Glaucoma Study Results and Masked Adjudication of Endpoints
American Journal of Ophthalmology, March 2019
The commingling of glaucomatous and nonglaucomatous endpoints in clinical trials can lead to overestimation of glaucoma incidence or progression, underestimation of treatment effect, or reduction in statistical power. The FDA and the European Medicines Agency recommend centralized adjudication if treatment assignment is unmasked or if endpoints are subjective or involve complex definitions. Gordon et al. evaluated the effect of a masked Endpoint Committee on estimates of the incidence of primary open-angle glaucoma (POAG), treatment efficacy, and statistical power in the Ocular Hypertension Treatment Study–Phase 1, an unmasked randomized trial of the safety and efficacy of ocular hypotensive medication for preventing or delaying POAG onset. Their new research showed that masked adjudication of endpoints improved POAG incidence estimates, increased statistical power, and increased the calculated treatment effect by 23%.
The Endpoint Committee comprised three practicing clinicians who decided independently whether an endpoint was “most probably due to POAG” or “most probably not due to POAG.” For optic disc deterioration, each member specified whether the change was clinically significant. The Committee reviewed 267 first endpoints from 1,636 participants and attributed 155 (58%) of them to POAG. The incidence of all-cause endpoints versus POAG endpoints was 19.5% versus 13.2% (respectively) for the observation group and 13.1% versus 5.8% (respectively) for the medication group. Treatment effect for all-cause endpoints was a 33% reduction in risk (relative risk, 0.67) and a 56% reduction in risk for POAG endpoints (relative risk, 0.44). Post-hoc statistical power for detecting treatment effect was 0.94 for all-cause endpoints and 0.99 for POAG endpoints.
The authors advocate endpoint adjudication for clinical trials in which common ocular or systemic comorbidities could compromise the results. Given the strong treatment effect in this trial, the increased power was not crucial. However, it could be important in studies of interventions that have less robust effects.
The original article can be found here.