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? One‐in‐four randomized controlled trials in ophthalmology are single‐armed, which poses challenges for interpreting their efficacy relative to standard of care. Recent conceptual advances in the methods of causal inference and in the emulation of target trials suggests that the standard‐of‐care arms representing the counterfactual intervention can be approximated with observational data. WHAT QUESTION DID THIS STUDY ADDRESS? How real‐world cohorts representing the counterfactual intervention can aid the interpretation of single‐armed ophthalmological trials. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our study highlights how real‐world cohorts representing the counterfactual intervention could aid the interpretation of single‐armed ophthalmological trials when undertaken in accord with the target trial framework. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? External counterfactual arms could reduce the time and cost to reach potential regulatory approval

Macular Telangiectasia Type 2

Purpose: To develop a severity classification for macular telangiectasia type 2 (MacTel) disease using multimodal imaging. Design: An algorithm was used on data from a prospective natural history study of MacTel for classification development. Subjects: A total of 1733 participants enrolled in an international natural history study of MacTel. Methods: The Classification and Regression Trees (CART), a predictive nonparametric algorithm used in machine learning, analyzed the features of the multimodal imaging important for the development of a classification, including reading center gradings of the following digital images: stereoscopic color and red-free fundus photographs, fluorescein angiographic images, fundus autofluorescence images, and spectral-domain (SD)-OCT images. Regression models that used least square method created a decision tree using features of the ocular images into different categories of disease severity. Main Outcome Measures: The primary target of interest for the algorithm development by CART was the change in best-corrected visual acuity (BCVA) at baseline for the right and left eyes. These analyses using the algorithm were repeated for the BCVA obtained at the last study visit of the natural history study for the right and left eyes. Results: The CART analyses demonstrated 3 important features from the multimodal imaging for the classification: OCT hyper-reflectivity, pigment, and ellipsoid zone loss. By combining these 3 features (as absent, present, noncentral involvement, and central involvement of the macula), a 7-step scale was created, ranging from excellent to poor visual acuity. At grade 0, 3 features are not present. At the most severe grade, pigment and exudative neovascularization are present. To further validate the classification, using the Generalized Estimating Equation regression models, analyses for the annual relative risk of progression over a period of 5 years for vision loss and for progression along the scale were performed. Conclusions: This analysis using the data from current imaging modalities in participants followed in the MacTel natural history study informed a classification for MacTel disease severity featuring variables from SD-OCT. This classification is designed to provide better communications to other clinicians, researchers, and patients. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references