Biostatistics 1:49-67 (2000)
© 2000 Oxford University Press
The validation of surrogate endpoints in meta-analyses of randomized experiments
1 International Institute for Drug
Development, 430 avenue Louise B14, B1050 Brussels, Belgium
mbuyse{at}id2.be
2 Center for Statistics, Limburgs
Universitair Centrum, B3590 Diepenbeek, Belgium
The validation of surrogate endpoints has been studied by
Prentice (1989). He presented a definition as well as a set of
criteria, which are equivalent only if the surrogate and true
endpoints are binary. Freedman et al. (1992) supplemented
these criteria with the so-called ‘proportion explained’.
Buyse and Molenberghs (1998) proposed replacing the proportion
explained by two quantities: (1) the relative effect linking the
effect of treatment on both endpoints and (2) an individual-level
measure of agreement between both endpoints. The latter quantity
carries over when data are available on several randomized trials,
while the former can be extended to be a trial-level measure of
agreement between the effects of treatment of both endpoints. This
approach suggests a new method for the validation of surrogate
endpoints, and naturally leads to the prediction of the effect of
treatment upon the true endpoint, given its observed effect upon the
surrogate endpoint. These ideas are illustrated using data from two
sets of multicenter trials: one comparing chemotherapy regimens for
patients with advanced ovarian cancer, the other comparing
interferon-
with placebo for patients with age-related macular
degeneration.
Keywords: Ovarian cancer; Macular degeneration; Random-effects model; Surrogate endpoint; Two-stage model; Validation
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