Surrogate and Mediating Endpoints: Current Status and Future Directions
Authors: Ross L. Prentice
Journal: JNCI Journal of the National Cancer Institute (2009)

The identification of surrogate endpoints that can replace “true” endpoints in clinical trials could provide an important advance for the evaluation of therapeutic or preventive interventions. Outcome events that are more frequent in occurrence and more proximate in time, compared with customary disease-specific mortality or incidence outcomes, could give answers that are based on smaller trials of shorter duration. However, reliance on surrogate outcomes is justifiable only if treatment comparisons that are based on a surrogate are a faithful reflection of comparisons that are based on the true endpoint. I took this perspective, almost 20 years ago ( 1 ), in defi ning a surrogate outcome to be “a response variable for which a test of the null hypothesis of no relationship to the treatment groups under comparison is also a valid test of the corresponding null hypothesis based on the true endpoint,” thinking that this was a minimal requirement for a short-term outcome to provide some reliable treatment effect information for the longer term outcome. However, this apparently simple requirement translates to some strong restrictions on the relationship of the treatment to the surrogate and true outcomes: Consider a treatment indicator variable x , a time to response surrogate S , and a time to response true outcome T . A dependence of T on x will imply a dependence of S on x if 1. the hazard rate for T depends on S and 2. the hazard rate for T given S does not depend on x . The fi rst criterion is typically readily verifi ed empirically, whereas the second, which requires the surrogate to fully mediate the treatment effect on true outcome, is not. Rather, empirical data alone, even if extensive, will not provide certainty concerning criterion 2. Criterion 2 typically entails detailed knowledge of the biological pathways whereby x may affect T and detailed knowledge about the time course of such effects — knowledge that one would not expect to be available if there is uncertainty concerning whether x has any effect on T . For criterion 2 to hold, the surrogate must be comprehensive in being responsive to all pertinent pathways and the implications of the surrogate event occurrence for the true outcome risk must be equivalent in each treatment group being compared. The article by Ray et al. ( 2 ) in this issue considers both the occurrence of distant metastases and general clinical treatment failure as potential surrogate outcomes for prostate cancer – specifi c death in the context of evaluating the effect of long-term androgen deprivation therapy among prostate cancer patients with locally advanced disease. Among patients who were alive 3 years after randomization, the hazard ratio for prostate cancer – specifi c death, when long-term androgen deprivation therapy was compared with control treatment, was 0.76 (95% confi dence interval [CI] = 0.51 to 1.11) among patients without distant metastases and 0.95 (95% CI = 0.60 to 1.50) among patients with distant metastases. In the context of a corresponding unconditional hazard ratio of 0.69 (95% CI = 0.52 to 0.93) for prostate cancer – specifi c mortality, these analyses convey useful information about the importance of a reduction of distant metastasis in mediating the treatment effect on prostate cancer – specifi c survival, but they do not provide persuasive