Mainstream methods for clinical trial design do not yet use prior probabilities of clinical hypotheses, mainly due to a concern that poor priors may lead to weak designs. To address this concern, we illustrate a conservative approach to trial design ensuring that the frequentist operational characteristics of the primary trial outcome are stronger than the design prior. Compared to current approaches to Bayesian design, we focus on defining a sample size cost commensurate to the prior to ensure against the possibility of prior-data conflict. Our approach is ethical, in that it calls for quantification of the level of clinical equipoise at design stage and requires the design to be appropriate to disturb this initial equipoise by a pre-specified amount. Four examples are discussed, illustrating the design of phase II-III trials with binary or time to event endpoints. Sample sizes are shown to be conductive to strong levels of overall evidence, whether positive or negative, increasing the conclusiveness of the design and associated trial outcome. Levels of negative evidence provided by standard group sequential designs are found negligible, underscoring the importance of complementing traditional efficacy boundaries with futility rules.
翻译:临床试验设计主流方法尚未使用临床试验设计的主流方法,主要因为担心前科差可能导致设计薄弱。为解决这一关切,我们举例说明了一种保守的试验设计方法,以确保初级试验结果的经常操作特点比前期设计更强。与目前巴耶斯设计方法相比,我们侧重于确定与前期设计相对应的样本规模成本,以确保不发生前期数据冲突的可能性。我们的方法是道德的,因为它要求在设计阶段对临床设备水平进行量化,并要求设计适当,以预定的数量扰动这一初始设备。我们讨论了四个例子,用二至三阶段试验的二、二至三阶段设计与事件结束点相配。样本规模显示,总体证据水平强,不管是正面还是负面,提高了设计和相关试验结果的确定性。标准组顺序设计提供的负面证据水平微不足道,强调用引信规则补充传统功效界限的重要性。