Abstract:Time-to-event endpoints are central to evaluating treatment efficacy across disease areas. In clinical trials with time-to-event endpoints, the information available for interim and final analyses is often determined by the number of observed events rather than by the number of enrolled patients. Interim monitoring therefore requires assessing how many additional events are expected to accrue by scheduled future analysis dates. Quantifying uncertainty around these counts is essential for assessing whether planned information levels are likely to be reached, anticipating delays or event overrunning, and supporting operational decisions while the trial is ongoing. This is especially relevant where event accrual is low as in pediatric hemato-oncology trials. Although methods for predicting time to endpoint maturation are well established, interval prediction for event counts at fixed calendar times remains less developed. We propose a patient-level framework for constructing such intervals at interim analyses of time-to-event trials. Conditionally on the interim data, the future count follows a Poisson--binomial law with patient-specific event probabilities; we estimate this law using a conditional parametric bootstrap. Under standard regularity conditions, the bootstrap is consistent and yields asymptotically calibrated prediction intervals. The framework accommodates staggered entry, patient-level covariates, administrative censoring, loss to follow-up, and possible dependence between entry dates and loss to follow-up, before conditioning on the realised interim data. We study its operating characteristics in simulation studies and illustrate the method using a real-world phase III trial in childhood acute lymphoblastic leukaemia.
From: Edoardo Ratti [view email]
[v1]
Wed, 7 Jan 2026 18:58:45 UTC (466 KB)
[v2]
Thu, 15 Jan 2026 22:33:34 UTC (467 KB)
[v3]
Thu, 11 Jun 2026 16:08:24 UTC (493 KB)
[v4]
Thu, 27 Aug 2026 09:23:59 UTC (511 KB)
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