Highlighting the drawbacks of the FDA’s accelerated approval, a newly published study has found that medications for only 75% of non-oncology conditions where drugs were cleared through the pathway were converted to regular approvals.
The accelerated approval program created in 1992 allows the FDA to clear drugs based on surrogate measures such as intermediate clinical endpoints and biomarkers, which can reasonably predict actual clinical endpoints.
It can take as little as five months or even a few weeks for the agency to greenlight a drug based on the accelerated path compared to the 10 months a formal approval can take.
As part of the accelerated approval, the manufacturer is required to conduct post-approval trials and add an official label to inform the public that the drug’s clinical benefit has not been established.
If the post-approval trial confirms clinical benefit, the label is revised, and the approval is converted to regular approval. If the FDA requirements are not met, or the post-approval trial fails, the drug may be pulled from the market.
The study published last week in The Journal of the American Medical Association evaluated 48 drugs that FDA greenlighted from June 1992 to May 2018 across 57 noncancer conditions based on data from 93 clinical trials.
However, drugs for only 75% of those indications went all the way to receive FDA’s full approval, researchers from Japan’s Fukushima Medical University and Kyoto University Graduate School of Medicine have found.
It took a median of 53.1 months to convert the accelerated approvals to regular approvals, while the median duration from the receipt of the manufacturer’s application to accelerated approval stood at 7.8 months.
Since the accelerated approval, 27 indications (47%) had required post-approval label modifications on boxed warnings. The labeling change that indicates a serious safety risk had taken effect after more than 20 years of median duration.
Out of 86 confirmatory trials required for accelerated approval, 20% did not meet the FDA requirements, and nine (10%) failed to prove clinical efficacy. While the median time to complete a confirmatory trial reached 39.4 months, only one out of eight indications (2%) were withdrawn, and that is also more than a decade after the approval.
“Once granted accelerated approval, delaying further testing could only benefit manufacturers while harming consumers,” the researchers wrote, arguing that patients with no therapeutic options will continue to rely on costly drugs despite the lack of evidence on their clinical benefit.
Researchers pointed to a 2018 FDA review which indicated that out of 93 oncology indications with accelerated approvals from December 1992 to May 2017, only 55% had met the post-approval requirements, while 5% were withdrawn due to unconfirmed clinical efficacy. They attributed the inferior post-approval performance in oncology drugs to poorly designed pre-approval cancer trials and longer follow-ups that allow sponsors to observe more events.
The researchers noted that the accelerated approval pathway expedited the regulatory clearance of noncancer drugs by nearly 4.5 years. However, they pointed to safety-related label changes and unconfirmed clinical efficacy to suggest that the full evaluation of such drugs could take more than a decade.
“These findings emphasize the importance of due diligence in conducting confirmatory trials within a reasonable time frame and withdrawing approval immediately if the trial does not demonstrate clinical benefits outweighing the risks,” the researchers added.
The study had several limitations, including insufficient information on the FDA drug database regarding label changes before July 1996.
FDA’s accelerated approval sparked debate in 2021 when the agency went against its own advisors and approved Aduhelm, the Alzheimer’s drug developed by Biogen (NASDAQ:BIIB) and Eisai (OTCPK:ESALY) (OTCPK:ESALF) based on surrogate endpoints. However, in May, Biogen (BIIB) pulled marketing support for the treatment amid payer pushback for its coverage while clinicians questioned its efficacy.
In June, the House passed a bill that would give explicit legal authority to the FDA to require that confirmatory trials are underway for a drug before its accelerated approval, and streamline the process for withdrawal if the drug is proved ineffective.
An upcoming FDA decision on Amylyx Pharma’s (AMLX) amyotrophic lateral sclerosis (ALS) therapy AMX-0035 will add further scrutiny on accelerated approval ahead of September 29 PDUFA date as patient advocates call for its approval.
Reversing an earlier decision, an independent panel of the FDA voted 7–2 in favor of AMX-0035 for ALS last week. The decision was based on data from a Phase 2 trial which met the primary endpoint but lacked evidence supporting the survival endpoints.
In a highly unusual move, AMLX Co-Chief Executive Justin Klee said during the meeting that after a potential approval, if the ongoing Phase 3 trial, which considers survival benefit of AMX-0035, fails, the company would voluntarily pull the drug from the market.
Meanwhile, bluebird bio (BLUE) became the latest to win FDA accelerated approval on Friday for its gene therapy Skysona (elivaldogene autotemcel) to slow the neurologic dysfunction in patients aged 4 – 17 years with early cerebral adrenoleukodystrophy.