OBJECTIVES: Gene therapies (GTs) often lack comparators in their pivotal clinical trials when they first seek market access, especially when targeting rare diseases where only symptomatic treatment exists. Furthermore, rare diseases represent a challenge in terms of patient population and clinical trial sample size. Therefore, GT manufacturers resort to single-arm trials and develop indirect treatment comparisons (ITCs) for health technology assessment (HTA). Our aim is to understand HTA bodies’ evidence requirements for ITCs for GTs, and identify key drivers and limitations.

METHODS: The countries of scope were the US, England and Wales, France, and Germany. Official regulatory websites of these countries were reviewed to identify GTs with marketing authorization between Jan 1^st, 2018 until present. HTA bodies’ feedback on ITCs was extracted from publicly available reports from ICER, NICE, HAS, and G-BA websites, respectively.

RESULTS: Fifteen approved GTs were identified in the countries of scope. Fourteen had HTA reports and one was approved but had not been assessed. A total of 53 appraisals were extracted. Overall, ITCs were discussed in 66% (35) of HTA reports for nine GTs. ICER did not conduct a single ITC due to scrutiny on differences in population characteristics, entry criteria, outcome assessments and lack of patient-level data. NICE and G-BA highlighted important differences across patient populations in terms of prognosis factors which could not be adjusted for. G-BA accepted an ITC with a large effect size in morbidity and structurally similar comparison arms. HAS mostly criticized the post-hoc nature of ITCs and the use of small trials which limited the effective sample size.

CONCLUSIONS: Learnings from previously submitted ITCs can be leveraged by GT manufacturers to meet HTA bodies evidence requirements and maximize market access.