Four experts from the FDA Oncology Center of Excellence participated in the New England Journal of Medicine yesterday to make the case not only for improving the agency’s ability to quickly obtain pending expedited approvals when, on rare occasions, confirmatory trials fail, but also by improving “the quality and efficiency of the access ramp AA”.
The timely prospect comes as Congress has exactly one week to draft, publish and sign the reauthorized user fee agreements before layoff notices are sent to drug reviewers. This package, which is likely to stall with continued resolution, may or may not include several policy riders (opposed by Republicans), including one that would allow the FDA to require confirmatory trials be underway before an SA is granted, and would improve the process by which the FDA can withdraw SAs.
The FDA authors clearly state the need for such an AA amendment because for oncology indications that obtained AAs, the median time to start the withdrawal process “was longer if the confirmatory trial was launched after the approval (see figure). This difference was most striking among the indications withdrawn, with a median time to withdrawal of 3.8 years if the confirmatory trial was in progress at the time of the AA, against 7.3 years if such a trial had not. not been launched. Delayed withdrawals in this latter scenario pose the greatest risk to patients.
Lola Fashoyin-Aje, Gautam Mehta, Julia Beaver and Richard Pazdur of OCE also offer several initial options for those pursuing AA.
For example, sponsors could pursue a single randomized trial, potentially in a prior treatment setting, that could both support AA and verify clinical benefit, they say, with accelerated approval based on a planned interim analysis of ORR and conversion to full approval granted based on clinical benefit (improvement in OS) at end of trial.
“This approach would provide a more thorough assessment of safety and earlier definitive evidence of the benefit-risk ratio. It would also reduce the risk of prematurely stopping the development of a drug with a limited overall response rate that could still improve overall survival,” they wrote.
Another potential strategy for sponsors would be to agree in advance on the criteria for obtaining the AA and on the criteria for withdrawing the indication. Sponsors could then conduct two concurrent studies: a single-arm AA study examining ORR in patients with no other available treatments, and a randomized trial focusing on clinical benefits in patients who received fewer treatments.
“If these studies recruited patients at around the same time, an interim analysis of safety and overall response rate in the confirmatory trial could provide supporting evidence and greater confidence for AA on the basis of the single-group study,” they explain.
In the future, Fashoyin-Aje et. al. explain how the sometimes-delayed withdrawal process (the focus on congressional efforts) should not overshadow the preparation for approval.
“Public debate has focused on improving the AA exit ramp, suggesting specific timelines for completing confirmatory trials, patient recruitment steps to assess timely trial completion, and procedures alternatives for removal of indications But equally important are procedures to strengthen the quality and effectiveness of the on-ramp to AA, which should include a comprehensive forward-looking strategy detailing plans for AA and verification of benefits clinical trials, with the aim of accelerating therapeutic progress and shortening this period of uncertainty,” they concluded.