Motivation for the use of intermediate endpoints or surrogates

Ideally, when studying the effects of an E/I, the appropriate outcome measure is the true clinical end-point of interest (CE), which is usually survival or the incidence of a clinical event. However, the CE may require invasive tests, be expensive, occur rarely or be temporally distant from the E/I. For example, in trials of cholesterol-lowering drugs, the fundamental end-point of interest may be death or development of coronary artery disease (CAD). Such a study may require the recruitment of thousands of patients followed up for many years. Clinicians, patients and funding bodies are keen to assess the effectiveness of promising new therapies quickly. This leads investigators to explore markers that may serve as intermediate end-points or surrogate end-points (IE/Ss) of the CE and which are more frequently occurring and temporally closer to the E/I. Therefore, for example, it is of interest to know how useful a reduction in post-treatment cholesterol will be in predicting reductions in the incidence of CAD.

Fundamentally, an IE/S should be sufficiently closely related to the CE such that changes in the IE/S accurately predict changes in the CE. Implicit in this idea is the

Figure 3.1 The position of an intermediate end-point or surrogate (IE/S) on the pathway between an exposure or intervention (E/I) and a clinical end-point of primary interest (CE).

condition that the CE should not be greatly influenced by factors independent of the chosen IE/S. Thus, all confounding factors should precede the measurement of the IE/S and act through the IE/S disease pathway. A poor choice of IE/S will overestimate the effects on the true CE, may underestimate confounding and side effects, and could lead to inappropriate treatment.

There may be other benefits in using IE/Ss. Since they are measured closer in time to the E/I, they may be easier to interpret. For example, in a study of surgical patients, deaths within 30 days may be easier to attribute to the procedure than deaths within 12 months, which may be influenced by many factors. A further benefit may be that identifying a useful IE/S adds to the understanding of the underlying disease process and, thus, potential intervention strategies may be suggested. A related point follows: if we can intervene based on the IE/S, we may prevent or attenuate the impact of the CE, thus addressing the underlying problem earlier in the disease process.

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