Repeated significance testing in longitudinal clinical trials

Abstract

When longitudinal clinical trials are monitored, multiplicity from repeated significance testing as well as from repeated measures has to be accounted for properly to control the overall type I error. This often involves a multidimensional integration procedure to compute group sequential boundaries. We establish an independent increments structure of sequentially computed test statistics based on the generalised estimating equations of Liang & Zeger (1986) for longitudinal data. This simplifies the computational procedure for group sequential boundaries to one involving recursive one-dimensional integrations and allows the use of standard methodology for group sequential tests. We also apply the error spending function approach of Lan & DeMets (1983) by defining information fraction in this setting.