FDA's OCE makes the case for accelerated approval rider in user fee reauthorization
Four experts from the FDA’s Oncology Center of Excellence took to the New England Journal of Medicine yesterday to make the case for not only improving the agency’s ability to expeditiously pull dangling accelerated approvals when, on the rare occasion, confirmatory trials fail, but also better building “quality and efficiency into the AA on-ramp.”
The timely perspective arrives as Congress has exactly one week left to draft, release and sign off on the reauthorized user fee deals before layoff notices will be sent to drug reviewers. That package, which is likely to hitch a ride with the continuing resolution, may or may not include several policy riders (opposed by Republicans), including one that would allow the FDA to require confirmatory trials to be underway before an AA is granted, and would improve the process by which FDA can withdraw AAs.
The FDA authors make clear the need for such an AA rider as for oncology indications that have been granted AAs, the median time to beginning the withdrawal process “was longer if the confirmatory trial was initiated after the approval (see figure). This difference was most striking among withdrawn indications, with a median time to withdrawal of 3.8 years if the confirmatory trial was ongoing at the time of AA, as compared with 7.3 years if such a trial had not been initiated. Delayed withdrawals in this latter scenario represent the greatest risk to patients.”
OCE’s Lola Fashoyin-Aje, Gautam Mehta, Julia Beaver, and Richard Pazdur also offer several upfront options for those pursuing AAs.
For instance, sponsors could pursue a single randomized trial, potentially in an earlier treatment setting, that could both support AA and verify clinical benefit, they say, with the accelerated approval coming on the basis of a planned interim analysis of ORR, and a conversion to full approval granted on the basis of clinical benefit (OS improvement) at the trial’s conclusion.
“This approach would provide a more thorough safety assessment and earlier definitive evidence of the benefit–risk balance. It would also reduce the risk of prematurely halting development of a drug with a limited overall response rate that might nevertheless improve overall survival,” they wrote.
Another potential strategy for sponsors would be to agree in advance on the criteria for attaining AA, and the criteria for withdrawing the indication. Sponsors could then run two concurrent studies: a single-group AA study examining the ORR in patients without other available therapies, and a randomized trial focused on clinical benefit in patients who have received fewer treatments.
“If these studies enrolled patients around the same time, an interim analysis of safety and overall response rate in the confirmatory trial could provide supportive evidence and greater confidence for the AA based on the single-group study,” they explain.
Moving forward, OCE’s Fashoyin-Aje et. al. explain how both the at-times delayed withdrawal process (the focus on Congressional efforts) should not overshadow the lead-up to an approval.
“Public discussion has focused on improving the AA off-ramp, suggesting specific time limits for completing confirmatory trials, patient enrollment milestones for evaluating timely trial completion, and alternative procedures for withdrawing indications. But equally important are procedures to build quality and efficiency into the AA on-ramp, which should include a prospective comprehensive strategy detailing plans for AA and the verification of clinical benefit, with the aim of expediting therapeutic advances and shortening this period of uncertainty,” they concluded.