Seamless Phase II/III Design: A Useful Strategy to Reduce the Sample Size for Dose Optimization

Authors

Liyun Jiang
Ying Yuan

Publication Date

9-7-2023

Journal

Journal of the National Cancer Institute

Abstract

Background: The traditional more-is-better dose selection paradigm, originally developed for cytotoxic chemotherapeutics, can be problematic when applied to the development of novel molecularly targeted agents. Recognizing this issue, the US Food and Drug Administration initiated Project Optimus to reform the dose optimization and selection paradigm in oncology drug development, emphasizing the need for greater attention to benefit-risk considerations.

Methods: We identify different types of phase II/III dose-optimization designs, classified according to trial objectives and endpoint types. Through computer simulations, we examine their operating characteristics and discuss the relevant statistical and design considerations for effective dose optimization.

Results: Phase II/III dose-optimization designs are capable of controlling family-wise type I error rates and achieving appropriate statistical power with substantially smaller sample sizes than the conventional approach while also reducing the number of patients who experience toxicity. Depending on the design and scenario, the sample size savings range from 16.6% to 27.3%, with a mean savings of 22.1%.

Conclusions: Phase II/III dose-optimization designs offer an efficient way to reduce sample sizes for dose optimization and accelerate the development of targeted agents. However, because of interim dose selection, the phase II/III dose-optimization design presents logistical and operational challenges and requires careful planning and implementation to ensure trial integrity.

Keywords

Humans, Antineoplastic Agents, Computer Simulation, Drug Development, Research Design, Sample Size, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic

DOI

10.1093/jnci/djad103

PMID

37243720

PMCID

PMC10483325

PubMedCentral® Posted Date

5-27-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes