Consideration on the Estimation of Efficacy and Study Design for Full Approval Under the Conditional and Time-limited Approval System

Abstract

 In the development of regenerative medicine products, the methods for estimating efficacy under the conditional and time-limited approval system are unclear, and there is a significant evidence gap between estimating efficacy and providing sufficient evidence for full approval. The conditional and time-limited approval system is intended to work based on a development strategy with the ultimate goal of obtaining full approval. If gaps in trial design, such as sample size, endpoints, and comparison methods, are too large, it becomes extremely difficult to predict the probability of success for full approval at the time of estimating efficacy. This paper proposes the application of a dual boundary approach, inspired by the concept of the “Promising Zone” in adaptive design. This approach does not require pre-determining samples sizes and allows for the estimation of efficacy by statistically evaluating the probability of success in confirming efficacy. It also has the advantage of minimizing the sample size when efficacy is clear and allowing for earlier stopping in cases of no efficacy. If the Promising Zone is achieved early, it is possible to apply for conditional approval, or to continue the trial as an expanded trial aiming for full approval. In cases where it is difficult to fully compare with a randomized control group, one option is to apply the Hybrid Control method, which combines external controls and randomized controls in the expanded trial part, or to seamlessly transition to confirmation based on endpoints with higher clinical significance than those used in the efficacy estimation part, even if confirmation using true endpoints is difficult. The proposals in this paper are expected to contribute to scientific discussions on more rational utilization of the system.