Approaches to Combining Phase II Proof-of-Concept and Dose-Finding Trials

Abstract

There are two objectives in Phase II clinical development: establishing proof-of-concept that the drug is efficacious (PoC) and identifying an appropriate dose for late phase developments (dose-finding). In this chapter, we illustrate and explore various practical adaptive design strategies that seamlessly combine the two objectives in one single study. Such adaptive strategies are compared against more traditional approaches of two separate studies or a combined non-adaptive fixed design, with a numerical example in designing a hypothetical Phase II clinical program. The numerical results identify two adaptive designs that achieve better balance between the statistical efficiency and the risk mitigation, under various scenarios. Such seamless designs speed up the drug development process, reasonably control the risk of large upfront investment, and are relatively easy to implement compared to other adaptive dose-ranging studies with adaptive randomization.