FDA Backs Randomized Trials for Accelerated Drug Approval

In an important update to its policies for conducting clinical trials to support accelerated approval of important oncology and other lifesaving therapies, FDA is articulating a preference for randomized controlled trials (RCTs), as opposed to single-arm studies, to support fast approvals of breakthrough drugs. A new draft guidance, Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics was published on March 24, 2023. The document discusses ways to reduce “clinical uncertainty for patients” by encouraging sponsors to conduct RCTs to support accelerated approval. “Building quality and efficiency into the design of oncology clinical trials is a crucial component in providing maximum benefit to those living with cancer,” stated Oncology Center of Excellence (OCE) Director Richard Pazdur.

In moving quickly to outline this research policy, FDA aims to address mounting criticisms of its accelerated approval pathway, which has permitted some therapies to remain on the market for years due to delays in obtaining results from confirmatory studies. Pazdur and colleagues believe that improving the quality and efficiency of initial clinical studies through broader use of RCTs will avoid problems that have delayed confirmation of clinical benefit.

The guidance presents RCTs as “the preferred approach” to support accelerated approval and seeks to limit single-arm studies to specific situations where RCTs present clear difficulties. Sponsors may conduct one RCT to support both accelerated and then full approval or may opt for two RCTs—one for accelerated approval and another to confirm effects for full approval. In both cases, sponsors should pick endpoints appropriate to predicting clinical benefit and consult with FDA on such plans.

In the two-RCT approach, the first study will measure an early response rate, and the second trial will track progression-free survival or overall survival to verify clinical benefit. An important change is that FDA calls for the second study to be well underway at time of accelerated approval. Under recently approved legislation, FDA now can require the launch of confirmatory trials to document clinical benefit at time of awarding an accelerated approval for a new therapy, and here agency officials are moving quickly to clarify how it will implement that new authority. In the draft guidance, FDA advises sponsors to initiate a second or confirmatory study at the time of that approval to verify clinical benefit in a more timely manner. This approach builds on OCE’s Project Confirm, which it launched last year to promote transparency in the accelerated approval process for cancer thereapies and has been adopted more broadly by the Center for Drug Evaluation and Research.

At the same time, the advisory discusses how sponsors still may determine the adequacy of single-arm studies to support an application. If retaining the single-trial approach, sponsors should plan for extending that same study to confirm a longer-term clinical endpoint. Trials should be large enough to detect clinically meaningful and statistically significant improvements in study endpoints as well as to verify longer term benefit. FDA encourages early consultation with the agency on the appropriateness of a planned endpoint for a single trial and its potential to predict benefit to support accelerated approval.

By requiring timely evidence to confirm benefit, the proposal seeks to continue and enhance the benefits of the accelerated approval program, which FDA estimates has advanced patient access to life-saving cancer thereapies by three or more years. This will involve further clarification of appropriate endpoints for oncology and other studies that fall short of documenting increased overall survival.

Comments on the draft guidance are due May 26, 2023.

About the author

Jill Wechsler is Washington editor for BioPharm International.