The Role and Potential of Surrogate Outcomes in Clinical Trials: Have We Made Any Progress in the Past Decade?

Randomized clinical trials are the standard method for evaluating new interventions or comparing existing ones. Trials which use clinical outcomes as the primary outcome can be large, require lengthy follow-up, and can be expensive. For these reasons, researchers have sought to use intermediate outcomes such as biomarkers as a substitute or surrogate for the clinical outcome. Over a decade ago, this practice had become common. Fleming and DeMets (Ann Intern Med 125:605–613, 1996) reported many cases where the use of a biomarker as a surrogate outcome failed to reliably assess the effect of the intervention, in some cases missing harmful effects including mortality. Recently, the Institute of Medicine (IOM) reviewed the state of the art and came to similar conclusions that biomarkers have often proved to be unreliable as a surrogate [Committee on Qualifications of Biomarkers and Surrogate Endpoints in Chronic Disease, Michael C, Ball J (eds) (2010) Evaluation of biomarkers and surrogate endpoints in chronic disease. National Academies Press, Washington]. They proposed that biomarkers must meet certain criteria including analytic validity, strong correlation with the clinical outcome and the ability to capture the full effects of the intervention. The use of a biomarker as a surrogate must be done so in the context of its intended use, and done so with great caution. While the IOM report further clarifies the necessary requirements of a potential biomarker as a surrogate, the report still recommends caution in using surrogate outcomes in final phases of intervention evaluation as did Fleming and DeMets (Ann Intern Med 125:605–613, 2004).