The FDA is planning to shake up its approach to the accelerated approval of oncology drugs—and wants to know what you think of its proposals. In draft guidance, the agency outlined plans to move away from single-arm studies and instead favor randomized controlled trials that can potentially serve as the basis for both accelerated and full approval.
Sponsors typically run single-arm studies that measure partial and complete tumor responses to support accelerated approval of their cancer drug candidates. The FDA has issues with the approach, noting that it fails to spot rare adverse events, offers limited insights into time to tumor progression and survival, struggles to predict clinical benefit of some molecules and relies on challenging cross-trial comparisons.
“These and other limitations of single-arm trials can add uncertainty to the assessment of the safety and/or effectiveness of a drug such that accelerated approval based on a single-arm trial may not be justified in a given clinical setting,” the agency wrote in its draft guidance.
The solution? Randomized controlled trials (RCTs). In the draft text, the FDA calls RCTs “the preferred approach to support an application for accelerated approval.” Single-arm trials offered sponsors a faster, cheaper route to market than RCTs, enabling them to secure accelerated approval before starting a more robust study to confirm the effects. The draft guidance marks a split from that approach.
Going forward, the FDA wants to limit single-arm studies to specific situations, such as when there are significant concerns about the feasibility of running a RCT. Most sponsors will either run two RCTs—one for accelerated approval, another to confirm the effects for full approval—or design a single RCT to deliver the data for both accelerated and full approval.
Adopting the proposed “one-trial” RCT approach “may allow for the evaluation of a new drug in an earlier treatment setting, thereby enabling access to a new drug earlier in the course of the disease when more patients are likely to benefit.” FDA leaders discussed other benefits of the one-trial model, including lowering the risk of prematurely halting development, in a journal article last year.
The guidance sets out what sponsors need to consider when planning a one-trial approach. The FDA is recommending sponsors pick an endpoint for accelerated approval “that is appropriate and feasible to evaluate earlier in the disease and earlier during the conduct of the trial.” Before starting a trial, the FDA wants sponsors to talk to its staff about the endpoint’s ability to predict clinical benefit.
Response rate is the obvious accelerated approval endpoint. But the draft guidance states that “depending on the disease course, the intended population, and guidance from FDA, use of endpoints other than response rate could also be evaluated in a ‘one-trial’ approach together with subsequent evaluation of clinical benefit endpoints.”
The FDA is also asking sponsors to consider the potential for bias. When the sponsor evaluates the early data and files for accelerated approval, they may “inadvertently introduce bias,” the guidance states. To evaluate the risk, sponsors should consider the anticipated impact of crossover, the preliminary data on the drug’s effects and the treatment used in the control arm, among other factors.
If a sponsor opts for a two-trial approach, the FDA wants the second study to “be well underway, if not fully enrolled, by the time of the accelerated approval action.” The statement reflects the agency’s view that “timely completion of the trial(s) intended to verify clinical benefit is critical.”
The FDA is accepting feedback on the draft guidance until May 26.