Acceptability of external control-arm use in nononcology health technology assessment submissions

<b>Aim:</b> This study assessed the acceptability of external control-arm (ECA) use in nononcology health technology assessment (HTA) submissions in Europe. <b>Materials & methods:</b> We conducted a sequential mixed method study to investigate the study objective. First, we summarized published documentation from three HTA agencies in Europe - the National Institute for Health and Care Excellence (NICE) in England, the French National Authority for Health (HAS) and the German Institute for Quality and Efficiency in Healthcare (IQWiG) - to assess the availability of guidance on ECA methodology and implementation. We then reviewed independent nononcology HTA appraisals common across England, France, Germany and Italy to understand variations in agencies' perceptions of ECA use. Finally, we conducted six double-blinded interviews with HTA experts from England, France, Germany and Italy to validate the findings and obtain illustrative insights on drivers of acceptability. <b>Results:</b> While NICE and HAS provide some level of ECA-related guidance on topics such as data suitability, methods and reporting, guidance from IQWiG remains limited. Overall, ECA use is mainly restricted to oncology, particularly given that only two nononcology appraisals were common across HTA agencies. However, NICE appears more open to accepting ECA use in supplementing clinical trial data, whereas IQWiG has a strong preference for traditional controlled clinical trials. Experts indicate that ECA use is most acceptable when accompanied by valid justification, suitable data sources and a rigorous methodology to minimize the risk of bias. Situations that experts perceive as appropriate for ECA use include missing comparators (i.e., single-arm trials), limited comparator data availability, or rapidly changing standards of care. <b>Conclusion:</b> There is a need to focus awareness on the value of ECA use as a supplement to randomized controlled trials, and to engage with HTA agencies early in clinical development.