Decision-making for marketing approval of cell and gene based therapy products in the European union, United States and Canada

Innovative characteristics of gene and cell-based therapy products (GCTs) often hinder standardized regulatory assessment based on existing guidance documents. As a result, decision-making for marketing approval in this area is still largely done on a case-by-case basis. We aimed to compare assessment procedures for approved GCTs in the European Union (EU), United States (US) and Canada. A comparative analysis was designed to provide insight in the assessment procedures until December 2016. Data was collected in relation to 1) product profiles, 2) scientific evidence and 3) regulatory assessment criteria. We subsequently analysed how these three components relate to each other in decisions for approval between jurisdictions. We included 8 assessment procedures in the EU, 5 in the US and 1 in Canada. Two products were approved in both the EU and US. Product profiles consisted of cell based therapy products (n = 10) and gene based therapy products (n = 4) that mainly target cancers and musculoskeletal diseases. Additional EU and Canadian GCTs target congenital and immunologic disorders, whereas US products include a cosmetic and periodontal GCT. Three GCTs were based on allogeneic starting material. Concerning evidence, significant results on the primary efficacy endpoints were provided for a large proportion of approvals (10/14). Less than half of approvals involved orphan drugs (EU = 4, US = 1). Orphan drugs in the EU were often approved under alternative (e.g. conditional approval) pathways (3/4), enabling single arm trial design and non-significant results on clinical endpoints. On the contrary, approvals under US (4/5) and Canadian (1/1) alternative (e.g. US accelerated approval) pathways are predominantly based on randomized, controlled, phase III trial design (US, Canada) and significant results on clinical endpoints (US). Unmet medical need is often considered together with safety and efficacy uncertainties in decision-making for approval in the EU (5/8; US 2/5; CA 1/1). In conclusion, product profiles differ between jurisdictions, which influences scientific evidence and regulatory assessment criteria to gain GCT approval. More orphan drug designation in the EU results in approval under alternative pathways based on less robust clinical trial design and efficacy evidence compared to the US.