Analysis of Time-to-Event Data With Incomplete Event Adjudication

Abstract

In many multicenter, randomized clinical trials, the primary outcome is the time to the first of a number of possible clinical events. An event classification committee may be convened to determine whether events that have been reported by investigators meet the predetermined criteria for primary endpoint events. When interim analyses are performed in such trials, the final classification for many reported events will not be known. Failure to account for the uncertain status of these events may result in incorrect interim analysis. The probability that an unadjudicated event will be confirmed as a primary event can typically be estimated from those events for which adjudication is complete. We show that if each unadjudicated event is weighted according to the probability that it will be the first primary event, then consistent estimates of survival probabilities and regression parameters can be obtained and unbiased log-rank tests of treatment differences performed. Moderate sample consistency of point estimates and variance estimates is verified by simulation. The procedure is illustrated using data from the Coumadin Aspiring Reinfarction Study (CARS) and the Weekly Intervention with Zithromax for Atherosclerosis and Related Diseases (WIZARD) study.

KEY WORDS :

• Counting process
• Empirical process
• Event adjudication
• Interim analysis
• Survival analysis