An Adaptive Optimal Design for the E_max Model and Its Application in Clinical Trials

Abstract

A project team working on a compound to treat Alzheimer's disease is carrying out a first-time-in-human dose-escalation study in patients. The team wished to maximize the efficiency of the study by using doses targeted at maximizing information about the dose-response relationship within certain safety constraints. We have developed an adaptive optimal design tool to recommend doses when the response follows an E _max model, with functionality for pretrial simulation and in-stream analysis. We present the results of a simulation to investigate the operating characteristics of the applied algorithm.

Key Words:

• Adaptive design
• Constrained dose selection
• E _max model
• Optimal model-based design
• Unknown parameters in variance

ACKNOWLEDGMENTS

The authors wish to thank Valerii Fedorov, Alun Bedding, Linda Haines, Judith Quinlan, and Mike Sheehan for valuable discussions and two anonymous referees for their constructive and insightful comments.