FDA officials urge ‘comprehensive’ approach to accelerated approval reforms

Regulatory NewsRegulatory News
| 22 September 2022 | By Mary Ellen Schneider 

Critics of the US Food and Drug Administration’s (FDA) accelerated approval pathway have focused on the need to generate confirmatory evidence faster and to withdraw products that fail to show benefit. But officials in FDA’s Oncology Center of Excellence (OCE) suggest that focus is also needed on different trial designs and end points that could help build quality and efficiency into the front end of the process.
In a perspective in the New England Journal of Medicine, Richard Pazdur, MD, director of the Oncology Center of Excellence, along with three other FDA staff members, outlined considerations for “on- and off-ramps” that should be part of a “comprehensive” approach, including trial design, end points, study population, and timelines for obtaining data. (RELATED: Health policy experts call for stronger accelerated approval reforms, Regulatory Focus 06 July 2022)
“We believe that a comprehensive [accelerated approval] strategy should provide sufficient evidence of effectiveness and adequate assurance of safety, while expediting access to drugs and minimizing the time between [accelerated approval] and demonstration of clinical benefit or lack of clinical benefit,” the authors wrote.
The authors called for sponsors to conduct adequate dose-optimization and activity-finding studies on the front end of development and raised questions about the suitability of the durable overall response rate as a surrogate endpoint for certain types of oncology drugs, such as checkpoint inhibitors. “For checkpoint inhibitors, such as antibodies directed toward the programmed cell death 1 pathway, for example, robust improvements in overall survival have been observed in the absence of large effects on overall response rate; this disconnect raises questions regarding the suitability of overall response rate as an end point to support [accelerated approval] for this drug class,” they wrote.
Pazdur and colleagues also proposed two study approaches that could potentially expedite the availability of confirmatory evidence. Instead of starting a confirmatory clinical trial after accelerated approval is granted based on a single-group study, the authors suggested that sponsors conduct a single randomized trial to support both accelerated approval and ultimately confirm clinical benefit. In this scenario, the accelerated approval could be granted based on a planned interim analysis of the overall response rate, with traditional approval coming if overall survival (or another end point demonstrating clinical benefit) was improved at the end of the trial.
“This approach would provide a more thorough safety assessment and earlier definitive evidence of the benefit-risk balance,” Pazdur and colleagues wrote. “It would also reduce the risk of prematurely halting development of a drug with a limited overall response rate that might nevertheless improve overall survival.”
Another option would be to conduct two studies – a single-group study and a randomized trial – concurrently. “If these studies enrolled patients around the same time, an interim analysis of safety and overall response rate in the confirmatory trial could provide supportive evidence and greater confidence for the [accelerated approval] based on the single-group study,” they wrote.
The authors reported having no financial disclosures.
New England Journal of Medicine perspective


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