OBJECTIVES: Cell and gene therapies aim to manipulate genetic materials for the treatment of inherited or acquired diseases. They are a promising solution for managing diseases with few or no alternative therapies, but are often associated with potential risks and high costs. We sought to highlight the positive features and limitations cited by HTA agencies in submissions for cell and gene therapies.

METHODS: HTA submissions from NICE, CADTH, HAS, and G-BA/IQWiG were searched for available completed submissions for cell and gene therapies. Positive remarks, uncertainties, and limitations highlighted by the HTA committees were identified and summarized.

RESULTS: In total, 17 HTA submissions were reviewed, of which 11 incorporated an economic assessment. Most submissions received a positive recommendation (15/17). Two submissions were rejected by IQWiG because comparative effectiveness could not be established. The remaining submissions reported meaningful clinical benefit, despite some results derived from single-arm trials. Indirect comparison with real-world evidence (RWE) data was frequently reported as a limitation in assessing comparative effectiveness. Use of historical cohorts with incomplete patient characteristics or cohorts that did not fully match the population were the most common critiques of the evidence. Most economic models were deemed appropriate for decision-making despite their complexity. They were largely criticized for the use of utility values that lacked robustness or methodological limitations in the approach used to derive. The approach and assumptions for estimating long-term efficacy were important sources of uncertainty due to insufficient data and had an impact on cost-effectiveness.

CONCLUSIONS: The uncertainties related to long-term outcomes and the high costs associated with cell and gene therapies are often surpassed by the significant benefits demonstrated in populations with high unmet need. The robustness of comparative effectiveness assessments is highly influenced by the choice of RWE data in the absence of randomized trials.