A Generalized Phase 1-2-3 Design Integrating Dose Optimization With Confirmatory Treatment Comparison

Authors

Yong Zang
Peter F Thall
Ying Yuan

Publication Date

1-29-2024

Journal

Biometrics

Abstract

A generalized phase 1-2-3 design, Gen 1-2-3, that includes all phases of clinical treatment evaluation is proposed. The design extends and modifies the design of Chapple and Thall (2019), denoted by CT. Both designs begin with a phase 1-2 trial including dose acceptability and optimality criteria, and both select an optimal dose for phase 3. The Gen 1-2-3 design has the following key differences. In stage 1, it uses phase 1-2 criteria to identify a set of candidate doses rather than 1 dose. In stage 2, which is intermediate between phase 1-2 and phase 3, it randomizes additional patients fairly among the candidate doses and an active control treatment arm and uses survival time data from both stage 1 and stage 2 patients to select an optimal dose. It then makes a Go/No Go decision of whether or not to conduct phase 3 based on the predictive probability that the selected optimal dose will provide a specified substantive improvement in survival time over the control. A simulation study shows that the Gen 1-2-3 design has desirable operating characteristics compared to the CT design and 2 conventional designs.

Keywords

Humans, Clinical Protocols, Computer Simulation, Dose-Response Relationship, Drug, Probability, Research Design, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Bayesian design, cell therapy, dose finding, phase 1-2 clinical trial, phase 1-2-3 clinical trial

DOI

10.1093/biomtc/ujad022

PMID

38364811

PMCID

PMC10873567

PubMedCentral® Posted Date

2-16-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes