Evaluation of Incident Advanced Age-Related Macular Degeneration and of Progression on the AREDS 9-Step Severity Scale as Surrogate Outcome Measures in Clinical Trials

Abstract

Purpose: : To evaluate candidate surrogate outcome measures for loss of visual acuity in clinical trials for patients with early and intermediate age-related macular degeneration (AMD).

Methods: : Criteria from the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use were applied to candidate surrogate outcome measures for vision loss in clinical trials involving patients with early or intermediate AMD. Criteria included 1) biological plausibility; 2) accuracy, reliability, and responsiveness to change; 3) demonstration in epidemiological studies of the prognostic value of the surrogate for the clinical outcome; and 4) evidence from clinical trials that treatment effects on the surrogate correspond to effects on the clinical outcome. The pattern of steps over time was also examined for the AREDS scale. Data from observational studies and clinical trials, including the Age Related Eye Disease Study (AREDS) and the Complications of AMD Prevention Trial (CAPT), were used to assess 2 candidate surrogates: incidence of advanced AMD documented by fundus photography and progression on the AREDS 9-step severity scale documented by fundus photography.

Results: : Each of candidate surrogate outcome measures meets the first 3 criteria cited above based on data from several independent studies. For the 4^th criterion, treatment effects on advanced AMD correspond with treatment effects on visual acuity : dietary supplements use decreased both incidence of advanced AMD and VA loss in AREDS, and laser treatment had no effect on either incidence of advanced AMD or VA loss in CAPT). However, treatment effects on the components of the AREDS scale score did not correspond to treatment effects on visual acuity in AREDS and in CAPT. In addition, among 261 CAPT untreated eyes followed annually for 5 years without development of advanced AMD, 141 (55%) had at least one improvement in step score between years.

Conclusions: : Using incidence of advanced AMD as a surrogate outcome measure for visual acuity is consistent with established criteria for appropriate use. Because progression on the AREDS scale does not meet the criteria for a surrogate outcome measure, progression on the scale should not be used an outcome measure in clinical trials.

Keywords: clinical (human) or epidemiologic studies: biostatistics/epidemiology methodology • age-related macular degeneration