Decision-making on marketing authorization of advanced therapy medicinal products in the European union

Abstract

Introduction: Advanced Therapy Medicinal Products (ATMPs) are innovative products receiving increasing interest. While many clinical trials with GCTs have been performed in Europe, currently only fifteen marketing authorization (MA) applications have been submitted (December 2016), which resulted in eight MAs. This study aims to investigate how decision-making and the underlying evidence for (non-)MA is built up in the EU. Methodology: A comparative analysis was used to investigate the justification of MA-decision procedures of ATMPs. This was subcategorized and scored into product profiles, scientific evidence and regulatory assessment criteria. How these factors relate to each other is compared between MAs and non-MAs. Preliminary Results: Eight applications were granted approval, including standard MA (n = 5) and alternative MA (n = 3). Six applications were not granted approval (non-MA). Clinical trial design differed between standard and alternative MA, whereas the clinical trial designs of the non-approved products showed high variability. Alternative MA (n = 3) trials included less patients (mean alternative MA = 57 vs. mean standard MA = 244) and randomized controlled phase III trials were not conducted. Furthermore, these alternative MAs were all designated as orphan drugs, for which alternative treatment was lacking, and the products showed added clinical benefit. Moreover, considerations of unmet medical need were part of decisionmaking for these alternative MA products. For standard MA, decision was always based on statistical significant results on the primary efficacy endpoints, whereas such results were not always obtained for alternative MAs. Moreover, for the non-MA products statistical significant efficacy on primary and secondary endpoints were lacking. Conclusion: This study suggests that key assessment criteria in approval of ATMPs in the EU are trial design, significant outcomes, orphan designation and unmet medical need. In particular, ATMPs developed for orphan indications generally enter alternative regulatory pathways, which influences clinical trial design, clinical outcomes and the weight of unmet medical need in decisionmaking for ATMP approval.