Platform trials have become increasingly popular for drug development programs, attracting interest from statisticians, clinicians and regulatory agencies. Many statistical questions related to designing platform trials - such as the impact of decision rules, sharing of information across cohorts, and allocation ratios on operating characteristics and error rates - remain unanswered. In many platform trials, the definition of error rates is not straightforward as classical error rate concepts are not applicable. For an open-entry, exploratory platform trial design comparing combination therapies to the respective monotherapies and standard-of-care, we define a set of error rates and operating characteristics and then use these to compare a set of design parameters under a range of simulation assumptions. When setting up the simulations, we aimed for realistic trial trajectories, such that e.g. a priori we do not know the exact number of treatments that will be included over time in a specific simulation run as this follows a stochastic mechanism. Our results indicate that the method of data sharing, exact specification of decision rules and a priori assumptions regarding the treatment efficacy all strongly contribute to the operating characteristics of the platform trial. Furthermore, different operating characteristics might be of importance to different stakeholders. Together with the potential flexibility and complexity of a platform trial, which also impact the achieved operating characteristics via e.g. the degree of efficiency of data sharing, this implies that utmost care needs to be given to evaluation of different assumptions and design parameters at the design stage.
翻译:对药物开发方案而言,平台试验越来越受欢迎,吸引统计人员、临床医生和监管机构的兴趣。许多与设计平台试验有关的统计问题,例如决策规则的影响、跨组共享信息以及操作特点和误差率的分配比率等,仍未得到答复。在许多平台试验中,错误率的定义并非直截了当,因为传统误差率概念并不适用。对于将综合疗法与各自的单一疗法和护理标准进行比较的公开进入、探索性平台试验设计,我们界定了一套误差率和操作特点,然后用这些来比较一系列模拟假设下的一系列设计参数。此外,在建立模拟时,我们的目标是现实的试验轨迹,例如,事先我们并不知道在特定模拟运行过程中将列入的确切治疗次数。对于把综合疗法与各自的单一疗法和护理标准进行比较,我们的结果表明,数据共享的方法、决定规则的精确规格和先验假设都有力地促进了平台试验的运作特点。此外,不同的操作特点对于不同的利益攸关方来说可能很重要,在设计这一最复杂程度上分享数据,这又意味着在设计上实现最灵活程度。