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

Chapter 56

Phase I Trials

Sylvie Chevret

56.1 Introduction

Phase I includes the initial introduction of an investigational new drug into humans, aiming at developing a safe and efficient drug administration. These first-in-human studies are closely monitored and are usually conducted in an inpatient clinic, where a small number of healthy volunteer subjects (usually, 20–80) can be observed by full-time medical staff. The subject is usually observed until several half-lives of the drug have passed. These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. Thus, sufficient information about the drug’s pharmacokinetics and pharmacological effects should be obtained during these trials to permit the design of well-controlled, scientifically valid, Phase II studies. However, some circumstances can occur when toxicity is anticipated and patients are used, such as with oncology (cancer) and HIV drug trials [1,2]. In these settings, risk is regarded as a necessary price to pay for the chance of benefit [3]. Thus, drug therapy is considered tolerable if the toxicity is acceptable. Therefore, the specific goal of such Phase I clinical trials is to find the maximum tolerated dose (MTD) of the new drug for a prespecified mode of administration. Because cancer Phase I trials are considered among the most risky in all of medicine, the design ...