Between Rigor and Relevance: Why the EU HTA Guidelines on Indirect Comparisons Miss the Mark

Indirect treatment comparisons (ITCs) are essential in the context of joint clinical assessments (JCAs) under Regulation (European Union [EU]) 2021/2282, bridging evidence gaps where head-to-head data are lacking and enabling assessment across diverse national patient, intervention, comparator, and outcome (PICO) requirements. This paper critically reviews the EU Health Technology Assessment Coordination Group's (HTACG) guidelines on direct and indirect comparisons, with particular focus on ITCs. While the guidelines promote transparency and rigorous evaluation of assumptions, they adopt a restrictive stance on assumption violations, the use of unanchored comparisons, and population-adjusted methods such as matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC). The guidance shows limited support for Bayesian methods and undervalues meta-regression in favor of subgroup analyses. Operational implications for health technology developers (HTDs) are substantial, including new requirements for dual systematic reviews, multiple network structures, and shifted null hypothesis testing. Moreover, the guidelines effectively dissuade the use of non-randomized comparisons in rare or rapidly evolving indications and may inadvertently hinder access to effective treatments. Emerging practices such as external control arms (ECA) or target trial emulation are underdeveloped. Notably, there is no indication that the guidelines are grounded in systematic methodological validation studies. As JCAs evolve, greater methodological flexibility, empirical grounding, and clear operational guidance will be essential. Refining the guidelines along these principles would enhance their practical utility, mitigate intrinsic assessment variability, support consistent assessments across Member States (MS), and ultimately improve patient access to innovative therapies.