Up-and-down designs for phase I clinical trials

Various up-and-down designs have been proposed to improve the operating characteristics of the traditional "3 + 3" design, but they have been of limited use in practice. A major impediment to the adoption of the improved up-and-down designs is a lack of general guidance and a comprehensive assessment of the operating characteristics of these designs under practical clinical settings. To fill this gap, we review six up-and-down designs: the "3 + 3" design, accelerated titration design, biased coin design, k-in-a-row design, group up-and-down design and cumulative group up-and-down design. We conduct comprehensive simulation studies to evaluate their operating characteristics under various practical settings, and compare their performance to a theoretical optimal bound of nonparametric designs. The results show that the cumulative group up-and-down design has the best overall performance in terms of selecting the maximum tolerated dose (MTD), assigning patients to the MTD and patient safety. Its performance is generally close to the upper bound of nonparametric designs, but improvement seems possible in some cases.