FDA Issues New Draft Guidance on Getting Confirmatory Trials “Underway” for Accelerated Approvals

On January 7, 2025, the U.S. Food and Drug Administration (FDA or the Agency) released a draft guidance document titled, “Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway” (the Draft Confirmatory Trial Guidance).¹ The draft guidance describes how FDA will interpret whether a confirmatory trial is “underway” for accelerated approval pathway purposes and outlines the factors that the Agency will take into consideration when making such a determination.

FDA’s issuance of this draft guidance document follows the Agency’s issuance of a related draft guidance document in December 2024, titled “Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics,” which addresses FDA’s accelerated approval program more generally. See Arnold’s & Porter’s Advisory regarding that guidance.

Background

Sponsors whose drugs (including biologics) have been granted accelerated approval must conduct confirmatory studies to verify and describe the anticipated clinical benefit of the surrogate or intermediate endpoint used to support approval.² The Food and Drug Omnibus Reform Act of 2022 (FDORA) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to provide FDA with direct authority to ensure that these confirmatory trials are conducted in a timely manner, including the authority to “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.”³ Congress granted this new authority to FDA in the face of mounting frustration with the timeliness which the confirmatory studies have been conducted — and in some instances questions over whether such studies would be completed at all.⁴

Obligation To Complete Confirmatory Trial

The Draft Confirmatory Trial Guidance takes the position that the Agency presumptively will, with only limited exceptions, require the sponsor to demonstrate that the confirmatory trial (or trials, as appropriate to the product) is well “underway” prior to accelerated approval. If it is not, the Agency “does not intend to grant accelerated approval until this deficiency is addressed.”⁵

FDA acknowledges the impact of an accelerated approval itself on trial enrollment, which can make it more difficult to enroll patients in confirmatory studies because the drug is then available on the market outside of clinical studies. In FDA’s view, those challenges with continued enrollment and retention are a reason to push confirmatory trial work even earlier; in some cases the Agency may require enrollment to be complete at the time of the accelerated approval.

The Draft Confirmatory Trial Guidance also acknowledges that there could also be circumstances in which a confirmatory trial does not need to be underway prior to accelerated approval, but that such circumstances would be rare. And the example illustrates the rarity point: the draft guidance provides that such a circumstance could exist if the confirmatory trial is dependent on a future event, such as an infectious disease outbreak that has not yet occurred.

FDA also notes that the clinically relevant endpoints and the disease natural history may not necessitate randomization in the confirmatory trial, when such a “design could reduce the challenge of enrolling and completing the study if it is not underway prior to approval,”⁶ though the draft guidance cabins this flexibility in terms as available “for certain rare diseases.” FDA has previously noted that randomized trials may not always be possible in cases where there aren’t enough patients with a rare disease to fulfill two trial arms, or, as can sometimes occur with urgent life threatening diseases such as cancer, if patients refuse the possibility that they might be administered a placebo.⁷

Underway Determination

The Draft Confirmatory Trial Guidance focuses on what the sponsor must do to demonstrate that a confirmatory trial is “underway” prior to accelerated approval. In particular, FDA expects to see that:

• 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 provides sufficient assurance to expect timely completion of trial.
• Enrollment of the confirmatory trial has been initiated.

The draft guidance further explains that plans for, and discussions with, FDA regarding confirmatory trials should occur relatively early on in the development process. As soon as practicable and “generally soon after the End-of-Phase 2 meeting”⁸ there should be an agreement between FDA and the sponsor regarding the design of the confirmatory trial, and that by such time FDA expects to have been able to review the draft protocol for the confirmatory trial. On this note, the draft guidance provides that after sponsors and FDA reach a preliminary understanding that the drug could receive accelerated approval, sponsors should seek to meet with FDA to discuss plans for the confirmatory trial.

Target Completion Date

The draft guidance provides that timelines for the confirmatory trial should be discussed with FDA prior to submission of an application seeking accelerated approval. Considerations that FDA will look to for the target trial completion date include:

• Natural history of the disease
• Availability of alternative treatments
• Anticipated recruitment timeline
• Projected timeline for efficacy analysis, taking into consideration event rate and/or minimum follow-up required, depending on the outcome of the interest

The Draft Confirmatory Trial Guidance acknowledges that appropriate target completion dates may differ across therapeutic areas. FDA notes as an example that in oncology the median time from accelerated approval to verification of benefit is approximately three years.

Other Factors FDA Intends To Consider When Deciding Whether a Trial Is Underway

The draft guidance indicates that the core question is whether the sponsor has provided sufficient assurance to FDA of diligent and timely completion of the trial for the Agency to feel confident that the trial will be timely completed. If one or more of the sponsor’s benchmark(s) has not been met prior to the accelerated approval action date, FDA will consider whether accelerated approval is appropriate, after taking into consideration the sponsor’s justification for the delayed progress and the sponsor’s plan to address the delay. To this end, FDA may consider additional factors, including participant accrual to date, participant accrual rates, number of active sites to date, and projected rate of additional site activation. Sponsors should propose benchmarks for these and other relevant factors to FDA to help facilitate FDA’s determination as to whether the trial is “underway.”

Conclusion and Look Ahead

Ultimately, the Draft Confirmatory Trial Guidance indicates that FDA’s default rule going forward will be that confirmatory trials must be underway prior to FDA granting accelerated approval, and that FDA will seek to apply its newfound FDORA authority strictly. This draft guidance in particular reflects FDA’s planned thinking that the Agency will not grant an accelerated approval unless assured by the sponsor that the confirmatory trial is feasible, appropriately designed, and will be completed in a diligent and timely manner. Drug and biologic developers and sponsors considering the accelerated approval pathway should make sure they understand and are comfortable with meeting FDA’s expectations and requirements regarding confirmatory trials.

Of note, FDA has been working (relatively) rapidly to implement the FDORA accelerated approval guidance, with a major guidance last month and several more potentially coming on accelerated approval this year, including guidance on accelerated approval of human gene therapy products for rare diseases⁹ and guidance on civil monetary penalties for failure to meet accelerated post-marketing requirements.¹⁰ This one, while short, has the potential to seriously impact programs considering or planning for accelerated approval.

Comments are due to FDA on the draft guidance by March 10, 2025. If you have any questions about the content discussed here or would like more information, please reach out to one of the authors of this Advisory or to your existing Arnold & Porter contact.

© Arnold & Porter Kaye Scholer LLP 2025 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.