FDA Issues Draft Guidance for Accelerated Approval Confirmatory Clinical Trials

FDA

The FDA’s Oncology Center of Excellence has released a draft guidance document describing the FDA’s interpretation of when a confirmatory clinical trial for an accelerated approval is underway.^1,2 The finalized document will also include policies for implementing the requirement of a confirmatory trial such as factors the agency will consider when determining whether a confirmatory trial is underway prior to an accelerated approval action.

The FDA wrote that they generally consider a confirmatory trial to be underway prior to accelerated approval if the following conditions are satisfied: 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; the sponsor’s progress and plans for post-approval conduct of the trial provide sufficient assurance to expect timely completion of the trial; and enrollment of the confirmatory trial has been initiated.²

In 2023, Congress amended section 506(c) of the FD&C Act (21 U.S.C. 356(c)) via the Consolidated Appropriations Act to offer additional authorities to help ensure timely completion of confirmatory trials.¹ This included language that stated the FDA “may require, as appropriate, a study or studies to be underway prior to approval, or within a specified time period after the date of approval, of the applicable product.”

Section 506(c) regarding accelerated approval provisions of the FD&C Act provide that the FDA may grant accelerated approval to a “product for a serious or life-threatening disease or condition… upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.”²

Agents that receive accelerated approval are required to undergo confirmatory study to verify their effect on irreversible morbidity, mortality, or other clinical benefits. Although many confirmatory studies are completed in a timely manner, a portion have been slow to be initiated or have stalled, causing delays and uncertainty in their completion.

In their draft guidance, the FDA wrote that after they reach preliminary alignment on a development program that could support an accelerated approval, sponsors should request a meeting with the agency to discuss a comprehensive drug development program, including plans for confirmatory trial(s). In general, there should be an agreement between the FDA and the sponsor on the design of the confirmatory trial(s), including the FDA’s review of draft protocol(s), as soon as practicable and usually soon after the End-of-Phase 2 meeting.

When determining if a confirmatory study is considered to be underway, in terms of the confirmatory trial target completion date, the FDA noted that it should be informed by factors including the natural history of the disease, availability of alternative treatments, anticipated recruitment timeline, and projected timeline for efficacy analysis. Other factors the FDA will consider when deciding if a trial is underway consist of accrual to date and projected accrual rate as well as the number of active sites to date and the projected rate of additional site activation.

The FDA acknowledged that there are circumstances where they may not require a confirmatory trial to be underway prior to an accelerated approval, such as if the confirmatory study was contingent on a future event. The agency also encouraged sponsors to participate in early discussions with them concerning the plan and timeline of a post-approval study, including timing for initiation of the confirmatory study, and appropriate justification for the plan and timeline.

References

1. Accelerated approval and considerations for determining whether a confirmatory trial is underway. FDA. January 6, 2025. Accessed January 7, 2025. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/accelerated-approval-and-considerations-determining-whether-confirmatory-trial-underway
2. Accelerated approval and considerations for determining whether a confirmatory trial is underway guidance for industry draft guidance. FDA. January 7, 2025. Accessed January 7, 2025. https://www.fda.gov/media/184831/download