Accelerated approval: FDA explains when it considers confirmatory trials underway

The US Food and Drug Administration (FDA) has proposed a guidance that would hold sponsors of drugs with accelerated approval more accountable for conducting confirmatory studies in a timely manner. The draft guidance is based on additional authorities given to the agency by Congress under the 2023 Consolidated Appropriations Act (CAA) and is intended to clarify when a trial is considered underway prior to approval.

A major criticism of FDA’s accelerated approval program has been that confirmatory trials are often completed late, or in some cases not at all, leaving important questions about products’ efficacy unanswered while the studies are pending. (RELATED: Study: Half of confirmatory studies for accelerated approvals are late, Regulatory Focus 4 April 2023; Study: 'Little incentive’ for drugmakers to complete confirmatory trials for accelerated approvals, Regulatory Focus 29 August 2022)

“While many confirmatory trials are completed in a timely fashion, some have been slow to initiate or have stalled, resulting in long delays or even uncertainty about whether studies can be completed,” said FDA. “In the Consolidated Appropriations Act, Congress provided FDA with additional authorities to help prevent such delays, including that FDA may, when appropriate, require a confirmatory study or studies to be underway prior to approval.”

“FDA generally intends to consider a confirmatory trial to be ‘underway’ prior to accelerated approval if (1) the trial has a target completion date that is consistent with diligent and timely conduct of the trial, considering the nature of the trial’s design and objectives, (2) the sponsor’s progress and plans for postapproval conduct of the trial provide sufficient assurance to expect timely completion of the trial, and (3) enrollment of the confirmatory trial has been initiated,” the agency added.

FDA can grant accelerated approval to products to treat serious or life-threatening diseases or conditions where there may be a lack of alternative treatments. As a result, eligible products can get to patients quicker, but with less certainty about their effectiveness. In recent years, some two dozen oncology accelerated approvals have been withdrawn after failing to confirm clinical benefit. (RELATED: Study: Accelerated approvals leave lingering uncertainty about cancer drugs’ benefits, Regulatory Focus 8 April 2024; FDA and industry support fixes to accelerated approval program, Regulatory Focus 18 May 2023)

“The risks of this approach include the possibility that patients may be exposed to the risks of a drug that eventually fails to verify clinical benefit,” noted FDA. “In addition, a drug granted accelerated approval is generally supported by smaller or shorter clinical trials than is typical for a drug receiving traditional approval, which may mean there is less information about the occurrence of rare or delayed adverse events.”

“Sponsors have therefore been required to conduct postapproval trials to verify clinical benefit of drugs granted accelerated approval,” the agency added. “These confirmatory studies protect the public health and the integrity of the drug approval process by balancing earlier approval of drugs with an assurance that studies will be conducted to resolve residual uncertainty about benefit.”

FDA typically requires sponsors to complete confirmatory trials after the product has been allowed on the market under accelerated approval to collect more data and ensure it works as anticipated. The agency said the trials must be completed promptly, especially in cases where the drug has considerable toxicity, to prevent unnecessary harm to patients.

FDA noted that it plans to publish other guidances based on its CAA authorities on what it intends to do if sponsors don't complete their confirmatory studies on time.

“The Consolidated Appropriations Act authorizes FDA to specify the conditions for the progress of a required postapproval trial, which may include enrollment targets, the study protocol, and milestones, including the target date of study completion,” said FDA. “Failure to conduct a trial with due diligence, including with respect to these conditions, can be grounds for withdrawing approval using expedited withdrawal procedures.”

The agency also noted that under the CAA, sponsors are required to report the progress of their confirmatory trials approximately every 180 days.

FDA recommended sponsors seeking accelerated approval speak to reviewers early about their drug development plans and plans for conducting confirmatory studies. More specifically, the agency said that sponsors and regulators should generally agree on a feasible and appropriate design for a confirmatory study soon after the End-of-Phase 2 meeting.

“The timelines for the confirmatory trial – and in particular, the expected completion date – should be discussed with FDA prior to the submission of the application for accelerated approval,” said FDA. “The timeline for confirmatory trial completion should reflect timely completion of the trial, including diligent conduct of the trial by the sponsor in a manner that limits the amount of time the drug will remain approved without verification of clinical benefit.”

“FDA generally intends to consider a confirmatory trial to be 'underway' ... if the sponsor’s progress to date and plans for postapproval conduct of the trial (specifically, the trial period intended to provide confirmation of benefit) provide sufficient assurance to expect timely completion of the trial,” the agency added.

Stakeholders can comment on the guidance on www.regulations.gov under docket no. FDA-2024-D-3334 until 10 March.

Draft guidance

Accelerated approval: FDA explains when it considers confirmatory trials underway

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