then in June, FDA pulled out the accelerated approval pathway, seemingly out of nowhere, to sign off on Biogen’s controversial Alzheimer’s drug Aduhelm. It hadn’t even been mentioned at the drug’s adcomm.
And just this week, the FDA cancelled another adcomm to review two more dangling AAs, one of which was pulled by Secura Bio.
The rain of criticism continues to pour onto FDA, as two professors from the University of Pennsylvania and Boston University on Thursday afternoon published a new perspective in Science arguing that the early access to these new medicines under the AA pathway is not being followed up with the appropriate proof in the confirmatory trials. They said that the Aduhelm approval also risks FDA’s reputation and undermines “its core role in keeping the market free of worthless or dangerous medical products.”
As the alarm bells sound, Rick Pazdur’s Oncology Center for Excellence at FDA initiated a review of the accelerated approval pathway about a year ago, while more recently, HHS’ Inspector General said it also will review the pathway, following that accelerated OK for Aduhelm.
“One approach OIG should consider is examining the details of trials that have further evaluated a drug’s approved indication after marketing approval, looking to distinguish the features of trials that were more versus less successful,” professors Holly Fernandez Lynch and Christopher Robertson wrote, adding:
Accelerated approval is an important regulatory pathway worth trying to save, if the evidence suggests that meaningful improvements in confirmatory trials are possible. While this evidence is gathered, companies, patients, and policy-makers should prioritize efforts to meaningfully improve access to investigational products in the preapproval period, without further pushing the boundaries of accelerated approval.
Lynch and Robertson also explained how once a drug is marketed via the AA pathway, the company’s incentives to perform a speedy confirmation trial “drop off precipitously,” and patients may also be unwilling to participate in a confirmatory trial in which they may be randomized to something other than the drug that won approval.
Lynch added via email to Endpoints that “meaningful improvements in confirmatory clinical trials could be several-fold: faster timelines and stricter deadlines for completion, insistence on more rigorous designs (blinding, randomization, concurrent controls, rejection of further use of surrogate endpoints), requiring confirmatory trial design to be agreed upon (and perhaps even requiring the trials to be underway) at the time of granting accelerated approval, and stronger ability and willingness on the part of FDA to rapidly pull products if post-approval trials fail to confirm benefit.”
But she said, the “main point of the piece, though, is that policy changes need to be informed by additional evidence about why confirmatory trials are failing to live up to expectations. For example, if the issue is that not enough patients are willing to enroll in rigorous confirmatory trials, it won’t matter for FDA to insist on them and we’ll need to figure out alternative ways to encourage participation or better ways to procure access prior to marketing approval while still gathering rigorous data.”
Anna Kaltenboeck, health economist and policy researcher at Memorial Sloan Kettering Cancer Center, and ICER’s Amanda Mehlman and Steven Pearson also published an article in the Journal of Comparative Effectiveness Research in August outlining 10 possible ways to reform the accelerated approval pathway.
The researchers pointed to similar reforms in the premarket and postmarket trials, such as by strengthening the selection and use of surrogate endpoints, developing standardized review templates and requiring greater use of randomized controlled trials, as well as creating a new label alert for accelerated drugs and better enforcing the completion of confirmatory trials.
Another review of accelerated approvals, published in JAMA Open Network last month, also raised questions about the use of AA pathway for certain drugs, “especially if postapproval confirmatory trials neither consistently evaluate clinical outcomes nor are much longer than pivotal trials using surrogate endpoints,” the authors wrote.