Estimating the Potential Benefits of Confirmatory Trials for Drugs with Accelerated Approval: A Comprehensive Value...

The US Food and Drug Administration's Accelerated Approval (AA) policy provides a pathway for patients to access potentially life-saving drugs rapidly. However, the use of surrogate endpoints, single-arm designs, and small sample sizes in preliminary trials that support AAs can lead to uncertainty regarding the clinical benefits of such drugs. This study aims to develop a comprehensive value of information (VOI) framework for assessing the potential benefits of future confirmatory trials, accounting for the various uncertainties inherent in preliminary trials.

I formulated an expected value of information from confirmatory trial (EVICT) metric, which evaluates the potential benefits of a confirmatory trial that would reduce those uncertainties by using a clinically meaningful endpoint, a randomized control, and increased sample size. The EVICT metric can quantify the expected benefits of a well-designed confirmatory trial or an inadequately designed one that continues to use surrogate endpoints or single-arm design. The framework was illustrated using a hypothetical AA drug for metastatic breast cancer.

The case study demonstrates that a highly uncertain preliminary trial of an AA drug was associated with a substantial EVICT. A confirmatory trial with an increased sample size for this AA drug, utilizing a clinically meaningful endpoint and randomized control, yielded a population-level EVICT of $12.6 million. Persistently using a surrogate endpoint and single-arm trial design would reduce the EVICT by 60%.

This framework can provide accurate VOI estimates to guide coverage policies, value-based pricing, and the design of confirmatory trials for AA drugs.