ABSTRACT
Marc Buyse, Tomasz Burzykowski, Geert Molenberghs, and Ariel Alonso
CONTENTS
18.1 Introduction ................................................................................................334 18.2 Longitudinal Biomarkers .......................................................................... 336
18.2.1 Deˆnitions.......................................................................................336 18.2.2 Example: Prostate-Speciˆc Antigen (PSA) .................................338 18.2.3 PSA as a Prognostic Biomarker ....................................................338 18.2.4 PSA as a Pharmacodynamic Biomarker ..................................... 339
18.3 Validation of a Surrogate Endpoint in a Single Trial ............................340 18.3.1 Prentice’s Deˆnition and Criteria ................................................342 18.3.2 Freedman’s Proportion Explained ..............................................343 18.3.3 Relative Effect and Adjusted Association ..................................344 18.3.4 Limitations of Analyses Based on a Single Trial .......................344 18.3.5 PSA as a Surrogate in a Single Trial ............................................346
18.4 Validation of a Surrogate Endpoint in Multiple Trials .........................348 18.4.1 Meta-Analytic Model for Gaussian Endpoints ..........................349 18.4.2 Simpliˆed Modeling Strategies .................................................... 351 18.4.3 Binary Endpoints ........................................................................... 352 18.4.4 Failure-Time Endpoints.................................................................353 18.4.5 Longitudinal Endpoints ................................................................354 18.4.6 PSA as a Surrogate in Multiple Trials .........................................354
18.5 Prediction of the Treatment Effect ........................................................... 357 18.5.1 Some Theoretical Situations ......................................................... 358 18.5.2 Surrogate Threshold Effect ........................................................... 358 18.5.3 Design of Trials Using Surrogate Endpoints ............................. 359 18.5.4 Constancy Assumption .................................................................360
18.6 Other Approaches to Surrogacy .............................................................. 361 18.6.1 Variance Reduction and Information Theory ............................ 361 18.6.2 Principal Stratiˆcation and Causal Inference ............................363
18.7 Concluding Remarks .................................................................................364 Acknowledgments ..............................................................................................365 References .............................................................................................................365
