OBJECTIVES: Oncology drugs and advanced therapy medicinal products (ATMPs) will be subject to JCA from 2025 onward. Per definition JCA requires a comparative analysis of the clinical evidence with one or more other health technologies. Randomized Controlled Trials (RCTs) are considered the gold standard, but the regulation also requests methodology adaptations to include specificities of new technologies where data maybe lacking. This would apply to gene therapies where evidence is mostly based on single-arm, non-blinded studies with small sample sizes and short follow-up. How these characteristics have been considered in JCA is being assessed.

METHODS: Proposed JCA guidance documents and methodologies have been reviewed with respect to exemptions from standard requirements. Evidence of four recently approved gene therapies and reimbursement decisions have been evaluated with respect to a JCA assessment.

RESULTS: JCA draft methodologies on validity of clinical studies, endpoints and applicability of evidence follow high quality evidence-based medicine (EBM) standards. Specific considerations for evidence generation refer to single-arm trial data where an external control arm can be used for comparative statistical analysis. Similarly surrogate endpoints are acceptable when it is not feasible to measure a final outcome and a strong association or correlation of effects is demonstrated. However, gene therapies have been approved for reimbursement despite limiting evidence and comparisons with the patient’s own baseline. Remaining uncertainty regarding the duration of the effect is usually linked to evidence development requests.

CONCLUSIONS: Specific considerations are rather limited in the drafted methodologies although requested in the HTA regulation. When lacking appropriate comparisons such as matching external control arms, surrogate validation, and long-term data, JCA will likely conclude a high level of uncertainty or even insufficient data for gene therapy assessment. More tailored solutions should be adopted in the new framework to establish JCA as useful tool for decision making enhancing patients' access to new treatments.