On Assessing Surrogacy in a Single Trial Setting Using a Semicompeting Risks Paradigm


  • Debashis Ghosh

    Corresponding author
    1. Departments of Statistics and Public Health Sciences, The Pennsylvania State University, 514A Wartik Building, University Park, Pennsylvania 16802, U.S.A.
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email: ghoshd@psu.edu


Summary There has been a recent emphasis on the identification of biomarkers and other biologic measures that may be potentially used as surrogate endpoints in clinical trials. We focus on the setting of data from a single clinical trial. In this article, we consider a framework in which the surrogate must occur before the true endpoint. This suggests viewing the surrogate and true endpoints as semicompeting risks data; this approach is new to the literature on surrogate endpoints and leads to an asymmetrical treatment of the surrogate and true endpoints. However, such a data structure also conceptually complicates many of the previously considered measures of surrogacy in the literature. We propose novel estimation and inferential procedures for the relative effect and adjusted association quantities proposed by Buyse and Molenberghs (1998, Biometrics54, 1014–1029). The proposed methodology is illustrated with application to simulated data, as well as to data from a leukemia study.