Biomarkers and surrogate endpoints in glaucoma clinical trials

Abstract

Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies.

Keywords: Clinical Trial; Glaucoma; Imaging; Intraocular Pressure.

Figure 1

Schematic representation of an ideal surrogate endpoint. In this case, all mechanisms of action to the true endpoint are mediated through the surrogate endpoint.

Figure 2

Examples of invalid surrogacy. (A) The disease causally influences the proposed surrogate endpoint as well as the true clinically relevant endpoint. As a result, the surrogate is correlated with the clinical endpoint. However, as the surrogate does not lie in the biological pathway by which the disease process actually influences the occurrence of the true clinical endpoint, then affecting the surrogate might not affect the clinical endpoint. (B) The proposed surrogate endpoint lies in only one of the pathways by which the disease process influences the risk of the true endpoint. The intervention affects only the pathway that includes the surrogate endpoint and, therefore, the effect of treatment on the true endpoint could be overestimated by an analysis relying only on the effect of treatment on the surrogate. (C) Here, the proposed surrogate also lies in only one of the pathways by which the disease process influences the risk of the true endpoint, but in this case, the intervention affects the pathway that does not include the surrogate. The effect of treatment on the true endpoint could then be underestimated by an analysis that includes only its effect on the surrogate. (D) The intervention might actually affect the true endpoint by unintended mechanisms of action that are independent of the disease process and are not captured by the surrogate.