Dual-Criterion Approach Incorporating Historical Information to Seek Accelerated Approval With Application in...

The urgency of delivering novel, effective treatments against life-threatening diseases has brought various health authorities to allow for Accelerated Approvals (AAs). AA is the "fast track" program where promising treatments are evaluated based on surrogate (short term) endpoints likely to predict clinical benefit. This allows treatments to get an early approval, subject to providing further evidence of efficacy, for example, on the primary (long term) endpoint. Despite this procedure being quite consolidated, a number of conditionally approved treatments do not obtain full approval (FA), mainly due to lack of correlation between surrogate and primary endpoint. This implies a need to improve the criteria for controlling the risk of AAs for noneffective treatments, while maximizing the chance of AAs for effective ones. We first propose a novel adaptive group sequential design that includes an early dual-criterion "Accelerated Approval" interim analysis, where efficacy on a surrogate endpoint is tested jointly with a predictive metric based on the primary endpoint. Secondarily, we explore how the predictive criterion may be strengthened by historical information borrowing, in particular using: (i) historical control data on the primary endpoint, and (ii) the estimated historical relationship between the surrogate and the primary endpoints. We propose various metrics to characterize the risk of correct and incorrect early AAs and demonstrate how the proposed design allows explicit control of these risks, with particular attention to the family-wise error rate (FWER). The methodology is then evaluated through a simulation study motivated by a Phase-III trial in metastatic colorectal cancer (mCRC).