On Monday, the U.S. Food and Drug Administration (FDA) published draft guidance regarding the design of clinical trials that the agency hopes can support the accelerated approval (AA) applications for drugs in oncology clinical trials. Accelerated approval is frequently used in oncology trials due to the urgency of clinical need for treating some cancer indications and also because of existing intermediate clinical endpoints that suggest a likely clinical benefit.
“The FDA’s accelerated approval program has provided patients with cancer earlier access to novel treatments that can be practice changing,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence. “Today’s draft guidance provides recommendations to sponsors for designing clinical trials to support accelerated approval.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.”
Among the key factors covered in the draft are clinical trial design, methods for improving the data that is available for the accelerated approval and outlines the need to reduce treatment uncertainty for patients via timely initiation of postmarketing confirmatory research.
Postmarketing confirmatory trials have been required to verify and describe the anticipated clinical benefit of drugs granted accelerated approval. The new draft guidance also entertains the possible potential that randomized clinical trials–compared to single-arm trials–by highlighting that use of the one-trial approach, in appropriate cases, may not require separate clinical trials because longer term follow-up in the same trial could fulfill a postmarketing requirement to verify clinical benefit. It also noted that confirmatory trials that are already proceeding at the time of the accelerated approval have the potential to minimize the period of uncertainty for patients.
As noted in a commentary from the staff at the the FDA’s Oncology Center of Excellence, published last fall in the New England Journal of Medicine “A comprehensive AA strategy should also focus on the timely generation of evidence to confirm or refute clinical benefit. With the exception of rare diseases, for which the FDA has accepted the further characterization of the overall response rate and response durability as verification of clinical benefit because of the infeasibility of conducting randomized trials, oncology drug sponsors have typically conducted a single-group study to support AA and subsequently conducted a randomized, controlled trial evaluating a long-term outcome such as survival to verify clinical benefit,” they wrote. “Although the FDA has recommended that confirmatory trials be well under way, if not fully enrolled, at the time of the AA, sponsors frequently delay initiating these trials until the single-group study is completed or AA has been granted.”
Such delays can significantly affect the median time to deliver results of confirmatory trials, the commentary added, with the most striking difference among withdrawn indications. In these instances, confirmatory trials that were ongoing at the time of the AA showed a median tie to withdrawal of 3.8 years, compared with 7.3 years if the trial had not been initiated. The authors noted that the second instance represents the greatest risk to patients from AA drugs.
A possible way to mitigate this risk and to quickly get results from a confirmatory trial, could be the use of a single arm trial.
“Most AA studies enroll patients for whom there are limited or no available therapies,” the authors noted. “Subsequent confirmatory trials are usually performed in a population with less refractory disease, since it may be infeasible after approval to initiate a randomized trial in the original population. Rather than waiting to initiate the trial after AA, sponsors could pursue a single randomized trial, potentially in an earlier treatment setting, that could both support AA and subsequently verify clinical benefit. AA could be granted on the basis of a planned interim analysis of overall response rate, and traditional approval granted on the basis of clinical benefit (usually improvement in overall survival) at the trial’s conclusion.”