II Contemporary Surrogate Endpoint Evaluation Methods: Multiple-Trial Methods

Two Continuous Outcomes

Ariel Alonso Abad

KU Leuven, Belgium

Wim Van der Elst

Hasselt University and Janssen Pharmaceutica, Belgium

Introduction

Over the years, it has become clear that the single-trial setting is too restrictive for the evaluation of surrogate endpoints (for details, see Chapter 3). Nowadays, general agreement has grown that there is a need for trial-level as well as individual-level replication. A first formal proposal along these lines used Bayesian methods (Daniels and Hughes, 1997). These ideas were subsequently extended using the theory of linear mixed-effects models (Buyse et al., 2000) and generalized estimating equations (Gail et al., 2000). This chapter focuses on the approach proposed in (Buyse et al., 2000). The methodology assumes that both endpoints are normally distributed random variables that are measured cross-sectionally. In Chapters 5-11, non-normally distributed endpoints (e.g., categorical, time-to-event, etc.) and longitudinally measured continuous endpoints will be considered.