Methods for practical validation of surrogate endpoints

Along with the development of different definitions of a surrogate endpoint, methods for verifying whether the definitions hold for a biomarker have been proposed. Recently, a new methodology, known as the “meta-analytic” validation approach, has been developed (Buyse et al., Biostatistics 2000). This method uses data from multiple randomized clinical trials and aims at assessing directly the precision of prediction of treatment effect on the true endpoint from the effect on the surrogate. Thus, it allows to assess whether “the effect of treatment on a surrogate endpoint is reasonably likely to predict clinical benefit”, as required by the Biomarkers Definitions Working Group definition. As such, it is a powerful tool that makes it possible to assess the suitability of candidate surrogate endpoints and to prevent erroneous use of them.

A big advantage for such a structured approach is that it allows quantifying the evidence in favor or against the use of a surrogate. The methodology has been already used, e.g., to evaluate the validity of using response rate and progression-free survival as surrogates for overall survival in colorectal cancer (Buyse et al., Lancet 2000; Sargent et al., Journal of Clinical Oncology 2005; Buyse et al., Journal of Clinical Oncology 2007); the validity of using PSA as a surrogate for overall survival in metastatic prostate cancer (Collette et al., Journal of Clinical Oncology 2005); or the validity of using response rate, disease control rate, time to progression, and progression-free survival as surrogates for overall survival in metastatic breast cancer (Burzykowski et al., Journal of Clinical Oncology 2007). Some of these results have been taken into account in the “FDA Project on Cancer Drug Approval Endpoints”, launched by FDA “to evaluate potential endpoints for cancer drug approval” ( Within the project, FDA holds public workshops to identify important issues that are discussed in meetings of the Oncologic Drugs Advisory Committee (ODAC). Subsequently, guidance documents are published describing FDA's view on endpoints for cancer drug approval. Thus far, workshops for multiple myeloma, ovarian cancer, primary brain tumors, lung cancer, colorectal cancer, prostate cancer, and acute leukemia, have been organized.


One needs to be aware of the fact that, even if a surrogate has been validated for a particular class of treatments in a particular disease, this does not automatically mean that the use of the surrogate is valid in another disease, or for another class of treatments. This is because the mechanisms of action of different treatments may differ, and their relevance for different diseases may also vary. Thus, the use of a surrogate endpoint will most likely always require a careful consideration whether the result of a validation exercise can apply to a particular situation.

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