Methods and Applications of Statistics in Clinical Trials, Volume 1: Concepts, Principles, Trials, and Designs

Chapter 19

Coherence in Phase I Clinical Trials

Ying-Kuen K. Cheung

19.1 Introduction

In the early phase clinical development of a new treatment, phase I trials are typically small studies that evaluate toxicity and determine a safe dosage range. Often, several doses of the treatment will be tested; in these situations, a more specific objective is to determine the maximum dose that does not exceed an acceptable level of toxicity, thus called the maximum tolerated dose (MTD). For ethical reasons, balanced randomization to each dose level is not feasible because it may unknowingly allocate many patients to excessively toxic doses. Rather, dose assignments in phase I trials are usually made in an outcome-adaptive manner in that previous outcomes in the trial form the basis of dose assignments for future subjects. Conventionally, the MTD is approached from lower doses according to the rule that escalates dose after a cohort of three subjects who show no treatment-related adverse or toxic event (Table 1). Although this conventional method has several limitations and shortcomings in terms of the statistical properties [1], it embraces a principle that appears to be clinically and ethically sound. When the most current subject suffers a treatment-related toxic event or dose-limiting toxicity (DLT), no escalation should take place for the next subject without testing the current or the lower doses in more subjects. This principle is called coherence in escalation [2]. For phase I trials ...