Schuetz, HelmutBurger, Divan AristoCobo, ErikDubins, David D.Farkas, TiborLabes, DetlewLang, BenjaminOcana, JordiRing, ArneShitova, AnastasiaStus, VolodymyrTomashevskiy, Michael2024-05-212024-05-212024-04Schütz, H., Burger, D.A., Cobo, E. et al. Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies. The AAPS Journal 26, 50 (2024). https://doi.org/10.1208/s12248-024-00921-x.1550-741610.1208/s12248-024-00921-xhttp://hdl.handle.net/2263/96098Comparative bioavailability studies often involve multiple groups of subjects for a variety of reasons, such as clinical capacity limitations. This raises questions about the validity of pooling data from these groups in the statistical analysis and whether a group-by-treatment interaction should be evaluated. We investigated the presence or absence of group-by-treatment interactions through both simulation techniques and a meta-study of well-controlled trials. Our findings reveal that the test falsely detects an interaction when no true group-by-treatment interaction exists. Conversely, when a true group-by-treatment interaction does exist, it often goes undetected. In our meta-study, the detected group-by-treatment interactions were observed at approximately the level of the test and, thus, can be considered false positives. Testing for a group-by-treatment interaction is both misleading and uninformative. It often falsely identifies an interaction when none exists and fails to detect a real one. This occurs because the test is performed between subjects in crossover designs, and studies are powered to compare treatments within subjects. This work demonstrates a lack of utility for including a group-by-treatment interaction in the model when assessing single-site comparative bioavailability studies, and the clinical trial study structure is divided into groups.en© The Author(s) 2024, corrected publication 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License.Average bioequivalenceGroup-by-treatment interactionMonte-Carlo simulationsRegulatory guidelinesArticle