Individual-Level versus Trial-Level Surrogacy

Notwithstanding these formal definitions, there is a critical ambiguity about the meaning of the term “surrogate” in practice. A surrogate endpoint may be used to predict the course of the disease in an individual patient, in order to adjust the treatment accordingly. In this book, we will refer to this situation as individual-level surrogacy. A surrogate endpoint may also be used to predict the effect of some therapy on the clinical endpoint of interest, based on the effect of this therapy on the surrogate endpoint. We will refer to this situation as trial-level surrogacy. The mathematical models described in this book have been developed to address both levels of surrogacy, thus building a useful parallel between the intended use of potential surrogates, and their statistical evaluation. In these models, the two levels of surrogacy are independent from each other, at least when the surrogate and the clinical endpoint are both captured by normally distributed variables. This intriguing feature of the two levels of surrogacy has created much confusion, and continues to plague their use. We will return to this issue in Section 1.2.5.

The International Conference on Harmonisation (ICH) Guidelines on Statistical Principles for Clinical Trials reflect the distinction between these two levels of surrogacy: “In practice, the strength of the evidence for surrogacy depends upon (i) the biological plausibility of the relationship, (ii) the demonstration in epidemiological studies of the prognostic value of the surrogate for the clinical outcome, and (iii) evidence from clinical trials that treatment effects on the surrogate correspond to effects on the clinical outcome” (ICH, 1998). Condition (i) involves biological rather than statistical considerations, condition (ii) is individual-level surrogacy, and condition (iii) is trial-level surrogacy. Surrogate endpoints can be put to different uses depending on the phase of drug development. Early or “intermediate” endpoints are commonly used in phase I or phase II trials when they have been shown to be individual- level surrogates. However, very few intermediate endpoints have been shown to be acceptable trial-level surrogates that can substitute for a clinical endpoint in pivotal phase III trials.

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