Contextualizing single‐arm trials with real‐world data: An emulated target trial comparing therapies for neovascular age‐related macular degeneration

ABSTRACT: One‐in‐four ophthalmology trials are single‐armed, which poses challenges to their interpretation. We demonstrate how real‐world cohorts used as external/synthetic control arms can contextualize such trials. We herein emulated a target trial on the intention‐to‐treat efficacy of off‐label bevacizumab (q6w) pro re nata relative to fixed‐interval aflibercept (q8w) for improving week 54 visual acuity of eyes affected by neovascular age‐related macular degeneration. The bevacizumab arm (n = 65) was taken from the ABC randomized controlled trial. A total of 4,471 aflibercept‐treated eyes aligning with the ABC trial eligibility were identified from electronic health records and synthetic control arms were created by emulating randomization conditional on age, sex, and baseline visual read via exact matching and propensity score methods. We undertook an inferiority analysis on mean difference at 54 weeks; outcomes regression on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to −15 Early Treatment Diabetic Retinopathy (ETDRS) letters at week 54; and a time‐to‐event analysis on achieving a change in visual acuity of greater than or equal to 15, greater than or equal to 10, and less than or equal to −15 ETDRS letters by week 54. The findings suggest off‐label bevacizumab to be neither inferior nor superior to licensed aflibercept. Our study highlights how real‐world cohorts representing the counterfactual intervention could aid the interpretation of single‐armed trials when analyzed in accord to the target trial framework. STUDY HIGHLIGHTS: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? WHAT QUESTION DID THIS STUDY ADDRESS? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? External counterfactual arms could reduce the time and cost to reach potential regulatory approval.