Exploring the Effects of Early Censoring and Analysis of Clinical Trial Survival Data on Effectiveness and Cost-effectiveness Estimation through a Case Study in Advanced Breast Cancer.

Abstract

Interim analyses of clinical trial data are frequently used to provide evidence to obtain marketing authorization for new drugs. However, results from such analyses may not reflect true estimates of relative effectiveness when trial follow-up is complete. Survival results, available at 2 time points from a breast cancer clinical trial, were compared to test the hypothesis that using immature data and a widely used right-censoring rule leads to biased survival estimates. Kaplan-Meier progression-free and overall survival data from 2 published CLEOPATRA trial reports (2012 and 2014) were digitized. Overlaying these results highlighted divergent trends. Parametric functions were fitted to both data sets but did not indicate consistent patterns that could be used as a basis for long-term extrapolation. Heavy censoring of patients in the early data cut coincides with sudden changes in hazard trends and survival patterns, supporting the hypothesis of censoring bias. This challenges the validity of estimates of clinical benefit (progression-free survival and overall survival) based on extrapolation of results from interim analyses of trial data, using a commonly employed censoring rule.