Continual reassessment method vs. traditional empirically based design: modifications motivated by Phase I trials in...

In this article we provide additional support for the use of a model-based design in pediatric Phase I trials and present our modifications to the continual reassessment method (CRM), which were largely motivated by specific challenges we encountered in the context of the Pediatric Brain Tumor Consortium trials. We also summarize the results of our extensive simulations studying the operating characteristics of our modified approach and contrasting it to the empirically based traditional method (TM). Compared to the TM, our simulations indicate that the modified version of CRM is more accurate, exposes fewer patients to potentially toxic doses, and tends to require fewer patients. Further, the CRM-based MTD has a consistent definition across trials, which is important, especially in a consortium setting where multiple agents are being tested in studies that are often running simultaneously and accruing from the same patient population.