Regulatory and health technology assessment of cell and gene therapies in Europe: convergence or divergence?

Background: Advanced therapy medicinal products (ATMPs) offer opportunities to treat conditions with a high unmet medical need. In Europe, to reach patients, both regulatory and health technology assessment (HTA) needs to be favorable.

Objectives: To assess similarities and differences between the evidence base used for regulatory benefit-risk assessment and HTA relative effectiveness assessment of ATMPs in Europe, including the role of real-world evidence (RWE) and remaining uncertainties.

Methods: We performed a retrospective cohort study of ATMPs authorized by the European Medicines Agency (EMA) up to June 2022. For these ATMPs, we searched for assessment reports by the EMA and the Dutch, French, German and English HTA institutions. From each assessment report, we extracted the number and type of studies in the submitted evidence package, the number and type of studies assessed, the duration of patient follow-up in these studies, the main efficacy endpoints assessed, key remaining uncertainties and HTA assessment outcomes. These data were compared between agencies to identify similarities and differences.

Results: Of 21 ATMPs that had been approved by the EMA, 18 had also been assessed by at least one of the HTA institutions. In total, 68 assessment reports were identified and included in the study. Although the number and type of assessed studies and the patient follow-up in these studies were largely similar between institutions, we identified differences in their assessment of the evidence. HTA institutions, the German and Dutch in particular, showed greater preference for overall survival data than the EMA when assessing anticancer ATMPs. For other ATMPs, the same (primary) endpoints were generally accepted by all institutions. Also, HTA institutions reported more uncertainties concerning efficacy than the EMA (45% vs. 35% of all uncertainties). Conversely, the EMA reported more uncertainties concerning safety (33% vs. 15%). Relevantly, the German HTA reported most uncertainties (59%) concerning the quality of the evidence submitted. Analysis of the role of RWE in the assessments and further detailed assessment of the uncertainties is currently ongoing.

Conclusions: Our preliminary findings indicate that the evidence packages assessed for ATMPs are similar between regulatory and HTA institutions, but that the actual assessments differ. This heterogeneity might cause heterogeneity in patient access and underscores the importance of discussing evidence requirements and stimulating collaborative efforts between manufacturers, regulators and HTA institutions during the early stage of ATMP development.