Accelerated Approval Guide Pushes Randomized Trials
Oncology drug developers are encouraged to focus on randomized clinical trials, according to FDA recommendations in a 3/24 draft guidance entitled “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.” FDA Oncology Center of Excellence director Richard Pazdur is quoted in a release as saying: “Building quality and efficiency into the design of oncology clinical trials is a crucial component in providing maximum benefit to those living with cancer.”
The release discusses how clinical trial designs can improve the data available at the time of accelerated approval and “reduce clinical uncertainty for patients by initiating postmarketing confirmatory studies in a timely manner,” it says. “Specifically, the draft guidance addresses the design, conduct and analysis of data through two randomized clinical trial approaches – conducting two separate randomized controlled clinical trials or using one trial for both accelerated approval and to verify clinical benefit. The draft guidance also provides considerations for sponsors to determine the adequacy of single-arm studies to support an application.”
Additionally, the guidance says randomized controlled trials are preferred to support accelerated approval due to the limitations of single-arm trials. “Although a randomized controlled trial is the preferred approach, there can be circumstances wherein a single-arm trial is appropriate in the development of a drug for accelerated approval, for example when there are significant concerns about the feasibility of a randomized controlled trial,” it says. “Careful consideration should be taken in determining whether a single-arm trial is appropriate in a particular clinical and regulatory context. Regardless of the approach under consideration, FDA recommends early discussion with the agency before initiating and, as appropriate, during the conduct of, a trial(s).”
Late last year, CDER researchers said that while the use of single-arm oncology trials has allowed for transformative oncology therapies to be made available to patients expeditiously, using such trials to support drug approval presents several challenges that must be carefully considered. Writing in JAMA Oncology, the researchers wrote that between 1/1/2002 and 12/31/2021, FDA granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals and 60 traditional approvals.
Identifying the optimal drug dose in a single-arm trial remains challenging, the researchers said. The lack of a comparator arm may make identifying a comparative data set to use for the presumed response rate in a historical control difficult. And there is no standard for what constitutes clinically relevant thresholds for durable response rates and points.
And, a New England Journal of Medicine commentary in 2022 also outlined the concepts included and expanded upon in the draft guidance.