The FDA has released draft guidance to clarify its expectations for confirmatory trials required for drugs granted accelerated approval. This guidance, titled "Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway," outlines the criteria the FDA will use to determine whether a confirmatory trial is sufficiently underway to support accelerated approval. The guidance aims to provide clarity to drug sponsors and ensure timely verification of clinical benefit for drugs approved through this expedited pathway.
Key Requirements for Confirmatory Trials
The FDA emphasizes that, in most cases, confirmatory trials should be underway before accelerated approval is granted. This requirement stems from the Food and Drug Omnibus Reform Act (FDORA) of 2022, which granted the FDA additional authority to ensure the timely completion of confirmatory trials. A trial is considered "underway" if it meets the following criteria:
- Target Completion Date: The trial has a target completion date consistent with diligent and timely conduct.
- Sufficient Progress: The sponsor's progress and plans provide sufficient assurance of timely completion.
- Initiated Enrollment: Enrollment in the confirmatory trial has begun.
The FDA acknowledges that there may be limited circumstances where a confirmatory trial need not be underway prior to approval, such as when the trial is dependent on a future event (e.g., an infectious disease outbreak). For certain rare diseases, the FDA may also consider non-randomized studies sufficient to verify clinical benefit, given the challenges associated with study enrollment and completion in small populations.
Early Engagement with the FDA
The guidance encourages sponsors to engage in early discussions with the FDA regarding their confirmatory trial plans. These discussions should occur as soon as practicable, generally soon after the End-of-Phase 2 meeting. The goal is to reach an agreement on the design of the confirmatory trial, including the FDA's review of draft protocols. The FDA has stated the trial "must be feasible to conduct and appropriately designed to verify and describe clinical benefit."
Factors Influencing Trial Completion Dates
When determining the target completion date for a confirmatory trial, the FDA will consider several factors, including:
- The natural history of the disease
- The availability of alternative treatments
- The anticipated recruitment timeline
- The projected timeline for efficacy analysis
Rare Disease Considerations
The guidance provides specific considerations for rare diseases, recognizing the unique challenges in initiating and completing confirmatory trials in these populations. The FDA may not require a confirmatory trial to be underway prior to approval in certain rare disease cases, particularly those with very small populations and high unmet need, provided appropriate justification is given. The agency also acknowledges that pre-planned assessments of surrogate endpoints from ongoing trials may support accelerated approval, with the trial continuing to verify clinical benefit.
Implications for Drug Sponsors
This draft guidance signals the FDA's intent to more rigorously enforce the requirement for timely confirmatory trials. Drug sponsors seeking accelerated approval should proactively engage with the FDA early in the development process to align on trial designs and timelines. Sponsors should also be prepared to provide clear and sound justifications for their proposed target completion dates and demonstrate sufficient progress in initiating and conducting confirmatory trials. The comment period for the draft guidance closes on March 10, 2025.
