P24 Seamless Phase II/III Design With Treatment Selection Using Surrogate Endpoint for Early Interim Decision

Seamless phase II/III designs are attractive trial design options to clinical development teams when there is a strong desire to expedite the development process, to lower operational burden, and to reduce overall costs. The most common seamless design involves selecting promising treatment group(s) out of multiple treatment groups at the end of the first stage and confirming the selected treatment group(s) at the end of the second stage, by inferentially combining data of both stages in the final analysis. To further speed up the treatment selection, one can consider using an endpoint strongly correlated with the primary endpoint to make an early selection so as to plan the design and to begin enrollment for the second stage even before completion of the first stage. The correlation size and timing of selection must be carefully examined and calibrated to enable efficient use of the seamless design. In the context of a 2-stage seamless phase II/III design with early selection of one promising treatment group based on a correlated endpoint, we will investigate three potential analytical methods (group sequential, p-value combination, and adaptive Dunnett methods) for final analysis of the primary endpoint with respect to both Type I error control and statistical power via simulations. We will also characterize the impact of different correlation sizes and timing on treatment selection. We will discuss and compare the versatility of these three analytical methods. This discussion may have wide applications across different therapeutic areas.

Clinical Trial Design (e.g., Innovative/Complex Design, Estimands, Master Protocol)

ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop 2024