The Growing Need for Validated Biomarkers and Endpoints for Dry Eye Clinical Research

Abstract

PurposeBiomarkers with minimally invasive and reproducible objective metrics provide the key to future paradigm shifts in understanding of the underlying causes of dry eye disease (DED) and approaches to treatment of DED. We review biomarkers and their validity in providing objective metrics for DED clinical research and patient care.MethodsThe English-language literature in PubMed primarily over the last decade was surveyed for studies related to identification of biomarkers of DED: (1) inflammation, (2) point-of-care, (3) ocular imaging, and (4) genetics. Relevant studies in each group were individually evaluated for (1) methodological and analytical details, (2) data and concordance with other similar studies, and (3) potential to serve as validated biomarkers with objective metrics.ResultsSignificant work has been done to identify biomarkers for DED clinical trials and for patient care. Interstudy variation among studies dealing with the same biomarker type was high. This could be attributed to biologic variations and/or differences in processing, and data analysis. Correlation with other signs and symptoms of DED was not always clear or present.ConclusionsMany of the biomarkers reviewed show the potential to serve as validated and objective metrics for clinical research and patient care in DED. Interstudy variation for a given biomarker emphasizes the need for detailed reporting of study methodology, including information on subject characteristics, quality control, processing, and analysis methods to optimize development of nonsubjective metrics. Biomarker development offers a rich opportunity to significantly move forward clinical research and patient care in DED.OverviewDED is an unmet medical need — a chronic pain syndrome associated with variable vision that affects quality of life, is common with advancing age, interferes with the comfortable use of contact lenses, and can diminish results of eye surgeries, such as cataract extraction, LASIK, and glaucoma procedures. It is a worldwide medical challenge with a prevalence rate ranging from 8% to 50%. Many clinicians and researchers across the globe are searching for better answers to understand the mechanisms related to the development and chronicity of DED. Though there have been many clinical trials for DED, few new treatments have emerged over the last decade. Biomarkers may provide the needed breakthrough to propel our understanding of DED to the next level and the potential to realize our goal of truly personalized medicine based on scientific evidence. Clinical trials and research on DED have suffered from the lack of validated biomarkers and less than objective and reproducible endpoints. Current work on biomarkers has provided the groundwork to move forward. This review highlights primarily ocular biomarkers that have been investigated for use in DED, discusses the methodologic outcomes in providing objective metrics for clinical research, and suggests recommendations for further work.

Comparing the needs and preferences of patients with moderate and severe dry eye symptoms across four countries

“…A recent review examining QoL and treatment satisfaction concluded that patient-reported symptoms should be integrated into the individualised approach to treatment in DED 18. Given the unmet need for adequate endpoints in clinical studies of DED,4 patient-based evidence can also provide valuable information for clinical trial design 8. However, despite an increased awareness of the need for patient preference studies in DED, the published literature in this area is limited.…”

“…The medical management of DED continues to remain an unmet need, as expressed by patients and physicians alike 2 3. Only few novel treatments have emerged over the last decade despite a comparably large number of clinical trials 4. The availability and use of dry eye therapies in everyday practice vary across countries: ocular anti-inflammatory agents (cyclosporine A, lifitegrast) have been used intensively in the USA for several years, while in Australia lifitegrast was granted approval in early 2019; artificial tears containing hyaluronic acid are widely used in Europe, especially in Germany, but are not available in the USA.…”

Conjunctival Inflammatory Gene Expression Profiling in Dry Eye Disease: Correlations With HLA-DRA and HLA-DRB1

“…Several multicenter trials have included this methodology as a tool evaluating ocular surface (OS) inflammation ( 13 , 15 ). Therefore, HLA-DR is now considered as one of the most promising markers of OS inflammation ( 16 , 17 ).…”

Ocular Surface Workup in Patients with Meibomian Gland Dysfunction Treated with Intense Regulated Pulsed Light

“…However, these measures are subjective, and prone to observer bias due to a low degree of standardization. Conversely, a comprehensive ocular surface workup with automated quantitative measurements may overcome these drawbacks, thus improving the objective monitoring of the disease course after treatment [38].…”