title: Sensitivity to censored-at-random assumption in the analysis of time-to-event endpoints.
abstract: Over the past years, significant progress has been made in developing statistically rigorous methods to implement clinically interpretable sensitivity analyses for assumptions about the missingness mechanism in clinical trials for continuous and (to a lesser extent) for binary or categorical endpoints. Studies with time-to-event outcomes have received much less attention. However, such studies can be similarly challenged with respect to the robustness and integrity of primary analysis conclusions when a substantial number of subjects withdraw from treatment prematurely prior to experiencing an event of interest. We discuss how the methods that are widely used for primary analyses of time-to-event outcomes could be extended in a clinically meaningful and interpretable way to stress-test the assumption of ignorable censoring. We focus on a 'tipping point' approach, the objective of which is to postulate sensitivity parameters with a clear clinical interpretation and to identify a setting of these parameters unfavorable enough towards the experimental treatment to nullify a conclusion that was favorable to that treatment. Robustness of primary analysis results can then be assessed based on clinical plausibility of the scenario represented by the tipping point. We study several approaches for conducting such analyses based on multiple imputation using parametric, semi-parametric, and non-parametric imputation models and evaluate their operating characteristics via simulation. We argue that these methods are valuable tools for sensitivity analyses of time-to-event data and conclude that the method based on piecewise exponential imputation model of survival has some advantages over other methods studied here. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Advisory Services Analytics, Quintiles Inc., Durham, NC, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Lipkovich
authors.affiliation: Advisory Services Analytics, Quintiles, Montreal, Québec, Canada.
authors.forename: Bohdana
authors.initials: B
authors.lastname: Ratitch
authors.affiliation: Advisory Services Analytics, Quintiles Ireland Ltd, Dublin, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Kelly
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D023381:Endpoint Determination / Q000379:methods*; D006801:Humans; D015233:Models, Statistical; D012107:Research Design; D016019:Survival Analysis; D013997:Time Factors
keywords: delta adjustment; multiple imputation; sensitivity analysis; time-to-event analysis; tipping point analysis