March 29, 2023 -
Recent Developments Related to Accelerated Approval
The new draft guidance is the latest action in a series of efforts to reform the accelerated approval program, which has been scrutinized in recent years due to a number of accelerated approval drugs for which FDA subsequently withdrew approval after confirmatory studies failed to verify clinical benefit as well as significant delays in sponsors completing required confirmatory studies in the first place. Since 2020 alone, FDA has withdrawn the accelerated approvals of 16 cancer drug indications.1
In October 2021, FDA’s Oncology Center of Excellence (“OCE”) launched the “Project Confirm” initiative to promote the transparency of outcomes related to accelerated approval for oncology indications. Through this initiative, OCE has, among other things, published summary information on FDA’s website regarding which accelerated approvals are the subject of ongoing confirmatory studies, which have been withdrawn, and which have completed confirmatory studies that verified clinical benefit.
In December 2022, Congress enacted amendments to the accelerated approval program as part of the Food and Drug Omnibus Reform Act (“FDORA”), expanding FDA’s authority to, among other things, use expedited withdrawal procedures if a sponsor fails to conduct a confirmatory clinical trial with due diligence and require a confirmatory trial be underway prior to granting an accelerated approval. See Ropes & Gray’s prior Alert for additional details.
Recent attention to the accelerated approval program has also come from the Centers for Medicare & Medicaid Services (“CMS”) in the drug pricing context. In February 2023, CMS announced a new drug pricing model for testing—the accelerating clinical evidence module—that, if implemented, would adjust the Medicare Part B payments for drugs subject to accelerated approval that have not yet completed their confirmatory trials.2 CMS stated it intends to consult with FDA to explore the feasibility of such a model and, if the agency determines the model is appropriate, would continue its development thereafter.
These efforts, together with FDA’s new draft guidance, seek to facilitate the timely completion of confirmatory studies and ensure that clinical data to support FDA approval are sufficiently robust.
Key Clinical Trial Considerations
FDA’s accelerated approval program allows for earlier approval of drugs that treat serious or life-threatening conditions, provide a meaningful advantage over available therapies, and have an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.3 For drugs that receive accelerated approval, FDA generally requires the sponsor conduct a confirmatory study to verify and describe the clinical benefit as a condition of continued approval.
Considerations for the One-Trial Approach
A one-trial approach should be designed, executed, and analyzed in a manner that permits a robust assessment of efficacy. In designing the trial, FDA emphasizes the importance of selecting an endpoint for accelerated approval that is clinically meaningful, of sufficient magnitude to be reasonably likely to predict clinical benefit, and feasible to evaluate earlier in the study considering factors such as disease progression and the drug’s mechanism of action. Although response rate is most commonly used to support accelerated approval, the guidance notes that other endpoints may also be appropriate depending on the intended patient population and disease course.
FDA recommends that the analysis of efficacy to support accelerated approval be delayed until the trial is close to or fully enrolled to mitigate potential challenges in patient enrollment if FDA grants accelerated approval.
Considerations for the Two-Trial Approach
Although the one-trial approach may increase efficiency, FDA notes that a sponsor may choose to conduct two RCTs: one study to support accelerated approval and one confirmatory study to verify clinical benefit and support traditional approval. FDA explains that to facilitate enrollment in the confirmatory trial, it may be acceptable to evaluate the drug in earlier lines of therapy than those for which accelerated approval was granted. In addition to facilitating enrollment, this would provide an opportunity for sponsors to assess the safety and efficacy of the drug in patients at an earlier stage of the disease at which the clinical benefit may be greater and could therefore support approval for its use in an expanded patient population. If the sponsor chooses to conduct two RCTs, FDA has long recommended that the confirmatory trial be underway at the time of application submission,4 and the new draft guidance now recommends that the confirmatory trial be near full enrollment at the time of the accelerated approval.
These recent actions potentially suggest a broader shift in FDA’s approach to accelerated approval drugs. FDA plans to hold a series of workshops this year to discuss the role of surrogate efficacy endpoints, their ability to predict OS, and the information necessary to make a risk–benefit determination for novel oncology drugs.
https://www.ropesgray.com/en/newsroom/alerts/2023/03/oncology-drug-development-in-focus-fda-offers-recommendations-for-clinical-trial-designs#:~:text=FDA's%20accelerated%20approval%20program%20allows,likely%20to%20predict%20clinical%20benefit.