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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 ...

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 ...

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.

BACKGROUND AIMS: As part of the advanced therapy medicinal product (ATMP) regulation, the hospital exemption (HE) was enacted to accommodate manufacturing of custom-made ATMPs for treatment purposes in the European Union (EU). However, how the HE pathway has been used in practice is largely unknown. METHODS: Using a survey and interviews, we provide the product characteristics, scale and motivation for ATMP manufacturing under HE and other, non-ATMP-specific exemption pathways in seven European countries. RESULTS: Results show that ATMPs were manufactured under HE by public facilities located in Finland, Germany, Italy and the Netherlands, which enabled availability of a modest number of ATMPs (n = 12) between 2009 and 2017. These ATMPs were shown to have close proximity to clinical practice, and manufacturing was primarily motivated by clinical needs and clinical experience. Public facilities used HE when patients could not obtain treatment in ongoing or future trials. Regulatory aspects motivated (Finland, Italy, the Netherlands) or limited (Belgium, Germany) HE utilization, whereas financial resources generally limited HE utilization by public facilities. Public facilities manufactured other ATMPs (n = 11) under named patient use (NPU) between 2015 and 2017 and used NPU in a similar fashion as HE. The scale of manufacturing under HE over 9 years was shown to be rather limited in comparison to manufacturing under NPU over 3 years. In Germany, ATMPs were mainly manufactured by facilities of private companies under HE. CONCLUSIONS: The HE enables availability of ATMPs with close proximity to clinical practice. Yet in some countries, HE provisions limit utilization, whereas commercial developments could be undermined by private HE licenses in Germany. Transparency through a public EU-wide registry and guidance for distinguishing between ATMPs that are or are not commercially viable as well as public-private engagements are needed to optimize the use of the HE pathway and regulatory pathways for commercial ...