The active comparator, new user (ACNU) design is an important design developed under the concept of the target simulation experimental framework. It aims to reduce indication confounding, immortal time bias, prevalence-incidence bias, and other unmeasured confounders by simulating head-to-head randomized controlled trials. It is widely applied in scenarios such as comparing the efficacy of newly marketed drugs with existing standard treatments, evaluating drug safety and adherence, exploring drug repurposing, and optimizing algorithms for processing medical big data. This article introduces the application and practice of the ACNU design in real-world data research from aspects such as concept, development, advantages and disadvantages, and implementation points, and also presents an outlook on its application in the field of traditional Chinese medicine. It is believed that with the progress in understanding the design of observational studies of real-world data, the ACNU design is expected to be more widely applied and provide new ideas for researchers' scientific research designs.
Randomised controlled trials are often difficult to conduct for rare diseases, the treatment of life-threatening and serious diseases with no effective treatment options, and single-arm clinical trials are one of the most common choices. However, single-arm clinical trials lack a control group, making it difficult to determine whether the observed treatment effects stem from the drug itself or are influenced by natural disease progression, placebo effects, or selection bias. In recent years, with the continuous accumulation of real-world data, it is possible to use real-world data to construct an external control for single-arm clinical trials. However, it is necessary to carefully consider how to select appropriate external control data to enhance the credibility of the results. Based on the existing studies and relevant laws and regulations in China and abroad, this study expounds the key considerations of using real-world data to construct the external control of single-arm clinical trials on the source data from the perspective of external control setting model, reference intervention selection, data source, and so on. This study could provide references for relevant researchers to conduct similar studies.