The clinical trial, a prospective study to evaluate the effect of interventions in humans under prespecified conditions, is a standard and integral part of modern medicine. Many adaptive and sequential approaches have been proposed for use in clinical trials to allow adaptations or modifications to aspects of a trial after its initiation without undermining the validity and integrity of the trial. The application of adaptive and sequential methods in clinical trials has significantly improved the flexibility, efficiency, therapeutic effect, and validity of trials. To further advance the performance of clinical trials and convey the progress of research on adaptive and sequential methods in clinical trial design, we review significant research that has explored novel adaptive and sequential approaches and their applications in Phase I, II, and III clinical trials and discuss future directions in this field of research. 1. Clinical Trials Medicine is of paramount importance for human healthcare. Development of novel successful medicines is a lengthy, difficult, and expensive process which consists of laboratory experimentation, animal studies, clinical trials (Phase I, II, and III), and postmarket followup (Phase IV). Clinical trials are FDA-approved studies conducted in human beings to demonstrate the safety and efficacy of new drugs for health interventions under pre-specified conditions. A clinical trial is conducted in a sampled small population and the conclusions reached will be applied to a whole target population; therefore, statistics is an indispensable and critical component of clinical trial development and analysis, which has become increasingly important in contemporary clinical trials. As the gold standard for the evaluation of a new drug, every contemporary clinical trial must be well designed according to its specific purpose and conducted properly under governmental regulations. The major roles of a statistician in a clinical trial are to design an efficient trial with minimum cost and length and maximum therapeutic effect for patients in the trial, and to draw convincing conclusions by applying appropriate cutting edge statistical knowledge. In the past several decades, numerous groundbreaking novel statistical methodologies have been developed and applied to clinical trials and have significantly improved their performance. Consequently, clinical trials have evolved from simple observation studies to hypothesis-driven and well-designed prospective studies. At present, contemporary clinical trials have become the most important part of
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