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Validation of Surrogate Markers in Multiple Randomized Clinical Trials with Repeated Measurements: Canonical Correlation Approach

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Part of the recent literature on the evaluation of biomarkers as surrogate endpoints starts from a multitrial context, which leads to a definition of validity in terms of the quality of both trial-level and individual-level association between the surrogate and true endpoints ( Buyse et al., 2000, Biostatistics1, 49–67). These authors concentrated on cross-sectional continuous responses. However, in many randomized clinical studies, repeated measurements are encountered on either or both endpoints. A challenge in this setting is the formulation of a simple and meaningful concept of “surrogacy.” Alonso et al. (2003, Biometrical Journal45, 931–945) proposed the variance reduction factor (VRF) to evaluate surrogacy at the individual level. They also showed how and when this concept should be extended to study surrogacy at the trial level. Here, we approach the problem from the natural canonical correlation perspective. We define a class of canonical correlation functions that can be used to study surrogacy at the trial and individual level. We show that the VRF and the R2 measure defined by Buyse et al. (2000) follow as special cases. Simulations are conducted to evaluate the performance of different members of this family. The methodology is illustrated on data from a meta-analysis of five clinical trials comparing antipsychotic agents for the treatment of chronic schizophrenia.

Keywords: Bivariate longitudinal data; Canonical correlations; Randomized clinical trials; Surrogate marker; Validation

Document Type: Research Article


Affiliations: 1: Center for Statistics, Limburgs Universitair Centrum, Transnationale Universiteit Limburg, Universitaire Campus, B3590 Diepenbeek, Belgium 2: Medical Statistics Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K. 3: Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium

Publication date: 2004-12-01

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