Does FDA's Shift From Two Pivotal Trials to One Represent a Genuine Evolution?

Harpreet Singh, MD, chief medical officer at Precision for Medicine and former FDA Oncology Division Director, offers a nuanced view of the FDA’s move from routinely requiring two pivotal trials to increasingly accepting a single pivotal trial for some approvals.

Singh characterizes the trend as “more of an evolution versus a revolution.” She notes that in oncology, and particularly in rare oncologic diseases under his prior purview, reliance on a single pivotal trial has long been accepted. The rationale, she explains, rests on treating life-threatening diseases where patients are dying during the course of trials. In those settings, a single “adequate and well controlled trial” has traditionally been considered sufficient to demonstrate safety and efficacy, with some residual risk accepted and further characterization of safety and long-term outcomes deferred to the post-marketing period.

Singh contrasts this with chronic conditions such as diabetes, multiple sclerosis, and cardiovascular disease, which, while potentially life limiting, are more accurately described as chronic comorbidities. Patients often remain on therapies for extended periods, sometimes lifelong, and these drugs treat much larger populations. Historically, the regulatory view in such settings has been that one pivotal trial cannot answer all relevant scientific questions. Accordingly, two adequate and well-controlled trials have been required to address issues of statistical variation, power, alpha allocation, P values, and population heterogeneity.