Amid recent backlash stemming from market withdrawals and trial delays, the FDA seeks to further clarify its requirements for confirmatory trials for therapies seeking the shortened path to market.
The FDA kicked off 2025 Monday with a spate of regulatory documents, offering guidance on the use of AI in drug development and the use of tissue biopsies in clinical trials, as well as attempting to provide much-needed clarity on its requirements for confirmatory trials supporting accelerated approvals. The new guidance reiterates that confirmatory trials must be underway for a therapy to receive the accelerated greenlight but still leaves much room for interpretation when it comes to determining whether a trial is indeed “underway.”
The FDA’s accelerated approval program, launched in 1992, has come under fire of late, due partly to a rash of market withdrawals and failed confirmatory trials of medicines that previously received accelerated approval. A particular bone of contention has been the significant delays in conducting these confirmatory studies, which are required following accelerated approvals as these nods are granted based on a surrogate endpoint that is reasonably likely to predict clinical benefit.
In 2022, NPR found that 42% of currently outstanding confirmatory studies took a year or more to begin following an accelerated approval, if they started at all. “Those follow-up studies are rarely done in a timely fashion,” Joel Perlmutter, a professor of neurology at Washington University School of Medicine in St. Louis, told BioSpace last year.
The FDA has attempted to address this concern in recent years, requiring that confirmatory trials be “well underway” before an accelerated approval can be granted. But the definition of “well underway” was somewhat murky, leaving drugmakers confused. In March 2024, the agency rejected Regeneron’s bispecific antibody odronextamab, citing issues with the enrollment status of its confirmatory trials. Following the Complete Response Letter, Regeneron hematology executive Andres Sirulnik expressed frustration with the decision, telling Fierce Biotech, “Eventually, it will be important for the industry and for the field to understand . . . what does it mean, ‘well underway’?”
Monday’s guidance seeks to answer this question. In the document, entitled “Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway,” the FDA says it “intends to require that the confirmatory trial(s) be underway” before accelerated approval can be granted.
The guidance states that a trial is considered “underway” if enrollment has been initiated, the trial has a target completion date that is consistent with the diligent and timely conduct of the trial and the sponsor has made measurable progress and can “provide sufficient assurance to expect timely completion of the trial.”
The new guidance contains a fair amount of nuance, however, with the FDA saying that the natural history of the disease, availability of alternative treatments, the progress of patient recruitment and the number of activated trial sites will factor into its determination of whether or not a confirmatory trial is “underway.”
In terms of drugs for rare diseases—a therapeutic space that is increasingly leveraging the accelerated approval program—the FDA provided additional guidance around randomization. “For certain rare diseases, the clinically relevant endpoints and disease natural history may enable postmarketing studies that do not require randomization to verify clinical benefit, and this design could reduce the challenge of enrolling and completing the study if it is not underway prior to approval,” according to the document.
Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, has advocated for greater flexibility in rare disease gene therapy trials, arguing that non-randomized, single-arm trials could be the best option in this case.
For Perlmutter, the timely completion of confirmatory trials is imperative to the accelerated approval program’s success. In the end, drugs with “potentially harmful effects” and “without adequate benefits” can remain on the market, he said in October.
Pfizer’s sickle cell disease therapy Oxbryta was on the market for five years before being withdrawn in September 2024 due to risk of death and other complications, while Gilead Sciences’ Zydelig was available to patients with lymphoma for more than seven years before the company withdrew the drug in 2022 after failing to complete follow-up studies.
