From Mouse to Man: The Early Clinical Testings

Abstract

In drug development from mouse to man, one of the primary goals of the Phase I studies is to estimate the maximum tolerated dose (MTD). Two considerations in designing Phase I studies are to treat as few patients as possible at doses much above the MTD and to escalate as fast as possible through the portion of the dose-toxicity curve where the chance of toxicity is very low. In some designs such as the Traditional Design, Up-and-Down Designs, and Two-Stage Designs, the dose escalation scheme is determined in advance. Whereas, the Stochastic Approximation (SA) Method, the Continual Reassessment Method (CRM), and the Modified CRM Designs are methods where the dose escalation is based on total accumulated patient information. Subsequently, the Extended CRM Design was developed, which is a combination of sampling schemes. The Extended CRM Design uses a traditional type of design to move quickly through the nontoxic dose levels until a toxicity is observed. Once toxicity is observed, the CRM is implemented as it tends to concentrate sampling around the appropriate preset percentile. The above methods were compared in their ability to estimate the MTD and results showed that the designs which used combined sampling schemes were superior.