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. 2012 Nov 10;31(25):2973-84.
doi: 10.1002/sim.5403. Epub 2012 Jun 18.

Biomarkers and surrogate endpoints in clinical trials

Thomas R Fleming  1 , John H Powers
Affiliations

Biomarkers and surrogate endpoints in clinical trials

Thomas R Fleming et al. Stat Med. .

Abstract

One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker.

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Figures

Figure 1
Figure 1
Illustrations where the biomarker is not in a causal pathway of the disease process, reducing the likelihood it could be shown to be a valid surrogate endpoint. “CEA” is carcinoembryonic antigen; “PSA” is the prostate specific antigen; “Ca.” is cancer.
Figure 2
Figure 2
Illustrations where the disease process has multiple causal pathways, and the biomarker lies in just one of those pathways. “MI” is myocardial infarction; “CGD” is chronic granulomatous disease.
Figure 3
Figure 3
An illustration where the biomarker lies in a causal pathway of the disease process that is impacted by the intervention, yet off target effects of the intervention reduce the likelihood the biomarker would be a valid surrogate endpoint.
Figure 4
Figure 4
Results from the Normal Hematocrit Trial (18). The x-axis is the achieved level of hematocrit %, after treatment. The dark bars represent percent deaths and the light bars represent the percent of patients, for each level of hematocrit %. “RR” is relative risk. “Hem” is hematocrit.
Figure 5
Figure 5
Data presented at the 15 June 2005 FDA Cardiovascular and Renal Drugs Advisory Committee. For controlled trials evaluating antihypertensive agents, the treatment effect on systolic blood pressure (x-axis) is plotted against the odds ratio for major cardiovascular events (y-axis).
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