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

Chapter 55

Phase II/III Trials

Qing Liu

55.1 Introduction

It is well known that in the past decade, the cost of conducting clinical trials has increased exponentially, whereas the success rate for phase 3 development has dropped to an all time low of about 50%. Part of the reason for such a low success rate is that drug companies are facing increasing time pressures to meet patient demands or to satisfy performance goals set by shareholders. Because phase 2 (dose-response) trials are often perceived to delay the timeline, many clinical development programs either omit or conduct phase 2 trials in parallel with phase 3 trials. Traditionally, phase 2 trials have served the purpose of informing the early halt of a clinical development program or providing critical information for moving the clinical development forward to large-scale phase 3 trials. Without data from phase 2 trials, larger phase 3 clinical programs are at an increased risk for attrition related to problems of lack of efficacy or unacceptable safety concerns; in addition, phase 3 designs and statistical analyses (e.g., choice of dose or hypothesis testing strategy for handling multiplicity) are often suboptimal.

A potential solution to these problems, while still limiting the overall development time and cost, is to incorporate the phase 2 component directly into a phase 3 trial, so that needed learning and redesigning take place while all relevant data contribute to integrated efficacy and safety analyses. Designs ...