OBJECTIVES: The assessment of relative effectiveness and safety in the joint clinical assessment (JCA) is a fundamental aspect of the EU Health Technology Assessment Regulation (HTAR). Given the variation in clinical practice between Member States, direct comparative evidence is unlikely to be available for all comparators in the JCA scope.

Therefore, indirect treatment comparisons (ITCs) will be a key source of evidence for relative effects in JCA submissions, which are covered by two methodological guidelines prepared by EUnetHTA21. This research aims to explore of the differences between the to be used in the JCA and select Member States.

METHODS: We conducted a review of HTA methodological guidelines from EUnetHTA21, Germany, France, Italy, Norway, and Poland. Guidelines were reviewed to identify areas of harmonisation and differences between EU and Member

RESULTS: The relevance of ITCs, using pairwise and network meta-analysis methods are universally accepted. Unadjusted comparisons are not accepted. Key areas of divergence include acceptance of disconnected networks and population-adjustment.

EUnetHTA requires patient-level data for comparisons in disconnected networks. Whilst Germany does not accept disconnected networks, this was not discussed by other HTA bodies.

EUnetHTA considers population-adjustment only suitable as exploratory analysis. In contrast, Germany states that population-adjustment is unsuitable whilst Norway and Poland allow submissions with these methods and provide guidance on methodological requirements.

CONCLUSIONS: Our review identified areas of harmonisation including a preference for direct comparisons, and methodological approaches for ITCs. However, key differences were found in the acceptance of disconnected networks and population-adjustment.

Given the methodological divergence, developing methodological guidelines by consensus presents clear challenges. However, the current guidelines limit the feasibility of ITCs to provide evidence for relative effectiveness for all relevant comparators in a JCA submission, with no to meet the objectives of EU HTAR and patients.