ISSUE: Due to the nature of highly specialized technologies for rare and complex conditions, Health Technology Assessment (HTA) bodies face high levels of evidential uncertainty at the time of launch due to a range of factors. These include challenges associated with population size, selection of relevant comparators and endpoint selection. Adam Parnaby will present the perspective of a technology developer in facing the challenge of generating evidence that meets the needs of HTA bodies in their assessment of rare or complex conditions. Sheela Upadhyaya will discuss the challenges faced by HTA agencies appraising treatments for very rare diseases, where there are substantial uncertainties. Lieven Annemans will propose a taxonomy of uncertainties that occur during evidence generation and provide a pragmatic tool to help identify what RWE may be suitable to address those uncertainties in rare conditions OVERVIEW: Real World Evidence (RWE) can be used to augment clinical data and inform modelling about value and value for money. As awareness grows about the role RWE can play in addressing and supporting HTA, there is a need to develop a structured framework to support evidence developers, reviewers and decision-makers in the appropriate use of RWE. A framework developed with multi-stakeholder input focused on highly specialized technologies for rare and complex conditions will be presented. The panel will discuss the use of the framework to address evidence uncertainty at the time of launch for these technologies.