Schmidli Heinz, Bretz Frank, Racine-Poon Amy
Novartis Pharma AG, CH-4002 Basel, Switzerland.
Stat Med. 2007 Nov 30;26(27):4925-38. doi: 10.1002/sim.2957.
Integration of a phase II and a phase III clinical trial into a single confirmatory study aims to shorten the development time without compromising the chance of success for a development program. These seamless phase II/III trials involve complex adaptations at the interim analysis, such as treatment selection, sample size reassessment, and stopping for futility. Bayesian methods can support these interim adaptations, and make this decision process more transparent. Use of a frequentist combination test for the final evaluation ensures that the type I error is controlled regardless of the adaptation rule employed at the interim analysis. In this paper, an adaptive seamless phase II/III trial design is proposed for studies where the endpoint is survival up to some specified timepoint and where Bayesian predictive power (PP) guides interim adaptations. For the evaluation of PP at the interim analysis, the event time is modelled as a piecewise exponential distribution, with informative priors for the hazard rates. As an illustrative example, regimen selection at interim in a four-arm trial with an active control is considered, where both non-inferiority and superiority to the control arm are tested. Frequentist properties of the adaptation criterion based on Bayesian PP are assessed by simulations.
将II期和III期临床试验整合为一项单一的验证性研究，旨在缩短研发时间，同时不影响研发项目成功的机会。这些无缝II/III期试验在中期分析时涉及复杂的调整，如治疗选择、样本量重新评估以及因无效而提前终止试验。贝叶斯方法可以支持这些中期调整，并使决策过程更加透明。在最终评估中使用频率学派联合检验可确保无论在中期分析中采用何种调整规则，I类错误均得到控制。本文针对终点为直至某个指定时间点的生存情况且贝叶斯预测能力（PP）指导中期调整的研究，提出了一种自适应无缝II/III期试验设计。为在中期分析时评估PP，将事件时间建模为分段指数分布，并对风险率采用信息先验。作为一个示例，考虑在一项有活性对照的四臂试验中进行中期方案选择，其中既要检验相对于对照臂的非劣效性，也要检验优越性。通过模拟评估基于贝叶斯PP的调整标准的频率学派性质。
