Continual Reassessment Method: A Practical Design for Phase 1 Clinical Trials in Cancer

TLDR

The approach seeks to balance dose‑finding needs with ethical requirements of medical practice. The paper proposes a new design and analysis method for Phase 1 cancer trials. The method concentrates trials at a dose with a target toxicity level, using a simple locally accurate model to estimate that level. Simulations show the model’s promise, and the shape of the dose‑toxicity curve is considered unimportant.

Abstract

This paper looks at a new approach to the design and analysis of Phase 1 clinical trials in cancer. The basic idea and motivation behind the approach stem from an attempt to reconcile the needs of dose-finding experimentation with the ethical demands of established medical practice. It is argued that for these trials the particular shape of the dose toxicity curve is of little interest. Attention focuses rather on identifying a dose with a given targeted toxicity level and on concentrating experimentation at that which all current available evidence indicates to be the best estimate of this level. Such an approach not only makes an explicit attempt to meet ethical requirements but also enables the use of models whose only requirements are that locally (i.e., around the dose corresponding to the targeted toxicity level) they reasonably well approximate the true probability of toxic response. Although a large number of models could be contemplated, we look at a particularly simple one. Extensive simulations show the model to have real promise.