OBJECTIVES: Cell and gene therapies (C&GT) offer therapeutic solutions for patients with previously untreatable conditions. However, these innovative therapies pose significant challenges in terms of health technology assessment (HTA), notably due to the difficulty of conducting traditional randomized controlled clinical trials, as C&GT trials are inherently associated with small patient populations. The objective of this study was to highlight the specific methodological challenges encountered in the economic and clinical evaluation of C&GT.

METHODS: A targeted literature review was conducted to identify all HTA appraisals of C&GT in oncology in France and UK in the past 5 years (2019–2023). The checklist from Drummond et al. was used to report and categorize limitations and methodological comments from HTA bodies. The statistical implication of each comment was then analyzed to identify the specificity of C&GT when using the standard evidence assessment framework.

RESULTS: Seven and six HTA reports from HAS and NICE were reviewed respectively (n=13). The most common indications for both HTA bodies were large-B cell lymphoma and multiple myeloma. All therapies were recommended for reimbursement by the HAS vs five by NICE. The main limitations flagged were related to data immaturity (n=10), use of a single-arm trial (n=9), extrapolation to long-term outcomes (n=8), small sample size (n=7), and the presence of a selection bias (n=6). When an indirect comparison was conducted, the omission of prognostic factors (n=5) and the heterogeneity of the studies included (n=3) were also highlighted. The relevance of the primary endpoint was also mentioned in three appraisals. From a methodological standpoint, the main concerns were related to the generalizability and reproducibility of the clinical evidence submitted.

CONCLUSIONS: Our work can help manufacturers anticipate methodological comments from HTA agencies. Anticipation and early preparation in the form of early meetings with HTA bodies, are crucial for identifying and overcoming potential challenges.