Methodological Advances and Challenges in Indirect Treatment Comparisons: A Review of International Guidelines and HAS TC Case Studies

Abstract: To evaluate methodological challenges and regulatory considerations of indirect treatment comparisons (ITCs) with the analysis of international health technology assessment guidelines and French Transparency Committee (TC) decisions. We conducted a pragmatic review of ITC guidelines from major health technology assessment (HTA) bodies and multistakeholder organizations. Then, we analyzed TC opinions published between 2021-2023. We extracted data on ITC methodology, therapeutic areas, acceptability, and limitations expressed by the TC. The targeted review of the main guidelines showed mainly agreements between HTA bodies and multistakeholder organizations, with some specificities. 138 TC opinions containing 195 ITCs were analyzed. Only 13.3% of these ITCs influenced TC decision-making. ITCs were more frequently accepted in genetic diseases (34.4%) compared to oncology (10.0%) and autoimmune diseases (11.1%). Methods using individual patient data showed higher acceptance rates (23.1%) than network meta-analyses (4.2%). Main limitations included heterogeneity/bias risk (59%), lack of data (48%), statistical methodology issues (29%), study design concerns (27%), small sample size (25%), and outcome definition variability (20%). When ITCs were the primary source of evidence, the proportion of important clinical benefit was lower (60.9% vs. 73.4%) than when randomized controlled trials were available. While ITCs are increasingly submitted, particularly where direct evidence is impractical, their influence on reimbursement decisions remains limited. There is a need for clear and accessible guides so manufacturers can produce clearer and more robust ITCs that follow regulatory guidelines, from the planning phase to execution.