Traditional Chinese medicine (TCM) is a treasure of the Chinese nation. Presence of clinical effects represents a fundamental issue for TCM development. Nevertheless, the complexities of TCM interventions often result in presented effects deviating from expected ones, a phenomenon so called as "effect off-target"; this issue has become a major challenge for the development and use of TCM interventions. In continuing efforts, we have proposed an innovative evidence-based medicine model for studying the effects of TCM interventions, termed "systems evidence-based medicine (sysEBM)". Essentially, the sysEBM model integrates clinical and non-clinical evaluation to develop a systematic pathway for studying effects of TCM interventions, and the methodological steps typically include the development of PICO framework for a putative effect, exploration of the effect and confirmation of the effect by using animal models, observational studies and clinical trials. As an additional step, multidisciplinary technologies including pharmaceutical, pharmacological, information and biological technologies will be used to provide multidimensional analyses of potential action networks and mechanisms of TCM interventions. Building on this concept, we have developed a sysEBM model ("6R" model) for acupuncture and marketed Chinese patent medicines by integrating real-world evidence, clinical trials, evidence syntheses, and rapid recommendation methodologies, as well as information technology and biomedical technologies. We also applied this model for developing TCM interventions for maternal health, critical care, and knee osteoarthritis.