Transitioning biomedical research toward human-centric methodologies: systems-based strategies

•Systemic thinking provides a promising framework of analysis to better understand model selection in biomedical research.•Modeling the biomedical research system and gathering adequate data and intelligence can help cast some light on the systemic nature of model selection in research.•Systemic thinking paves the way for innovative policy making to promote human-centered research methods beyond the traditional 3Rs approach.•System-based solutions will find new leverage points in diverse policy areas and will be collaborative and multistakeholder.•Several regional policy initiatives already signal a shift toward a systemic view on methods selection in research and could open pathways to unlock the potential of human-centered methods for patients while reducing animal use. Human-centric methodologies like microphysiological systems and in silico methods have shown promise in addressing the limitations of animal models in understanding human biology and responding to public health priorities. However, the prevailing paradigm based on animal research persists. The article proposes a systemic thinking approach, endorsed by the OECD and the EU, as a tool to leverage innovation to reframe the issue and achieve transformative policies. By identifying the complex factors shaping method selection in basic and biomedical research, a simplified model is presented to illuminate the systemic nature of this decision-making process. The goal is not to prescribe solutions but to offer policymakers a new framework for more-effective strategies, emphasizing collaboration among stakeholders and the need for robust data.