Accelerated approval is an expedited regulatory pathway designed to hasten the availability of drugs (including biologics) that treat serious conditions, offer advantages over existing therapies, and address 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.” Determining the seriousness of a condition is based on clinical judgment, considering factors such as survival, daily functioning, or the likelihood that the condition will worsen if untreated (21 CFR 312.300(b)(1)). 

The FDA’s 2014 guidance for the industry titled Expedited Programs for Serious Conditions highlights the importance of addressing serious conditions and unmet medical needs. Under 21 USC 35(c), [21 CFR part 314(H) and 21 CFR 601(E)], the FDA grants accelerated approval to drugs showing favorable benefit-risk profiles based on surrogate endpoints reasonably likely to predict clinical benefit. This pathway has been used since 1992, benefiting both sponsors and patients in various disease areas including oncology, neurology, infectious disease, and rare disease. 

However, accelerated approval comes with a condition: sponsors must conduct confirmatory trials to verify the drug’s anticipated clinical benefits using robust outcome measures. In addition to the different outcome measures and endpoints for assessing the clinical benefit, these trials may involve more patients or longer durations than the initial studies supporting the accelerated approval, leading to delays in the final determination of the product’s benefit-risk ratio. Concerns have arisen over delays—sometimes spanning over 7–8 years—that may expose patients to risks before confirmatory trials are completed. To address these delays, the FDA has required certain confirmatory trials to be underway before granting accelerated approval. 

The bridge from provisional to full approval

Confirmatory trials are designed to definitively prove that a drug’s early benefits hold up in more extensive, longer-term studies using established clinical endpoints to more directly assess the clinical benefit. Without these trials, the FDA cannot fully determine whether the initial benefit-risk assessment made during accelerated approval is justified. In essence, these trials are the final step that turns provisional approval into full approval. 

However, the challenges surrounding confirmatory trials often revolve around delays and the complexities of conducting them once a drug has already hit the market. Unfortunately, the very factors that allow a drug to gain accelerated approval often hinder the progress of confirmatory trials. 

In recent years, the FDA has increasingly required confirmatory trials to begin at the time of the New Drug Application (NDA) submission and to be underway or completed to a certain stage. This approach ensures timely completion of confirmatory trials in closer proximity to the initial approval. The 2022 FDORA Omnibus Act, enacted on December 29, 2022, further solidified this shift by making confirmatory trials a key component of the clinical development plan, contrasting with earlier practices where they were often a post-approval requirement. 

Recruitment challenge in confirmatory trials

One of the most prominent issues with confirmatory trials is patient recruitment. Once a drug receives accelerated approval and becomes available to patients outside the trial setting, it becomes far more difficult to recruit participants for confirmatory studies, especially for placebo-controlled trials. Patients who have access to the drug through regular prescriptions are unlikely to enroll in a clinical trial, particularly if it involves the risk of receiving a placebo or being in a control group. 

Along these lines, the FDA has voiced concerns over the timely completion of confirmatory trials. A report by the Office of Inspector General (OIG) in September 2022 revealed that over one-third of drugs granted accelerated approval had incomplete confirmatory trials, with 34% delayed beyond their original completion dates. This has prompted the FDA to impose stricter requirements for confirmatory trials to be underway at the time of NDA submission. 

From rare diseases to cancer: A focus on serious conditions

The FDA’s “Project Confirm” aims to enhance transparency around outcomes related to accelerated approvals, particularly in oncology. In its 2022 guidance, “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics,” the FDA underscores the importance of timely and rigorous confirmatory trials in oncology. While requiring confirmatory trials at the time of accelerated approval is not new, earlier cases like Folotyn® (2009) and Beleodaq® (2014) demonstrate how the FDA has, in the past, mandated full enrollment in such trials before approval. 

Recent case studies 

• Ocaliva® (Obeticholic Acid): This drug received an initial accelerated approval on May 27, 2016, for the treatment of primary biliary cholangitis. In September 2024, the FDA gathered an advisory committee to acquire expert advice on the final results of the completed confirmatory trials. The advisory committee voted that Ocaliva’s benefit-risk assessment is not favorable based on results of the confirmatory trials, where the controlled trial revealed higher rates of liver transplant in the intervention group. The FDA has yet to complete its review of the application (initial target date was October 15, 2024). The advisory committee recommendations are not binding for the FDA and the application review is ongoing by the agency. Given the limited treatment options for PBC patients, this case illustrates the challenges associated with delayed confirmatory trials, faced by both sponsors and regulatory authorities. 

• Camidanlumab Tesirine®: This treatment for relapsed or refractory Hodgkin lymphoma faced setbacks in 2022 when the FDA advised against submitting a Biologics License Application (BLA) without a well-underway Phase 3 confirmatory trial, delaying the approval process. This decision, communicated in November 2022, delayed the BLA submission as the confirmatory trial needs to reach full enrollment before submission of the marketing application. 

• Odronextamab®: The BLA for Regeneron’s CD20xCD3 bispecific, Odronextamab®, was submitted for accelerated approval in September 2023 for treating relapsed/refractory (R/R) follicular lymphoma and diffuse large B-cell lymphoma based on a Phase 1 and a Phase 2 trial. The confirmatory trials were started and included an initial dose ranging part, followed by the confirmatory effectiveness part. While the accelerated approval decision was expected in 2024, the FDA issued a complete response letter because the confirmatory trial was still in the dose ranging part and the confirmatory part of the study had not started enrollment. At the time of this decision there were other products available for this indication that were approved via the accelerated approval pathway.  

• Toferson (QALSODY®): In contrast, Toferson (SOD1-ALS treatment) complied with the FDA’s updated requirements. Its confirmatory trial began on June 18, 2021, well before the NDA submission in 2022, exemplifying what the FDA would expect as requirements for accelerated approval. 

Regulatory changes and industry impact

The 2022 FDORA Omnibus Act and updated FDA guidance (March 2023) have introduced stricter requirements for confirmatory trials in the accelerated approval process. These changes aim to ensure that the benefits of accelerated approvals are realized quickly, and that clinical benefits are verified in a timely manner. While these requirements are challenging, especially for smaller companies, they are critical to maintaining the integrity of the pathway. 

The amended USC 356(c) provides the FDA with more authority to ensure substantial progress in confirmatory trials before granting accelerated approval. This extends beyond the long-standing challenge of patient enrollment in placebo-controlled trials once a product becomes available. By shortening the time between accelerated approval and final full approval, the FDA seeks to provide timely updates on a product’s benefit-risk assessment. 

In 2023, the FDA established the Accelerated Approval Coordinating Council (AACC) to ensure the consistent and appropriate use of accelerated approval pathway across the agency. The council includes directors from various FDA centers and offices, meeting regularly to discuss policy issues and develop guidance to support the accelerated approval process. Furthermore, 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.  

Navigating the path forward

Despite greater regulatory scrutiny, there is a delicate balance between encouraging innovation and maintaining the integrity of the accelerated approval pathway. Early planning and coordination with the FDA are now more essential than ever for companies navigating this pathway. Acquiring agreement on confirmatory trial expectations early on during product development can help sponsors manage timelines, resources, and partnerships more effectively. 

Our multidisciplinary teams offer significant experience in navigating the dynamic field of accelerated approval, leveraging knowledge and expertise adapted for biotech, medtech, and pharma companies of various sizes and stages. For support with your program, please contact us.