Regulatory Framework and Scientific Rationale
Accelerated approval pathways were institutionalized through the FDA Accelerated Approval Program (AAP), codified in 21 CFR 314.510, which permits approval based on surrogate endpoints reasonably likely to predict clinical benefit (1). In oncology, these surrogate endpoints typically include progression-free survival, overall response rate, and duration of response rather than the gold standard of overall survival. The scientific premise underlying this approach considers that cancer patients facing poor prognoses cannot wait for the completion of lengthy Phase III randomized trials when preliminary evidence suggests substantial therapeutic benefit.
Drugs approved via the AAP are subject to post-approval requirements to verify clinical benefit. This conditional approval mechanism requires sponsors to submit protocols for confirmatory studies prior to full approval, ensuring continued evaluation of therapeutic efficacy through rigorous clinical investigation.
The utilization of surrogate endpoints in accelerated approvals necessitates careful consideration of their predictive validity for meaningful clinical outcomes. Progression-free survival has shown good correlation with patient benefit particularly in settings of metastatic disease where treatment options are limited. For example, palbociclib (Ibrance®) represented a landmark accelerated approval based on significant improvement in progression-free survival.
The PALOMA (Palbociclib: Ongoing Trials in the Management of Breast Cancer)-1 randomized Phase II trial achieved its primary endpoint with the combination of palbociclib and letrozole significantly prolonging progression-free survival compared with letrozole alone in post-menopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer (2).
Overall Response Rate has also been a valuable surrogate endpoint in rare cancers and heavily pretreated populations where traditional endpoints may be challenging to assess. Ivosidenib (Tibsovo®) achieved accelerated approval for isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory acute myeloid leukemia based on a 30% overall response rate in the AG120-C-001 study, a an open-label, single arm, Phase I trial (3). Mutations in the gene encoding IDH1 occur in 2% to 14% of patients with AML globally. Thus, this accelerated approval targeted an important genetic subset of AML patients.
While the AAP has led to breakthroughs in oncology and rare diseases, it has also raised concerns about high drug prices, delayed confirmatory trials and uncertain clinical benefits in some cases. Accelerated Approval drugs often enter the market at premium prices because of their value to patient care. Sponsors may delay mandatory post-approval trials, which can lead to prolonged uncertainty about a drug’s overall clinical effectiveness. FDA now has authority to require that a confirmatory study already be underway before granting approval under the AAP.
In addition, recent analyses of accelerated approvals in oncology reveal varying degrees of confirmatory trial success. In a cohort study evaluating 129 cancer drug–indication pairs that were granted accelerated approval from 2013 to 2023, among 46 indications with more than 5 years of follow-up, fewer than half (20/46, 43%) demonstrated a clinical benefit in confirmatory trials. This outcome distribution underscores both the utility and limitations of surrogate endpoint-based approvals in predicting long-term clinical benefit.
The AAP introduces complexity in clinical decision-making. Healthcare providers must interpret efficacy data based on surrogate endpoints while counseling patients about uncertain long-term benefits. The conditional nature of these approvals requires ongoing monitoring of emerging safety and efficacy data, potentially necessitating treatment modifications as confirmatory evidence becomes available.
The AAP fulfills unmet medical needs of patients with serious conditions by allowing for earlier approval of drugs based on initial evidence of safety and effectiveness. This evidence, generated by adequate and well controlled clinical trials must show a drug’s effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.
Future refinements to AAPs may incorporate real-world evidence generation and adaptive trial designs to strengthen the evidentiary basis for regulatory decisions. The integration of biomarker-driven patient selection and precision medicine approaches offers opportunities to enhance the predictive accuracy of surrogate endpoints while maintaining expedited access to transformative therapies.
Author:
Julie Rosenberg, MD
Linical