Quality principles in Phase I dose escalation design.

Abstract

This paper discusses quality principles for Phase I model-based dose escalation design. It emphasizes that a loss function underlying a dose escalation trial estimator can be usefully interpreted as a quantified representation of the ethical assumptions underlying the treatment decisions to be made in the trial. Based on this principle, it discusses additional general quality design principles developers of clinical trial design methods should consider, including the role of continuous loss functions in quality per Taguchi, and per Deming the role of asymmetric loss functions and the importance of understanding the underlying process and its order of operations. It provides a number of model-based dose escalation designs as examples, including the mTPI as an introductory example, the EWOC design, and the CRM and modifications to it. It introduces some foundational scientific underpinnings and principles of quality philosophy, and explains how the principles apply to the examples. It stresses the importance of an engineering process by which a study is designed to meet identified and investigated user requirements.