The FDA is intensifying its oversight of drugs receiving accelerated approval, implementing stricter requirements for confirmatory trials to ensure timely verification of clinical benefits. These changes address growing concerns about delays in confirming the efficacy of drugs approved through this expedited pathway, which is designed to hasten the availability of treatments for serious conditions with unmet medical needs. The FDA defines a serious condition as “a disease or condition associated with morbidity that has a substantial impact on day-to-day functioning.”
The Evolving Landscape of Accelerated Approvals
Accelerated approval, in use since 1992, allows the FDA to approve drugs based on surrogate endpoints reasonably likely to predict clinical benefit. However, this approval is contingent upon the completion of confirmatory trials that verify the anticipated clinical benefits using robust outcome measures. These trials may involve more patients or longer durations than the initial studies, and delays in their completion have raised concerns about exposing patients to potential risks without confirmed benefits.
In recent years, the FDA has increasingly required confirmatory trials to be underway at the time of NDA submission. The 2022 FDORA Omnibus Act further solidified this shift, making confirmatory trials a key component of the clinical development plan. This contrasts with earlier practices where they were often a post-approval requirement.
Recruitment Challenges and Regulatory Responses
One of the most significant hurdles in conducting confirmatory trials is patient recruitment. Once a drug receives accelerated approval and becomes available outside the trial setting, recruiting participants for placebo-controlled trials becomes exceedingly difficult. Patients are often unwilling to risk receiving a placebo when they have access to the drug through regular prescriptions.
Concerns over timely completion of confirmatory trials have prompted the FDA to impose stricter requirements. A 2022 report by the Office of Inspector General (OIG) revealed that over one-third of drugs granted accelerated approval had incomplete confirmatory trials, with 34% delayed beyond their original completion dates.
Project Confirm and Recent Case Studies
The FDA’s “Project Confirm” aims to enhance transparency around outcomes related to accelerated approvals, particularly in oncology. The FDA underscores the importance of timely and rigorous confirmatory trials in oncology in its 2022 guidance, “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.”
Several recent cases highlight the complexities and challenges associated with confirmatory trials:
- Ocaliva (Obeticholic Acid): Following initial accelerated approval in 2016 for primary biliary cholangitis, an FDA advisory committee in September 2024 voted that Ocaliva’s benefit-risk assessment was not favorable based on confirmatory trial results, which revealed higher rates of liver transplant in the intervention group. The FDA has yet to complete its review of the application.
- Camidanlumab Tesirine: In 2022, the FDA advised against submitting a Biologics License Application (BLA) for this treatment for relapsed or refractory Hodgkin lymphoma without a well-underway Phase 3 confirmatory trial, delaying the approval process.
- Odronextamab: Regeneron’s CD20xCD3 bispecific, Odronextamab, had its BLA for relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma rejected due to the confirmatory trial still being in the dose-ranging phase.
- Toferson (QALSODY): In contrast, Toferson (SOD1-ALS treatment) complied with the FDA’s updated requirements, initiating its confirmatory trial well before the NDA submission.
Regulatory Changes and Industry Impact
The 2022 FDORA Omnibus Act and updated FDA guidance (March 2023) have introduced stricter requirements for confirmatory trials. These changes aim to ensure that the benefits of accelerated approvals are realized quickly and that clinical benefits are verified in a timely manner. The amended USC 356(c) provides the FDA with more authority to ensure substantial progress in confirmatory trials before granting accelerated approval.
In 2023, the FDA established the Accelerated Approval Coordinating Council (AACC) to ensure the consistent and appropriate use of the accelerated approval pathway across the agency. A recent paper by the FDA published in the Journal of Clinical Oncology (October 2024) sheds light on the FDA’s current points of view in interpreting failed confirmatory trials.
These changes also affect the financial and developmental timeline for companies, as confirmatory trials must now be in progress (therefore, funded) before an NDA/BLA submission. Early engagement with the FDA is crucial, as the degree of progress of confirmatory trials is determined on a case-by-case basis. Therefore, discussing confirmatory trials early in the process can save time and facilitate streamlined development.
