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

Area of Science:

• Health Economics and Outcomes Research
• Biostatistics
• Regulatory Science

Background:

• Indirect treatment comparisons (ITCs) are crucial for joint clinical assessments (JCAs) under EU Regulation 2021/2282, especially when head-to-head data are absent.
• ITCs facilitate evidence synthesis across varied PICO (patient, intervention, comparator, outcome) requirements in different member states.

Purpose of the Study:

• To critically review the EU Health Technology Assessment Coordination Group's (HTACG) guidelines on direct and indirect comparisons, focusing on ITCs.
• To assess the operational implications of these guidelines for health technology developers (HTDs).

Main Methods:

• Critical review of the HTACG guidelines on direct and indirect comparisons.
• Analysis of the guidelines' stance on assumption violations, unanchored comparisons, population-adjusted methods (MAIC, STC), and Bayesian approaches.
• Evaluation of the guidelines' impact on dual systematic reviews, network structures, and null hypothesis testing.

Main Results:

• The HTACG guidelines are restrictive regarding assumption violations, unanchored comparisons, and advanced population-adjusted methods like MAIC and STC.
• Limited support for Bayesian methods and undervaluation of meta-regression in favor of subgroup analyses are noted.
• The guidelines may hinder the use of non-randomized comparisons for rare diseases and underdeveloped emerging practices like external control arms.

Conclusions:

• The current guidelines lack methodological flexibility and empirical grounding, potentially impacting patient access to innovative therapies.
• Refinement is needed to enhance practical utility, reduce assessment variability, and ensure consistent cross-member state assessments.
• Greater methodological flexibility, empirical validation, and clear operational guidance are essential for evolving JCAs.