For the analysis of a time-to-event endpoint in a single-arm or randomized clinical trial it is generally perceived that interpretation of a given estimate of the survival function, or the comparison between two groups, hinges on some quantification of the amount of follow-up. Typically, a median of some loosely defined quantity is reported. However, whatever median is reported, is typically not answering the question(s) trialists actually have in terms of follow-up quantification. In this paper, inspired by the estimand framework, we formulate a comprehensive list of relevant scientific questions that trialists have when reporting time-to-event data. We illustrate how these questions should be answered, and that reference to an unclearly defined follow-up quantity is not needed at all. In drug development, key decisions are made based on randomized controlled trials, and we therefore also discuss relevant scientific questions not only when looking at a time-to-event endpoint in one group, but also for comparisons. We find that different thinking about some of the relevant scientific questions around follow-up is required depending on whether a proportional hazards assumption can be made or other patterns of survival functions are anticipated, e.g. delayed separation, crossing survival functions, or the potential for cure. We conclude the paper with practical recommendations.
翻译:对于分析单臂或随机临床试验中的时间到活动终点的分析,人们普遍认为,对生存功能的某一估计或两个组之间的比较的解释取决于对后续行动数量的某种量化。一般而言,报告的数量中位数是某些定义松散的数量。然而,无论报告的平均中位数,一般都没有回答试验者实际上在后续量化方面所遇到的问题。在估计框架的启发下,本文件列出了试验者在报告时间到活动数据时所了解的有关科学问题的综合清单。我们说明了这些问题应当如何回答,根本不需要提及定义不明确的后续数量。在药物开发中,关键决定是根据随机控制的试验作出的,因此我们不仅在研究某一组的时间到活动终点时,而且还讨论有关的科学问题,并且进行比较。我们发现,对于后续研究中的某些相关科学问题,需要不同的思考,取决于是否能够作出相称的危险假设,或者是否有必要回答这些问题,而完全不需要提及界定的后续行动数量。在药物开发中,关键决定是根据随机控制的试验作出的,因此,我们不仅在研究某一组中的时间到一个组中的时间到活动终点时,而且还要讨论有关的科学问题。我们发现,对后续行动中的某些相关科学问题需要不同的思考,取决于是否能够作出相称的危险假设,或者是否能够跨越实际治疗,例如,我们预计,是否要跨越实际治疗的功能。