Quantification of follow-up time in oncology clinical trials with a time-to-event endpoint: Asking the right questions.

ABSTRACT

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, for example, delayed separation, crossing survival functions, or the potential for cure. We conclude the paper with practical recommendations.