Huang Wong-Shian, Liu Jen-pei, Hsiao Chin-Fu
Institute of Statistics, National Chiao Tung University, Hsinchu, Taiwan.
Pharm Stat. 2011 Mar-Apr;10(2):105-14. doi: 10.1002/pst.418.
The success rate of drug development has been declined dramatically in recent years and the current paradigm of drug development is no longer functioning. It requires a major undertaking on breakthrough strategies and methodology for designs to minimize sample sizes and to shorten duration of the development. We propose an alternative phase II/III design based on continuous efficacy endpoints, which consists of two stages: a selection stage and a confirmation stage. For the selection stage, a randomized parallel design with several doses with a placebo group is employed for selection of doses. After the best dose is chosen, the patients of the selected dose group and placebo group continue to enter the confirmation stage. New patients will also be recruited and randomized to receive the selected dose or placebo group. The final analysis is performed with the cumulative data of patients from both stages. With the pre-specified probabilities of rejecting the drug at each stage, sample sizes and critical values for both stages can be determined. As it is a single trial with controlling overall type I and II error rates, the proposed phase II/III adaptive design may not only reduce the sample size but also improve the success rate. An example illustrates the applications of the proposed phase II/III adaptive design.
近年来，药物研发的成功率急剧下降，当前的药物研发模式已不再奏效。这需要在突破性策略和设计方法上进行重大努力，以尽量减少样本量并缩短研发周期。我们提出了一种基于连续疗效终点的II/III期替代设计，它包括两个阶段：选择阶段和确认阶段。在选择阶段，采用随机平行设计，设置多个剂量组和一个安慰剂组来选择剂量。选择出最佳剂量后，所选剂量组和安慰剂组的患者继续进入确认阶段。还将招募新患者并随机分配，使其接受所选剂量或进入安慰剂组。最终分析使用两个阶段患者的累积数据进行。根据每个阶段预先设定的拒绝药物的概率，可以确定两个阶段的样本量和临界值。由于这是一个控制总体I型和II型错误率的单一试验，所提出的II/III期适应性设计不仅可以减少样本量，还可以提高成功率。一个例子说明了所提出的II/III期适应性设计的应用。
