Royston Patrick, Parmar Mahesh K B, Qian Wendi
Cancer Division, MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK.
Stat Med. 2003 Jul 30;22(14):2239-56. doi: 10.1002/sim.1430.
With the increasing pace of drug development, it is not unusual for several promising treatment regimens to be ready simultaneously for testing in a randomized phase III setting. Various limiting factors, including the time needed to transfer research results to clinical practice and a narrow 'window of opportunity', may make it unfeasible to perform trials to test such regimens sequentially against a control treatment in a traditional two-arm parallel group design. We present an approach to trial design based on eliminating inferior contenders at an early stage, allowing through to a second stage only treatments that show a predefined degree of advantage against a control treatment. The first stage of testing utilizes a marker known to be a valid intermediate outcome measure or surrogate for the definitive outcome. The experimental arms are compared pairwise with control according to this intermediate outcome measure. Arms that survive the comparison enter a second stage of patient accrual culminating in comparisons against control on the outcome measure of primary interest. We show how the design may be realized in practice by considering hypothetically distinct trials at stages 1 and 2, each with their own operating characteristics. The overall operating characteristics are computed from the stage 1 and 2 size and power and the correlation between the treatment effects on the intermediate and primary outcome measures according to a bivariate Normal approximation. The correlation is estimated by bootstrapping individual patient data from previous trials. We illustrate the general approach in a design of a real trial of four new chemotherapy regimens for advanced ovarian cancer. The intermediate outcome measure is progression-free survival. An international randomized controlled trial using the new design is already under way.
随着药物研发速度的加快，几种有前景的治疗方案同时准备好在随机III期试验中进行测试的情况并不罕见。各种限制因素，包括将研究结果转化为临床实践所需的时间以及狭窄的“机会窗口”，可能使得按照传统双臂平行组设计依次针对对照治疗对这些方案进行试验变得不可行。我们提出了一种试验设计方法，即基于在早期阶段淘汰较差的竞争者，仅允许对对照治疗显示出预定义优势程度的治疗方案进入第二阶段。测试的第一阶段利用一种已知为最终结果的有效中间结局指标或替代指标的标志物。根据这个中间结局指标，将试验组与对照组进行两两比较。在比较中幸存的试验组进入第二阶段的患者招募，最终根据主要关注的结局指标与对照组进行比较。我们通过假设在第1阶段和第2阶段进行不同的试验（每个试验都有其自身的操作特征）来说明该设计在实践中如何实现。总体操作特征根据双变量正态近似从第1阶段和第2阶段的样本量和检验效能以及中间结局指标和主要结局指标上治疗效果之间的相关性计算得出。相关性通过对先前试验的个体患者数据进行自助法估计。我们在一项针对晚期卵巢癌的四种新化疗方案的实际试验设计中阐述了这种通用方法。中间结局指标是无进展生存期。一项采用新设计的国际随机对照试验已经在进行中。
