FDA Issues Draft Guidance Describing When a Confirmatory Trial of a Drug Seeking Accelerated Approval Is “Underway”

In recent years, Congress and the U.S. Food and Drug Administration (“FDA”) have sought to reform the accelerated approval process, an expedited development and approval pathway for drugs that provide meaningful therapeutic benefit to patients over existing treatments for serious or life-threatening illnesses or conditions. The accelerated approval pathway enables FDA to approve therapies based on a “surrogate” or “intermediate clinical” endpoint reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit. FDA generally conditions such approval on the completion of one or more adequate and well-controlled confirmatory studies to verify the clinical benefit. As part of these efforts, FDA most recently issued a draft guidance document (the “Confirmatory Trials Guidance”) on January 6, 2025 further clarifying its expectations for the timing of such confirmatory trials.

Congress granted FDA additional authorities related to the accelerated approval pathway in late 2022 as part of the Food and Drug Omnibus Reform Act (FDORA). Among the relevant provisions, Congress authorized FDA to require that confirmatory trials be “underway” prior to granting accelerated approval. In addition, FDORA required that FDA issue guidance on various topics related to accelerated approval. The Confirmatory Trials Guidance comes on the heels of a draft guidance issued by FDA last month that clarifies various aspects of the accelerated approval pathway, including FDA’s expectations and procedures for granting and withdrawing such approval, which we covered in a prior Ropes & Gray Alert. There, FDA stated broadly that it generally intends to enforce the requirement that confirmatory trials be underway prior to approval, and the Confirmatory Trials Guidance describes considerations relevant to developing plans and setting completion dates for confirmatory trials, as well as the key considerations for determining whether a confirmatory trial is underway. A summary of important recommendations and implications is provided below.

What Does “Underway” Mean?

The Confirmatory Trials Guidance underscores that any analysis of whether a confirmatory trial meets the requirement of being “underway” is case-specific and may vary based on several considerations, including study design, therapeutic area, and availability of alternative therapies. As such, the Confirmatory Trials Guidance elects not to give specific time points or targets to assist sponsors in understanding where they fall in relation to FDA’s expectations. Instead, FDA encourages sponsors to have early discussions with FDA on the plan and timeline for a postapproval trial to ensure compliance.

FDA does, however, offer broad principles, stating that it “generally intends to consider a confirmatory trial to be ‘underway’ prior to accelerated approval” if each of the below three criteria are met; the Confirmatory Trials Guidance maintains significant flexibility for FDA in determining whether each of the criteria has been satisfied.

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.

The Confirmatory Trials Guidance states that the natural history of the disease, the availability of alternative treatments, the anticipated recruitment timeline (and any anticipated challenges), and the projected timeline for efficacy analyses may all inform an appropriate target trial completion date for which the sponsor should provide a “clear and sound justification.” The timeline for confirmatory trial completion should limit the amount of time that a drug remains approved without verification of clinical benefit. The Confirmatory Trials Guidance notes that this is critical to protect the public health by minimizing the time patients will be exposed to toxicity from a drug prior to verification of clinical benefit. FDA emphasizes that appropriate target timelines may vary across therapeutic areas.

2. The sponsor’s progress and plans for postapproval conduct of the trial provide sufficient assurance to expect timely completion of the trial.

The Confirmatory Trials Guidance notes that FDA will consider participant accrual rates as well as the pace of site activation to determine whether there is sufficient assurance to expect timely completion of the trial. As part of the planning process, sponsors should propose measurable benchmarks to FDA, which can include, for example, a participant recruitment goal, extent of site activity, and proportion of primary endpoint events accrued. Sponsors must ensure adequate trial resources to ensure that implementation meets benchmark timelines. In the case of a sponsor’s delay in meeting a benchmark(s), FDA will consider whether accelerated approval is appropriate after considering the sponsor’s justification for the delay and plans to address such delay.

3. Enrollment of the confirmatory trial has been initiated.

The Confirmatory Trials Guidance clarifies that initiation of enrollment prior to accelerated approval will generally be considered a minimum expectation. FDA does not specify, however, what the Agency considers to be initiation of enrollment. In cases where significant enrollment or retention challenges are anticipated, FDA may require enrollment to be complete prior to approval. FDA notes that sponsors should consider factors that may impact accrual, including whether wider availability of the drug following accelerated approval is likely to impact participant enrollment and retention, and whether the confirmatory trial is being conducted in the same patient population for which accelerated approval is sought (as compared to, for example, in an earlier disease stage or different treatment setting). FDA also states that sponsors should prioritize early U.S. recruitment, and that U.S. recruitment should generally be closer to completion at the time of approval.

When Might FDA Not Require a Confirmatory Trial to Be Underway Prior to Approval?

The Confirmatory Trials Guidance also explains that there may be limited circumstances in which a confirmatory trial need not be underway prior to approval. Examples provided by the Agency include:

• Situations where a confirmatory trial may be dependent on a future event (e.g., an infectious disease outbreak that has not occurred yet);
• Certain rare diseases where the clinically relevant endpoints and disease natural history may enable post-marketing studies that do not require randomization, which reduces the challenge of enrolling and completing the study if not already underway;
• Certain rare diseases where there are unique challenges with initiating confirmatory trials, including those with very small populations with high unmet need.

In addition, the Confirmatory Trials Guidance notes that there are instances, including in rare disease development programs, in which a pre-planned assessment of a surrogate or intermediate clinical endpoint from an ongoing trial may support accelerated approval, with the trial continuing after accelerated approval is granted to verify clinical benefit. In these instances, the trial would be considered “underway” if it is expected to complete in a timely manner.

Key Takeaways

A Focus on Flexibility: Throughout the Confirmatory Trials Guidance, FDA emphasizes that it is not putting forth a one-size-fits-all approach and that any assessment of this requirement will be case- and context-dependent. FDA seems focused on permitting flexibility—and thereby permitting innovation—in the rare disease context, as the guidance regularly uses rare disease programs as examples of instances in which exceptions, challenges, and special considerations may be relevant.

Early Interaction with FDA: Consistent with FDA’s recommendations in other guidance documents related to the accelerated approval pathway, FDA encourages sponsors to have early discussions with FDA on the plan and timeline for any confirmatory trial. FDA specifically notes that the sponsor and FDA should reach alignment on the design and timing of the confirmatory trial “as soon as practicable, and generally soon after the End-of-Phase 2 meeting.”

FDA’s Ongoing Efforts: Guidance related to the accelerated approval pathway has been a recent priority of FDA. The Confirmatory Trials Guidance is not likely to be FDA’s final effort to issue guidance on this topic, as the Confirmatory Trials Guidance states in a footnote that FDA intends to “address in other guidance complementary authorities” granted to FDA. Additionally, the 2024 Guidance Agenda issued by FDA’s Center for Biologics and Research (CBER) includes a planned draft guidance entitled, “Accelerated Approval of Human Gene Therapy Products for Rare Diseases,” which has not yet been published.

Interested parties may submit comments on the Confirmatory Trials Guidance by March 10, 2025. Ropes & Gray will continue to monitor developments in this area. If you have any questions about this Alert, please contact any member of our FDA regulatory practice or your usual Ropes & Gray advisor.