OBJECTIVES: Several methodological issues in the economic evaluation of Gene Replacement Therapies (GRT) have been previously identified, including: 1) assessment of clinical effectiveness and safety; 2) valuation of health outcomes; 3) time horizon and extrapolation; 4) different payment models. A literature review and expert interviews were conducted to provide potential methodological solutions for these challenges.

METHODS: A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges.

RESULTS: Experts agreed on factors to be considered to ensure historical cohorts acceptability by HTA bodies. For extrapolating the effectiveness of GRT, mixture cure models were proposed. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be elicited in a rigorous way, using for example Delphi panel techniques. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. Cost-benefit analysis was proposed as an approach to avoid the problems of eliciting utilities for pediatric diseases. While the self-perspective is usually recommended to elicit health state utilities, a change to social perspective could also resolve those difficulties. Additionally, experts mentioned the importance of considering elements of value that are often ignored: value of hope and value of cure, and weighting QALYs differently by age group. The use of innovative payment models may help to reduce the scope of evaluation and associated uncertainty.

CONCLUSIONS: While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with those treatments, others may be addressed by methodological research to be conducted by health economists.