Methods and Applications of Statistics in Clinical Trials, Volume 1: Concepts, Principles, Trials, and Designs

Chapter 74

Surrogate Endpoints

Thomas R. Fleming Victor DeGruttola, and David L. Demets

74.1 Introduction

The selection of the primary “outcome measures” or “endpoints” is a very important step in the design of clinical trials. Typically, the primary goal of the clinical trial is to assess definitively a treatment’s effect on these endpoints. Two major criteria should guide their selection. The endpoints should (i) be sensitive to treatment effects and (ii) be clinically relevant. Adequate attention is usually given to ensuring that the first criterion is satisfied. Unfortunately, ensuring that the endpoints also satisfy the criterion of clinical relevance is often improperly addressed. We focus on this second criterion and the corresponding controversial issues arising when surrogate endpoints are used as study outcomes.

The nature of clinical relevance depends on the stage of clinical experimentation. In Phase II trials, which provide a screening evaluation of treatment effect, the primary objective usually is to assess a treatment’s biological activity. Relevant endpoints in such a trial in cancer patients might be measures of tumor shrinkage; in HIV-infected persons, measures of viral load or immune function; and in patients with cardiovascular disease, blood pressure or lipid levels. In contrast, in Phase III clinical trials, where the intent is to define the role of a therapy in standard clinical practice, the primary objective should be to assess the treatment’s clinical ...