How Do HTA Agencies Manage Uncertainties in the Long-Term Clinical Benefit of Gene Therapies? An Analysis of Recent Gene Therapy HTAs in England, Germany, France, Italy, Canada, and the United States

OBJECTIVES: To date, seven gene therapies (GTs) have European regulatory approval and have been reimbursed at significant upfront costs. Assessing the long-term benefits of one-time GTs is challenging for payers due to the short duration of clinical data at the time of Health Technology Assessment (HTA). This research aims to understand the methods used by HTA agencies to assess the durability of GTs and whether the concept of biological plausibility is considered by payers.

METHODS: The methods manuals of six HTA agencies (NICE, G-BA, HAS, AIFA, CADTH, and ICER) were examined to compare guidance on the procedures used to estimate long-term durability. The appraisals of three GTs (voretigene neparvovec, onasemnogene abeparvovec, and valoctocogene roxaparvovec) were also analysed.

RESULTS: There is limited explicit guidance in HTA method manuals on how agencies determine long-term benefit in light of short-term clinical evidence, beyond the traditional economic modelling methods used in select countries. GT-specific guidance was also lacking. Only the NICE methods manual explicitly stated that clinical expert opinion could inform whether it was biologically plausible that the clinical effect would be maintained. Analysis of three GTs revealed that clinical expert opinion and biological plausibility were utilised to varying degrees between HTA agencies, with NICE, CADTH and AIFA employing biological plausibility. Four agencies required real-world evidence or innovative access agreements (IAAs) to help mitigate the financial risk of reimbursing GTs for which the durability of effect is uncertain.

CONCLUSIONS: Most agencies use traditional economic modelling or post-HTA evidence generation mitigation strategies (e.g., IAAs) to manage uncertainty in long-term benefit of GTs. IAAs may be practically unsustainable with the expected influx of GTs in coming years, due to the burden associated with implementation. HTA agencies, manufacturers, and the scientific community must adopt novel methods to suitably assess the long-term benefit of GTs during HTA.