Carreras Máximo, Gutjahr Georg, Brannath Werner
F. Hoffmann-La Roche AG, Basel, Switzerland.
Stat Med. 2015 Apr 15;34(8):1317-33. doi: 10.1002/sim.6407. Epub 2015 Jan 7.
The planning of an oncology clinical trial with a seamless phase II/III adaptive design is discussed. Two regimens of an experimental treatment are compared to a control at an interim analysis, and the most-promising regimen is selected to continue, together with control, until the end of the study. Because the primary endpoint is expected to be immature at the interim regimen selection analysis, designs that incorporate primary as well as surrogate endpoints in the regimen selection process are considered. The final testing of efficacy at the end of the study comparing the selected regimen to the control with respect to the primary endpoint uses all relevant data collected both before and after the regimen selection analysis. Several approaches for testing the primary hypothesis are assessed with regard to power and type I error rate. Because the operating characteristics of these designs depend on the specific regimen selection rules considered, benchmark scenarios are proposed in which a perfect surrogate and no surrogate is used at the regimen selection analysis. The operating characteristics of these benchmark scenarios provide a range where those of the actual study design are expected to lie. A discussion on family-wise error rate control for testing primary and key secondary endpoints as well as an assessment of bias in the final treatment effect estimate for the selected regimen are also presented.
本文讨论了采用无缝II/III期适应性设计的肿瘤学临床试验规划。在中期分析时，将两种实验性治疗方案与一种对照方案进行比较，并选择最有前景的方案与对照方案一起继续进行，直至研究结束。由于在中期方案选择分析时主要终点预计尚未成熟，因此考虑了在方案选择过程中纳入主要终点以及替代终点的设计。在研究结束时，针对主要终点将所选方案与对照方案进行比较的最终疗效检验使用了在方案选择分析之前和之后收集的所有相关数据。针对检验原假设的几种方法，评估了其检验效能和I型错误率。由于这些设计的操作特性取决于所考虑的具体方案选择规则，因此提出了基准方案，其中在方案选择分析时使用了完美替代终点和未使用替代终点的情况。这些基准方案的操作特性提供了一个范围，预期实际研究设计的操作特性将处于该范围内。还讨论了用于检验主要终点和关键次要终点的家族性错误率控制，以及对所选方案最终治疗效果估计中的偏差评估。
