Frailty modelling for survival data from multi-centre clinical trials.

Despite the use of standardized protocols in, multi-centre, randomized clinical trials, outcome may vary between centres. Such heterogeneity may alter the interpretation and reporting of the treatment effect. Below, we propose a general frailty modelling approach for investigating, inter alia, putative treatment-by-centre interactions in time-to-event data in multi-centre clinical trials. A correlated random effects model is used to model the baseline risk and the treatment effect across centres. It may be based on shared, individual or correlated random effects. For inference we develop the hierarchical-likelihood (or h-likelihood) approach which facilitates computation of prediction intervals for the random effects with proper precision. We illustrate our methods using disease-free time-to-event data on bladder cancer patients participating in an European Organization for Research and Treatment of Cancer trial, and a simulation study. We also demonstrate model selection using h-likelihood criteria.