A proof-of-concept-to-confirmatory multiple adaptation design in the development of an anti-viral treatment.

Abstract

In the clinical development of some new infectious disease drugs, early clinical pharmacology trials may predict with high confidence that the efficacious doses are well below the range of the safety margin. In this case, a dose-ranging study may be unnecessary after a proof-of-concept (PoC) study testing the highest dose. A multi-stage adaptive design spanning both PoC and confirmatory stages is proposed in this context. The design incorporates two interim analyses allowing strategies for stopping, continuing, or expanding the study. A conditional power threshold for a binary endpoint is proposed to assess futility. Additional components of early efficacy and sample size adjustment are also included to enhance the design's flexibility and robustness. Design operating characteristics are evaluated by numerical calculation. We show that the proposed streamlined trial design has the same statistical rigor as a conventional phase 3 clinical trial with adequate power and a properly controlled type 1 error rate. Additional adaptive design options are also investigated and discussed.