Outcome Measures to Assess Efficacy of Treatments for Age-Related Macular Degeneration Janet Wittes, PhD, Matthew Downs, MPH In a clinical trial of age-related macular degeneration (AMD), the outcome measure chosen to assess the efficacy of treatment should reflect the purpose of the trial and the stage of development of the treatment. This article considers 3 classes of outcomes: continuous variables, such as mean change in best visual acuity; binary (2-category) variables, such as experiencing a 15-letter loss; or 3-category variables, such as experiencing either a 15-letter loss or 15-letter gain. Each type of outcome has advantages and disadvantages. Trials using outcomes based on means require much smaller sample sizes than trials based on 2- or 3-category variables, but means do not address the experience of individuals. Two- and 3-category variables show what happens to individuals, but they are subject to misclassification and are statistically inefficient. The authors recommend considering continuous measures for early stage trials and for trials studying various dose regimens when a treatment has been well characterized. However, 2- and 3-category outcomes are particularly useful in confir- matory phase 3 trials of a new therapy. A new graphical method is proposed to provide insight into the distribution of the time course of changes in acuity on an individual patient basis. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the CME frontmatter. Ophthalmology 2009;116:S8 –S14 © 2009 by the American Academy of Ophthalmology. Outcomes typically used in randomized confirmatory (phase 3) clinical trials of diseases characterized by an inexorably declining clinical course measure the extent of, or rate of, decline in a measure of interest. For example, phase 3 trials studying treatment of incurable cancer often compare ther- apies with respect to time to death or time to tumor pro- gression; trials of chronic obstructive lung disease often use rate of decline in lung function; some trials of Alzheimer’s disease use decline in cognitive function. Similarly, phase 3 trials of interventions for age-related macular degeneration (AMD) have used measures of decline in vision as the primary outcome. For example, the primary outcomes of the National Eye Institute’s Age-Related Eye Disease Study trial were (1) photographic assessment of progression to, or treatment for, advanced AMD and (2) a loss from baseline in visual acuity of at least 15 letters. 1 Several other recent trials studying AMD also have used as the primary outcome a loss of at least 15 letters 2 or its obverse, loss of fewer than 15 letters. 3–5 Most of these studies observed participants for 12 months to compare outcomes of therapy for the test and control treatment and 24 months to evaluate long- term effect. Other primary outcomes used in trials of AMD include various continuous measures of visual acuity (e.g., best- corrected visual acuity or change from baseline in best- corrected visual acuity). 6–8 Henceforth, this article uses the term visual acuity to refer to best-corrected visual acuity. This article reviews the primary and secondary outcomes used in recent clinical trials, discusses recommended out- comes, and briefly describes how to calculate sample size for each type of outcome. In the current era of treatments that not only retard the progression of AMD, but often lead to increased visual acuity, the authors suggest that clinical outcomes should address both improvement and deteriora- tion in vision. The article addresses the appropriate length of follow-up for trials evaluating the effect of an intervention on AMD and examines some methods for handling missing data. To accompany the statistical analysis, effective graph- ical presentations allow understanding of patterns of change in vision over time on an individual patient level. The article concludes with some brief remarks. Primary Outcomes and Calculation of Sample Size for Each Randomized clinical trials have used 4 classes of outcomes to test interventions for AMD over a 12-month period: (1) a continuous measure of visual acuity (e.g., visual acuity at 12 months, change in visual acuity from baseline to 12 months, or the area under the curve of visual acuity from random- ization to 12 months); (2) an assessment of success (e.g., the proportion of participants gaining a fixed number of letters, having unchanged vision, or exhibiting vision that is 20/20 or better or 20/40 or better) or failure (e.g., the proportion of participants with severe loss of vision or vision that is 20/200 or worse) over a 12-month period; (3) the proportion requiring retreatment or alternative therapy; or (4) charac- teristics of the disease. The sample size required for a clinical trial depends on the outcome chosen. The generic formula for the sample S8 © 2009 by the American Academy of Ophthalmology ISSN 0161-6420/09/$–see front matter Published by Elsevier Inc. doi:10.1016/j.ophtha.2009.06.050