OBJECTIVES: The objective of this analysis was to systematically review trends in methodologies for indirect treatment comparisons (ITCs) in Highly Specialized Technology Assessments by NICE.

METHODS: A systematic review of all 2016-2024 NICE HST HTAs was conducted. For each assessment, the ITC methods were reviewed, summarized, and categorized. Comments from the assessment committee were categorized based on issues and concerns raised. Lessons and insights were developed for designing ITCs.

RESULTS: During 2016-2024, there were 28 Highly Specialized Technology (HST) assessments published by NICE. Overall, there were 7 assessments in which ITCs were reported. In 3 assessments, NICE agreed or was satisfied with the approach of conducting naive comparisons, adjusted ITCs, and unanchored ITCs. In these 3 assessments, the company presented feasibility analyses explaining the rationale for choosing the approach and reasons for not conducting more advanced ITCs. In 4 assessments, NICE raised several methodological concerns: baseline differences, missing adjustment for covariates, changes in treatment trends over time, immortal time bias, missing data, country-relevant comparators, geographical location of historical controls, and lack of data for some subgroups of patients.

CONCLUSIONS: Previous assessments provide valuable lessons for designing and conducting indirect treatment comparisons for ultra-rare disease products.