Ex-FDAer Schiller on Accelerated Approval Guide
Aetion chief legal/regulatory officer and former FDA associate commissioner for policy Lowell Schiller says the agency should address the use of external controls and real-world data/evidence (RWD/E) in the context of accelerated approvals, and harmonize its draft guidance on “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics” with the recent draft guidance on externally controlled trials. Lowell offered this feedback in just-posted docket comments on the clinical trial considerations guidance.
Oncology drug developers are encouraged to focus on randomized clinical trials, according to FDA recommendations in the 3/24 draft guidance. 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 guidance 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.”
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).”
But Schiller says that in many cases, “a placebo- or active-controlled trial may not be a feasible, practical, or ethical option for a drug qualifying for accelerated approval. In such cases, the choice is not necessarily a binary [one] between an uncontrolled single-arm trial and a randomized clinical trial; other approaches, such as RWD-based external controls, can provide a middle ground approach.”
Schiller notes that FDA also recognized the importance of externally controlled trials in its recent draft guidance, Considerations for the Design and Conduct of Externally Controlled Trials (ECT) for Drug and Biological Products, which outlined the use of externally controlled trials to support agency decision-making. “We strongly agree that external control arms built from reliable and relevant RWD and use of principled methods to address concerns around potential bias and confounding can provide meaningful evidence in the context of accelerated approval, just as they can in other settings,” he says.
RWE should be seen as a “helpful complement” to randomized controlled in the accelerated approval process, Schiller continues. “For example, an RWE-based external control can contribute to an adequate and well-controlled investigation to support FDA accelerated approval. Additionally, in appropriate cases, RW study designs and data can be used to generate confirmatory evidence to support traditional approval following an accelerated approval.”
He contends that “Given the important role that external controls can play in trials used to support decisions under the accelerated approval pathway, and the broader utility of RWD and RWE in the accelerated approval context, we believe the [accelerated approval] guidance would be enhanced by including a discussion of these topics, with reference to the ECT draft guidance and other recent guidance or draft guidance as relevant.”