The perils of surrogate endpoints

Our goals in medicine are (i) to improve the quality of patients' lives, (ii) help them to live longer, and (iii) to do so at a reasonable cost. These are our true endpoints: health status, survival, and cost. It is thus entirely consistent with this point of view that these are the fundamental concepts that can be united in a formal cost–utility analysis.1 These endpoints remain the best measures of efficacy in clinical trials comparing a new therapy to placebo or to an active control. All other measures may then be seen as surrogate endpoints or surrogates. Thus, even serious events such as myocardial infarction and stroke may be considered surrogates, as their effect is to adversely affect the critical endpoints of health status, survival, and cost. However, in common usage a surrogate is a relatively easy to measure endpoint, available over a relatively short timeframe that is used in place of the true endpoints. Generally, surrogates are not events, but rather measurements (physiological, laboratory, or test results, e.g. biomarkers) that predict events. Thus, surrogates are most commonly measures that we can record, often with much shorter timescales than is necessary for events.2 Surrogates are usually continuous variables, often but not necessarily with reasonable approximations of a normal distribution. Continuous variables, especially if approximating a normal distribution, will allow for much smaller sample sizes than dichotomous variables as well as shorter periods of follow-up and lower costs. Thus, compared with clinical outcome trials, studies with surrogate endpoints can be conducted rapidly and with much less resource use and expense …