Background <p>Beginning in January 2025, all new active substances must undergo evaluation of relative clinical effectiveness through European Union (EU) joint clinical assessments (JCAs). In the absence of head-to-head data, indirect treatment comparisons (ITCs) become indispensable in meeting the numerous population, intervention, comparators and outcomes (PICO) criteria to support decision-making.</p> Objective <p>This study examined ITCs in European Network for Health Technology Assessment (EUnetHTA) relative effectiveness assessments (REAs) to obtain valuable insights into their potential implications for future JCAs.</p> Methods <p>The EUnetHTA website was hand-searched for REAs of pharmaceutical products between 2010 and 2021. Information on PICO, ITC methods, ITC limitations/critiques, and relative effectiveness conclusions were systematically extracted. On the basis of the final EUnetHTA critiques, suitability of ITC evidence was categorised by the current study authors as appropriate, unsuitable or unclear.</p> Results <p>Twenty-three REAs were identified. Twelve REAs included an ITC, of which six were in oncology indications. Across the REAs, 64 comparisons were required, with a median of four comparators per REA (range 1–18). In total, 25 comparisons were informed by indirect evidence; the suitability of ITCs was categorised as unclear in all but one of the 25 comparisons.</p> Conclusion <p>Multiple analyses and ITCs were necessary to address multiple PICOs. Although most ITCs were categorised as unclear within the REAs, they were still considered appropriate to inform decision-making. The EU JCA process will most likely require health technology developers to use various ITC approaches to address the multiple PICOs requested, recognising the inherent limitations of these methodologies. Efforts to address potential challenges for EU JCA should focus on supporting JCA assessors/co-assessors and national HTA agencies in the evaluation and interpretation of ITCs to enable decision-making.</p>