The Glaucoma Research Community and FDA Look to the Future: A Report from the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium*

Abstract

On March 13–14, 2008, the National Eye Institute (NEI), of the National Institutes of Health (NIH), and the Food and Drug Administration Center for Drug Evaluation and Research (FDA CDER) held the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium to discuss the possible use of new structural and functional endpoints for evaluating glaucoma therapies in clinical trials. It was an important meeting where the FDA and the glaucoma research community advanced their common understanding of glaucoma clinical trials. An appreciation was gained by researchers and others within the glaucoma community of the receptivity of the FDA to new endpoints. Glaucoma is a complex, progressive optic neuropathy. It is the leading cause of irreversible and preventable blindness, affecting an estimated 2.2 million people in the United States and 70 million worldwide. Basic and clinical research initiatives are revealing the pathobiology and clinical course of glaucoma and are setting the stage for possible new treatments. Currently, clinical drug trials are focused on intraocular pressure (IOP) measurements and/or visual field tests (a functional outcome measure) for the assessment of clinical IOPlowering efficacy and changes in optic nerve function. In some studies, stereoscopic optic disc photography (a structural outcome measure) has been used as a secondary endpoint. The FDA considers optic nerve and retinal nerve fiber layer (RNFL) structural changes and new changes in visual function to be outcome measures in clinical trials that serve as the basis for approving neuroprotective glaucoma therapies, provided those outcomes are proven predictive of function that is clinically relevant to a patient. Although there are data suggesting the early involvement of central vision, glaucoma generally affects peripheral vision first in standard clinical testing. Functional visual field tests evaluate the presence and amount of visual field loss. Clinical observation of the optic nerve and examination of optic nerve photographs can be used to determine the presence of structural changes such as narrowing of the neuroretinal rim, loss of parapapillary fibers from the RNFL, increased excavation of the optic cup, -zone parapapillary atrophy, and optic disc hemorrhage. Accurate interpretation of the structural events has traditionally been dependent on the experience and subjective judgment of the observer. New computerized imaging devices for viewing the optic nerve are used widely to detect glaucomatous changes in the optic disc and RNFL and also to quantitate these changes. Measurements generally are objective and reproducible. Among these imaging technologies are confocal scanning laser ophthalmoscopy, scanning laser polarimetry, and optical coherence tomography. The purpose of the NEI/FDA CDER Glaucoma Clinical Trial Design and Endpoints Symposium was to provide a forum for discussing outcome measures— based on the newer technologies—for evaluating neuroprotective products (i.e., those that protect the optic nerve) for glaucoma in clinical trials to facilitate bringing safe and efficacious glaucoma pharmacotherapies to the U.S. market. Although there was no discussion in the Symposium directly comparing the various technologies and instruments, a future meeting on this subject is anticipated. The meeting was held in the Natcher Auditorium on the NIH campus. Participants from the glaucoma community left with a clearer understanding of FDA expectations for demonstrating the safety and efficacy of new pharmacotherapies, the relevancy of new endpoints, and the role of the FDA in providing guidance for meeting recognized standards for approval of new therapeutic agents. Symposium organizers were Robert N. Weinreb, MD, Uni