The newly revised The International Council for Harmonizsation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 R(3) sets out internationally accepted principles and standards for conducting clinical trials. The application of innovative technologies in clinical trials, consideration of risk proportionality, and the development of new models are all important drivers for the revision of ICH E6 R(3). The main features of this revision include: alignment with “ICH E8 R(1) General Considerations for Clinical Studies,” restructuring of the document, provision of guidance on data governance, encouragement of risk-proportionate and fit-for-purpose approaches, and the establishment of practical and feasible expectations for sponsors and investigators. The revision also adapts to innovations in clinical trial design, technology, conduct, and data sources; strengthens the protection of minor trial participants; emphasizes transparency in clinical trial registration and results reporting; and updates terminology. The revision of ICH E6 R(3) impacts sponsors, investigators, ethics committees, and service providers, offering guidelines that are both practical and flexible, and continuously responding to the rapid development of the clinical trial ecosystem.