Abstract

The Continual Reassessment Method (CRM) is an adaptive design for Phase I trials whose operating characteristics, including appropriate sample size, probability of correctly identifying the maximum tolerated dose, and the expected proportion of participants assigned to each dose, can only be determined via simulation, as process that can take several hours, depending upon the goals of the simulation. To that end, we have developed an approach that replaces a simulation study of thousands of hypothetical trials with a single simulation. Our approach, which is founded on the consistency of the CRM , very accurately reflects the results produced by a simulation study, but in a fraction of the time. Relative to traditional simulations, we extensively examine how our method is able to assess the operating characteristics of a CRM design for a hypothetical trial whose characteristics are based upon a previously published Phase I trial. We also provide a metric of nonconsistency and demonstrate that although nonconsistency can impact the operating characteristics of our method, the degree of over- or under-estimation is unpredictable. As a solution, we provide an algorithm for maintaining the consistency of a chosen CRM design so that our method is applicable for any trial. It is hoped that these methods lead to extensions that are applied to more complex Phase I designs.