The FDA's accelerated approval pathway, designed to expedite the availability of drugs for serious conditions with unmet needs, is facing increased scrutiny as several high-profile drugs approved through this mechanism have been withdrawn from the market. These withdrawals raise concerns about the reliability of surrogate endpoints and the timely completion of confirmatory trials. The pathway, implemented in 1992 during the HIV/AIDS epidemic, allows drugs to be approved based on a surrogate endpoint reasonably likely to predict clinical benefit, contingent on the completion of a confirmatory trial.
Recent Withdrawals Highlight Concerns
Pfizer's recent withdrawal of Oxbryta, a hemoglobin polymerization inhibitor for sickle cell disease (SCD), exemplifies the challenges associated with accelerated approvals. Approved in November 2019, Oxbryta was the first medicine to specifically target the root cause of SCD. However, in September 2024, Pfizer pulled the drug from global markets after new safety data indicated an imbalance of vaso-occlusive crises and mortality events in treated patients. The company concluded that Oxbryta's overall benefit no longer outweighed the risk, leaving providers and patients with limited treatment options.
Biogen and Eisai's Aduhelm, approved in June 2021 as the first Alzheimer's drug to address an underlying cause of the disease, also faced significant controversy. The FDA's decision to approve Aduhelm went against the recommendation of its advisory committee, which deemed the evidence from Phase III trials insufficient. After a difficult market rollout, Biogen discontinued Aduhelm in January 2024 to focus on Leqembi, which received traditional FDA approval as an anti-amyloid beta treatment.
Takeda's Exkivity, TG Therapeutics' Ukoniq, and Gilead Sciences' Zydelig are other examples of drugs that received accelerated approval but were later withdrawn due to failure to confirm clinical benefit or safety concerns. Exkivity, a tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) with EGFR exon 20 mutations, was withdrawn after the Exclaim-2 trial failed to confirm initial positive results. Ukoniq, a PI3K inhibitor for lymphoma, was pulled after data showed a possible increased risk of death. Gilead withdrew Zydelig for relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL) due to difficulties in completing confirmatory studies.
Addressing the Challenges
These withdrawals have prompted the FDA to strengthen the requirements for accelerated approvals. The agency now mandates that confirmatory trials be underway before granting accelerated approval. This change aims to address delays in completing these trials and ensure that clinical outcomes are rigorously evaluated. Joseph Ross, a professor of medicine and public health at Yale School of Medicine, emphasized the importance of focusing on clinical outcomes rather than relying solely on surrogate markers.
Sarepta's Elevidys: A Different Outcome
Despite failing to meet the primary endpoint in a confirmatory study, Sarepta Therapeutics' Elevidys, a gene therapy for Duchenne muscular dystrophy (DMD), secured full approval and a label expansion. The initial accelerated approval was based on increased expression of Elevidys' micro-dystrophin protein, a surrogate endpoint. Although the Phase III EMBARK study missed its primary efficacy endpoint, Sarepta presented additional evidence of clinically meaningful treatment benefit, leading to the FDA's decision to grant full approval.
Peter Marks, director of the FDA's Center for Biologics Evaluation and Research (CBER), has defended the accelerated approval mechanism, particularly for rare diseases, stating that biomarkers and intermediate endpoints can facilitate initial market access. However, the recent withdrawals underscore the need for careful evaluation of surrogate endpoints and timely completion of confirmatory trials to ensure the safety and efficacy of drugs approved through this pathway.
