Boundary Between FDA Approved and Non-Approved Anticancer Drugs in Survival Benefit: A Meta-analysis

Survival benefit is a fundamental property of anticancer drugs for cancer patients. However, the survival benefits observed in registrational trials broadly ranged from significant to marginal, even for US Food and Drug Administration (FDA)-approved drugs. This study explores the boundary of survival benefits between FDA-approved and non-approved drugs. We screened 3,463 phase 3 investigational studies initiated from January 1990 to January 2021 with survival measurement on ClinicalTrial.gov and identified 208 randomized controlled registrational trials for anticancer drugs with overall survival (OS) measurement. Among 208 studies, 79 (38%) were conducted for FDA-approved, and 129 (62%) were for FDA-non-approved drugs. The pooled mean risk reduction of death across FDA-approved drugs was 29% (Hazard ratio (HR) 0.71), whereas FDA-non-approved drugs exhibited only a 6% risk reduction in OS (HR 0.94). The probability of FDA approval showed a sharp sensitivity to the HR for OS in the logistic regression model. A boundary was observed ranging from 0.74 to 0.86 in the HR for OS, with a 50% probability of FDA approval at HR 0.80. Our findings delineate the required survival benefits for new anticancer drugs based on the clinical and regulatory outcomes over 20 years.