In recent years, the FDA has amped up its supervision of accelerated approvals, including by requiring that confirmatory trials at least be underway at the time of these conditional nods. But, after hearing some mixed messaging from the agency, drugmakers were left wondering what exactly “underway” means in this context.
Now, a new draft guidance document tries to clear the air on the agency’s interpretation of the term “underway.”
The FDA on Monday posted a draft guidance document titled “Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway.” Although the guidance doc was uploaded by the Oncology Center of Excellence, which has issued the majority of accelerated approvals, the policies are slated to apply to the entire FDA.
Drugmakers looking for a one-size-fits-all rule may be disappointed. In the document, the FDA maintained its regulatory flexibility, offering various scenarios in which a confirmatory trial may not be needed or should have completed enrollment prior to the associated accelerated approval.
Although the FDA specified that its guidance documents do not come with legally enforceable responsibilities—and should be viewed only as recommendations—drugmakers that run against agency guidance would likely face consequences.
Previously, the agency rejected Regeneron’s CD20xCD3 bispecific antibody odronextamab in follicular lymphoma and large B-cell lymphoma because it was not satisfied with the progress of the drug’s confirmatory trials.
At the time, Regeneron leaders voiced frustration over their lack of clarity on the FDA’s requirement for a confirmatory trial to be “well underway,” another term that agency leaders have used to describe their expectations from drugmakers. The two terms “underway” and “well underway” have created confusion among companies seeking accelerated approvals.
In the draft guidance document, the FDA says it generally “intends to require that the confirmatory trial(s) be underway” before granting an accelerated approval.
A trial is considered “underway” if it meets three criteria: The trial needs to have a target completion date “that is consistent with diligent and timely conduct of the trial.” Its sponsor must have made measurable progress, and its plans “provide sufficient assurance to expect timely completion of the trial.” And lastly, enrollment should have started.
Factors such as the natural history of the disease, availability of alternative treatments, the progress of patient recruitment and the number of activated trial sites will play into the FDA’s determination whether a trial can be viewed as “underway,” according to the document.
“In some cases, when FDA determines that continued enrollment/retention after the drug product is on the market is likely to be especially challenging, FDA may require enrollment to be complete at the time of approval,” the agency said in the draft guidance.
Companies should talk to the FDA and agree on the design of the confirmatory trial “generally soon after the end-of-phase 2 meeting,” according to the agency’s draft guidance.
Before a drug’s regulatory filing, the applicant is expected to propose benchmarks that can help the FDA measure the confirmatory trial’s progress. When the time comes, the agency will use these benchmarks, or consider the sponsor’s justification for any delays, before making the final decision on approval.
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For drugs developed against some rare diseases, sometimes longer follow-ups of prior trials could serve to verify clinical benefit, according to the FDA document. In such cases, a trial would be considered underway as long as it’s expected to complete in a timely manner.
Sometimes, the agency may waive the requirement that confirmatory trials be “underway” to grant accelerated nods, such as in the case of drugs for diseases with very small patient populations with high unmet need.
The FDA’s increased pressure on confirming benefits following accelerated approvals was enabled by an amendment to the Federal Food, Drug, and Cosmetic Act in 2023, which states that the FDA may require a confirmatory study to be underway prior to approval.
The move also follows years of frustration both from the public and within the FDA over protracted confirmatory trial timelines and difficulties in pulling a drug off the market when clinical benefit is not verified.