The integration of randomised controlled trials (RCTs), quasi-experimental studies, and target trial emulation represents a transformative approach to leveraging Real-World Evidence (RWE) for health technology assessments (HTA) and regulatory submissions. During this talk, following the “introduction to health economic evaluations” seminar I gave at DCR in January, I will present some of the methodologies that go beyond traditional trial paradigms to inform HTA. Utilising the FDA's considerations for non-interventional studies and the NICE guidance on real-world evidence, I will discuss ways of combining causal inference with within-trial economic evaluation and discuss the application of synthetic controls, external control arms, and target trial emulation. These methodologies facilitate a robust analysis of drugs and, in general, health interventions effectiveness’ and safety by addressing common challenges, such as selection bias, confounding, and limitations of observational data. Additionally, I explore the role of health economics in this framework, highlighting areas for development and application to enhance decision-making processes. By incorporating these advanced statistical methods and economic evaluations, stakeholders can better understand the real-world impact of interventions, ultimately informing policy and clinical practice in ways that traditional trials alone cannot.