Suchergebnisse

This study aimed to determine to which extent data on potential pharmacogenetic-pharmacokinetic (PG-PK) interactions are provided to, and assessed by, the European Medicines Agency (EMA) in novel drug marketing authorization applications (MAAs), and whether regulatory assessment of PG-PK interactions is adequate or could be optimized. For this purpose, we retrospectively analyzed MAAs of small molecule drugs assessed by the EMA between January 2014 and December 2017. As per two key requirements in the EMA's guideline, we analyzed cases where (i) a single functionally polymorphic drug metabolizing enzyme (DME) metabolizes > 25% of the drug, or (ii) the drug's PK shows high interindividual variability not explained by other factors than PG. Results showed that, of 113 drugs analyzed, 53 (47%) had ≥ 1 functionally polymorphic DME accounting for > 25% of the drug's metabolism, yielding 55 gene-drug pairs. For 36 of 53 (68%) of the products, CYP3A4 was the major DME. Compliance with European Union (EU) guidance on PG-PK issues in drug development was notably different for CYP3A4 substrates vs. non-CYP3A4 substrates. Adequate PG-PK data were provided during registration in 89% (16/18) of cases concerning non-CYP3A4 substrates, compared with 32% (12/37) of cases concerning CYP3A4 substrates. Concluding, PG-PK interactions related to non-CYP3A4 substrate drugs were, in general, addressed adequately in EU MAAs. PG-PK information on CYP3A4 substrates was available less frequently, despite some available evidence on the functional relevance of CYP3A4 polymorphisms. A more harmonized approach toward assessment of PG-PK issues in EU MAAs seems warranted, and a discussion on the relevance of CYP3A4 polymorphisms, such as CYP3A4*22, is recommended.

Pediatric legislations in the European Union (EU) and the United States (US) have increased medicines approved for use in the pediatric population. Despite many similarities between these frameworks, the EU Paediatric Regulation more often provides regulators with a mandate to require pediatric drug development for novel medicinal products compared to US regulators. If used, this could give rise to differences in the guidance for pediatric use provided for clinicians in the two regions. However, the level of discordance in the guidance for pediatric use between the two regions is unknown. This cross-sectional study compares guidance for pediatric use in the EU Summary of Product Characteristics (SmPC) and the US Prescription Information (USPI) on the level of indications granted for novel medicinal products approved after the pediatric legislations came in to force in both regions. For all indications granted as of March 2020 for novel medicinal products approved in both regions between 2010 and 2018, we compared the guidance for pediatric use in the EU SmPC and the USPI. The guidance for pediatric use differed for 18% (61/348) of the listed indications covering 21% (45/217) of the products, but without the guidance being contradictory. Where guidance differed, an equal share was observed for indications with a higher level of information for pediatric use in one region over the other (49% (30/61) in the US; 51% (31/61) in the EU). The discrepancies in pediatric information could be explained by differences in regulations for 21% (13/61) of the indications. Only a few conditions and diseases (EU n = 4; US n = 1) were observed to cover potential pediatric use outside the approved adult indication. Although the EU Paediatric Regulation more often provides regulators a mandate for requiring pediatric drug development as compared to the US PREA, this was not reflected in the prescription information approved by the two regulatory authorities.

Background and Objective: Biological medicinal products (biologics) are subject to specific pharmacovigilance requirements to ensure that biologics are identifiable by brand name and batch number in adverse drug reaction (ADR) reports. Since Member States collect ADR data at the national level before the data is aggregated at the European Union (EU) level, it is important that an unambiguous understanding of which medicinal products belong to the biological product category exists. This study aimed to identify the level of consistency between Member States regarding the classification of biologics by national authorities responsible for ADR reporting. Methods: A sample list of recombinant biologics from the European Medicines Agency database of European Public Assessment Reports was created to analyze five Member States (Belgium, the Netherlands, Spain, Sweden, and the UK) according to which products were classified as biologics by each Member State. We calculated the Fleiss kappa value to analyze interrater reliability. Results: A considerable divergence was identified regarding the classification of the 146 recombinant biologics from the sample list: one Member State classified 100 % of the recombinant biologics from the sample list as biologics, whereas the classification rates in the remaining four Member States ranged between 70 and 88 % for products available on the national market. The interrater reliability for 87 products available on the market in all five Member States was considered poor. Conclusion: Discrepancies exist between Member States in the classification of biologics; less divergence exists for common well-known biologics. These findings highlight the need to think about the best approaches to translate EU legislation into national practices. Additionally, we recommend a publicly available and frequently updated list of centrally authorized biologics.

Aim: The aim of the present study was to provide an insight into the characteristics and follow-up of postmarketing studies of medicines that were conditionally authorized in the European Union (EU). Methods: We compiled a list of all postmarketing studies attached as specific obligations to the licence of medicines that were granted conditional marketing authorization from January 2006 to April 2014. Studies were characterized based on their objective, design, status upon marketing authorization (MA) and due data set by authorities. They were linked to online study registrations (Clinicaltrials.gov, ENCePP) to determine completion date. We described and associated characteristics of studies and medicines, and determined whether studies were completed on time. Results: A total of 59 postmarketing studies were requested for 21 conditionally authorized medicines. Most studies had an interventional study design (73%), were ongoing upon MA (61%) and aimed to provide additional data on efficacy (45%). Interventional studies were more often ongoing and providing efficacy data, while observational and other studies were more often new and providing safety data. Frequent grounds for requesting postmarketing studies were 'long-term follow-up' and 'increase data on subpopulations'. Of the 34 studies eligible for follow-up analysis, 26 (76%) were completed and 17 (50%) completed on time. Actual completion time took a median (interquartile range) of 274 (−121 to 556) days longer than expected. Conclusions: Our results indicated that most postmarketing studies attached to a conditional marketing authorization were eventually completed but that half were completed with a substantial delay. The observations suggest caution when broadening the use of postmarketing studies for resolving uncertainties about benefits and risks after MA.

When medicines are granted a Conditional Marketing Authorisation (CMA) in Europe, specific obligations are requested to obtain comprehensive data on benefits and risks. We performed a retrospective cohort study to characterize obligations, examine changes to their description and due dates after initial authorization, determine timing of data submission relative to due dates, and identify drug-related, procedure-related, and obligation-related factors associated with change. We identified 69 obligations for 26 medicines conditionally authorized between 2006 and 2016. We found 39 changes to 27 obligations (39% of obligations), of which four substantially changed the obligation. For 55% of obligations, data submission was delayed. Eleven factors were associated with change, including the use of CMA as a rescue option. The results are potentially indicative of a continuous search by regulators to reduce uncertainties. Submission delays impact public health negatively by prolonging exposure of patients to unknown risks, particularly when the level of uncertainty is high.

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 ...