The FDA has released a draft guidance document specifying criteria for determining whether a confirmatory trial is underway prior to accelerated approval, as mandated by the Food and Drug Omnibus Reform Act (FDORA) of 2022. This guidance aims to clarify expectations for accelerated approval endpoints and confirmatory trials, as well as the FDA's process for withdrawing accelerated approval. The FDA is soliciting public comment on the Accelerated Approval Guidance until March 6, 2025, and on the Confirmatory Trial Guidance document until March 10, 2025.
Key Elements of the Draft Guidance
The draft guidance focuses on two main areas: requirements for granting accelerated approval and procedures for withdrawing such approval. It emphasizes that accelerated approval should not be considered if completing an adequate and well-controlled clinical trial to verify clinical benefit is infeasible.
Granting Accelerated Approval
The FDA explains that there are two types of endpoints that may be used as a basis for accelerated approval: surrogate and intermediate clinical endpoints. The FDA recommends that sponsors who intend to use novel surrogate or intermediate clinical endpoints as the basis for accelerated approval engage the FDA early in the development process. For rare diseases, the FDA will consider information from other available sources, including preclinical animal models, epidemiological data, and relevant clinical data.
Evidentiary Standards
The draft guidance underscores that an accelerated approval application must meet the same standards for safety and effectiveness as those granted traditional approval. It must also include adequate evidence that the proposed surrogate or intermediate clinical endpoint is reasonably likely to predict the intended clinical benefit of the drug. The FDA considers all relevant evidence in assessing a surrogate or intermediate clinical endpoint's predictive value.
Confirmatory Trials
Sponsors receiving accelerated approval generally must conduct post-approval confirmatory trials to verify and describe the drug's clinical benefit, carried out with due diligence. The FDA has interpreted the due diligence requirement to mean that sponsors must commit sufficient resources to conduct the trial(s) intended to verify the clinical benefit expeditiously so that a determination of whether the drug provides the expected clinical benefit can be made as soon as possible. The FDA intends to require that confirmatory trial(s) be underway prior to granting accelerated approval except in limited circumstances.
Withdrawing Accelerated Approval
Congress granted the FDA the authority to deploy expedited procedures to withdraw accelerated approval if certain conditions are met. Expedited withdrawal may be appropriate if:
- The sponsor fails to conduct any required confirmatory trial with due diligence.
- A confirmatory study fails to verify and describe the predicated effect on irreversible morbidity or mortality (IMM) or other clinical benefit.
- Other evidence exists that the product is not safe or effective.
- The sponsor disseminates false or misleading promotional materials for the product.
If the FDA determines that one or more withdrawal criteria has been met, the draft guidance provides a detailed overview of the expedited withdrawal procedures, including due notice, opportunity for public comment, opportunity for a written appeal, opportunity for a meeting, and final decision.
Key Takeaways
The draft guidance provides clarity on the expectations, processes, and timelines associated with obtaining and withdrawing accelerated approvals. The FDA emphasizes that many considerations in the accelerated approval process are case-specific or context-dependent, and are therefore not readily generalizable. As a result, the draft guidance instructs sponsors to engage directly with the FDA early and often during the development process.
