ABSTRACT
Safety evaluation is an important component of the design and analysis of clinical trials for the development of pharmaceutical, biological, and vaccine products. In early-phase clinical trials, the evaluation is mostly exploratory with a focus on serious adverse reactions to the product and is based on relatively small sample sizes and shorter study durations. In later phases of clinical development, the safety profile is characterized more fully because of larger numbers of patients and longer study durations of clinical trials. Some clinical trials may be designed with specific safety hypotheses concerning the equivalence or superiority of the candidate drug or vaccine to a control agent. Depending on the stage of clinical development, the objectives of the clinical trials may differ substantially. Although safety endpoints may or may not be of primary interest in these clinical trials, safety data are collected in various forms, including clinical adverse events, vital signs, laboratory test outcomes, and imaging results. This chapter presents study designs and data analysis methods that are commonly used to address pre-defined safety or toxicity issues in clinical trials. Section 4.1 begins with dose-escalation designs in phase I studies. Section 4.2 describes safety considerations in the design and analysis of phase II, phase III, and phase II/III clinical trials. In Section 4.3 we introduce clinical trial designs with both efficacy and safety endpoints. Section 4.4 presents the typical tabular formats for summarizing safety data from clinical trials. Statistical methods for their analysis are given in Section 4.5, and commonly used graphical displays of these data are described in Section 4.6. Section 4.7 concludes with supplements and problems.
