Both humanitarian and commercial considerations have spurred intensive search for methods to reduce the time and cost required to develop new therapies. The identification and use of surrogate endpoints, i.e., measures that can replace or supplement other endpoints in evaluations of experimental treatments or other interventions, is a general strategy that has stimulated both enthusiasm and skepticism. Surrogate endpoints are useful when they can be measured earlier, more conveniently, or more frequently than the "true" endpoints of primary interest. Regulatory agencies around the globe, particularly in the United States, Europe, and Japan, are introducing provisions and policies relating to the use of surrogate endpoints in registration studies. But how can one establish the adequacy of a surrogate? What kind of evidence is needed, and what statistical methods portray that evidence most appropriately?

"Both humanitarian and commercial considerations have spurred intensive search for methods to reduce the time and cost required to develop new therapies. The identification and use of surrogate endpoints, i.e., measures that can replace or supplement other endpoints in evaluations of experimental treatments or other interventions, is a general strategy that has stimulated both enthusiasm and skepticism. Surrogate endpoints are useful when they can be measured earlier, more conveniently, or more frequently than the "true" endpoints of primary interest. Regulatory agencies around the globe, particularly in the United States, Europe, and Japan, are introducing provisions and policies relating to the use of surrogate endpoints in registration studies. But how can one establish the adequacy of a surrogate? What kind of evidence is needed, and what statistical methods portray that evidence most appropriately?

Setting the Scene.- Regulatory Aspects in Using Surrogate Markers in Clinical Trials.- Notation and Motivating Studies.- The History of Surrogate Endpoint Validation.- Validation Using Single-trial Data: Mixed Binary and Continuous Outcomes.- A Meta-analytic Validation Framework for Continuous Outcomes.- The Choice of Units.- Extensions of the Meta-analytic Approach to Surrogate Endpoints.- Meta-analytic Validation with Binary Outcomes.- Validation in the Case of Two Failure-time Endpoints.- An Ordinal Surrogate for a Survival True Endpoint.- A Combination of Longitudinal and Survival Endpoints.- Repeated Measures and Surrogate Endpoint Validation.- Bayesian Evaluation of Surrogate Endpoints.- Surrogate Marker Validation in Mental Health.- The Evaluation of Surrogate Endpoints in Practice: Experience in HIV.- An Alternative Measure for Meta-analytic Surrogate Endpoint Validation.- Discussion: Surrogate Endpoint Definition and Evaluation.- The Promise and Peril of Surrogate Endpoints in Cancer Research.