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.

Combining optical coherence tomography with visual field data to rapidly detect disease progression in glaucoma: a diagnostic accuracy study

“…Potential surrogate outcomes also need to be shown to capture the effect of a treatment intervention on the clinically relevant outcome. 64,65 We therefore assessed the association of the rate of RNFL loss in individual participants with the time to VF event in a Cox proportional hazards model.…”

“…Alternative outcomes, such as structural measurements based on imaging, need to be correlated with the clinically relevant outcome, in this case VF loss, and capture the effect of a treatment intervention on that clinically relevant outcome. 64,65 The correlation between structural and VF measurements has been established 20,21,41,42 and the potential for scanning laser ophthalmoscopy measurements of the ONH to capture treatment effects has been demonstrated; 66 however, clinical trial data demonstrating that structural outcomes capture treatments effects on the VF have yet to be published. The potential benefits to patients and the NHS of combining VF and OCT data could be more sensitive (and therefore more rapid) identification of glaucoma deterioration and more accurate assessment of rates of deterioration, with consequently improved clinical outcomes, and a reduced frequency of patient visits and testing.…”

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

“…Treating physicians have generally relied on VF testing, IOP measurement, and optic nerve monitoring as metrics for assessing whether disease is adequately controlled (5). However, the nature of VF testing, lack of precise correlation of IOP with disease risk, and lack of validated normative databases for optic nerve imaging techniques, such as optical coherent tomography (OCT), contribute to the persistent challenges of glaucoma management.…”

Missed opportunity from randomised controlled trials of medical interventions for open-angle glaucoma

“…Evidence to support the management of patients with open-angle glaucoma (OAG) should rely on provider-important outcomes and on patient-important outcomes, for example, how well an intervention improves or stabilises functions that patients value 2. The definition of an outcome includes five elements,3 with the outcome ‘domain’ being the name of the outcome being measured.…”