Bivariate network meta-analysis for surrogate endpoint evaluation

Surrogate endpoints are very important in regulatory decision-making in healthcare, in particular if they can be measured early compared to the long-term final clinical outcome and act as good predictors of clinical benefit. Bivariate meta-analysis methods can be used to evaluate surrogate endpoints and to predict the treatment effect on the final outcome from the treatment effect measured on a surrogate endpoint. However, candidate surrogate endpoints are often imperfect, and the level of association between the treatment effects on the surrogate and final outcomes may vary between treatments. This imposes a limitation on methods which do not differentiate between the treatments. We develop bivariate network meta-analysis (bvNMA) methods which combine data on treatment effects on the surrogate and final outcomes, from trials investigating multiple treatment contrasts. The bvNMA methods estimate the effects on both outcomes for all treatment contrasts individually in a single analysis. At the same time, they allow us to model the trial-level surrogacy patterns within each treatment contrast and treatment-level surrogacy, thus enabling predictions of the treatment effect on the final outcome either for a new study in a new population or for a new treatment. Modelling assumptions about the betweenstudies heterogeneity and the network consistency, and their impact on predictions, are investigated using an illustrative example in advanced colorectal cancer and in a simulation study. When the strength of the surrogate relationships varies across treatment contrasts, bvNMA has the advantage of identifying treatment comparisons for which surrogacy holds, thus leading to better predictions.