Accelerated approvals under fire again as pivotal trials typically take about as long as confirmatory trials, research shows
One of the major reasons the FDA’s accelerated approval pathway receives so many accolades and so much support is that it speeds new and hopefully improved drugs to patients, usually in oncology, while confirmatory evidence on the clinical benefit can be gathered.
But a new research letter published Tuesday in JAMA Network Open raises fresh questions about the pathway, making the case that because the difference in the amount of time it takes to run the confirmatory trial vs. the pivotal trial is typically similar, the companies might as well run the equivalent of the confirmatory trial first.
The research comes as HHS is looking into the accelerated pathway, and as FDA has been sharply criticized for using the pathway to approve Biogen’s Alzheimer’s drug, despite scant evidence that it actually provides a clinical benefit. The FDA also granted Biogen a long runway (9 years) to complete its confirmatory trial.
Looking at 32/45 indications approved via the accelerated pathway, the Yale researchers, led by first author Joshua Wallach, found that overall the median pivotal trial duration was 10 months, while the post-approval trial duration was 17 months.
“These findings raise questions about the use of accelerated approval program for certain therapeutic agents, especially if postapproval confirmatory trials neither consistently evaluate clinical outcomes nor are much longer than pivotal trials using surrogate endpoints,” the authors noted.
They also cited the incredibly long delay between the time of the accelerated nod and when the confirmatory trial results are actually reported.
“The median time from approval to FDA-established postapproval trial results reporting deadlines for sponsors was 50 months (3-116 months), a median of 30 months (range, -19 to 106 months) more than the postapproval trial durations,” the authors wrote.
But they also note some of the limitations to the study, like their reliance on only publicly available data, the fact that different issues crop up with different therapeutic areas (i.e., rare disease accelerated approvals vs. oncology), and the fact that once a drug is marketed under an accelerated approval, it can take much longer to enroll a postapproval trial.
Meanwhile, in another research letter published by Wallach in JAMA Open Network on Tuesday, the authors poured cold water on the idea, often floated by industry and included in the 21st Century Cures Act, that the FDA should consider relying on real-world data to try to verify the clinical benefits of drugs granted accelerated approvals based on surrogate outcomes:
“The findings of this cross-sectional study suggest that none of the 50 FDA-required postapproval confirmatory trials for therapeutic agents granted accelerated approval between 2009 and 2018 could have been feasibly emulated using currently available claims and/or structured EHR data. In particular, the narrowly defined indications and strict inclusion and exclusion criteria of the FDA-required postapproval confirmatory trials precluded emulation using RWD.”
The researchers said their findings suggest that current observational methods and RWD “can complement, but are unlikely to replace, postapproval confirmatory trial requirements.”
On that same front, the FDA recently published a draft guidance attempting to spell out just how to use RWD, and how messy it can be.