Continual Reassessment and Related Dose-Finding Designs

TL;DR

This paper reviews and extends the continual reassessment method (CRM) for dose-finding in clinical trials, discussing its theoretical foundations, practical applications, and recent developments over the past two decades.

Contribution

It provides new insights and results on CRM, including generalizations and practical guidance for its application in Phase 1 and 2 studies.

Findings

CRM models are practically useful in dose-finding.

New theoretical results guide CRM implementation.

Extensions of CRM improve flexibility and applicability.

Abstract

During the last twenty years there have been considerable methodological developments in the design and analysis of Phase 1, Phase 2 and Phase 1/2 dose-finding studies. Many of these developments are related to the continual reassessment method (CRM), first introduced by O'Quigley, Pepe and Fisher (\citeyearQPF1990). CRM models have proven themselves to be of practical use and, in this discussion, we investigate the basic approach, some connections to other methods, some generalizations, as well as further applications of the model. We obtain some new results which can provide guidance in practice.