Accumulating data may be reviewed regularly in all phases of clinical development for decision-making based on safety or clinical benefit. This chapter discusses the process of reviewing accumulating clinical trial data in a formal manner. It provides an overview of the structure and the operations of a data monitoring committee (DMC), and elucidates the statistical issues and challenges of interim monitoring. The chapter describes several commonly used approaches for interim monitoring. Multi-center trials must be coordinated and administered efficiently. A DMC's objectivity is in part due to independence of the members. A formal statistical framework can enhance the objectivity by providing a universal language to communicate the accumulating evidence. Group sequential methods for determining the critical values to be used during interim analyses represent a key advancement in the theory and application of sequential analyses. EAST is highly regarded as an excellent tool for interim monitoring of clinical trials.

The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia study sought to compare the effectiveness and cost-effectiveness of four second-generation antipsychotics and one first-generation antipsychotic in the treatment of schizophrenia. This study design posed several challenges for statistical analysis. The authors describe the stratified Phase 1/1A randomization, and explain the steps for comparing treatment groups within the stratified randomization structure. They describe strategies to perform treatment group comparisons that control the inflation of Type 1 error due to multiple pair-wise testing, and focus on the evaluation of multiple outcomes. The authors examine the advantages of using all-cause treatment discontinuation as the primary effectiveness outcome and the specific statistical issues for its analysis, and address the impact of missing data due to phase discontinuation on analysis of the secondary outcomes. The authors contrast the statistical methods employed to address this issue, and consider further methods.