Development and Regulation of Gene and Cell-Based Therapies in Europe: A Quantification and Reflection.

Gene and cell-based therapies (GCTs) are said to hold great promise as treatments for previously untreatable and high-burden diseases. Here, we provide insight into GCT development and regulation activities in Europe, quantify clinical and regulatory success, and compare these with other medicinal products in order to reflect on regulatory changes and challenges.

Medicines Adaptive Pathways to Patients: Why, When, and How to Engage?

Medicines Adaptive Pathways to Patients (MAPPs) seeks to foster access to novel beneficial treatments for the right patient groups at the earliest appropriate time in the product life-span, in a sustainable fashion. We summarize the MAPPs engagement process and critical questions to be asked at each milestone of the product life-span. These considerations are of relevance for regulatory and access pathways that strive to address the "evidence vs. access" conundrum.

Challenges in Advanced Therapy Medicinal Product Development: A Survey among Companies in Europe.

Advanced therapy medicinal products (ATMPs) hold promise as treatments for previously untreatable and high-burden diseases. Expectations are high and active company pipelines are observed, yet only 10 market authorizations were approved in Europe. Our aim was to identify challenges experienced in European ATMP clinical development by companies. A survey-based cohort study was conducted among commercial ATMP developers. Respondents shared challenges experienced during various development phases, as well as developer and product characteristics. Descriptions of challenges were grouped in domains (clinical, financial, human resource management, regulatory, scientific, technical, other) and further categorized using thematic content analysis. A descriptive analysis was performed. We invited 271 commercial ATMP developers, of which 68 responded providing 243 challenges. Of products in development, 72% were in early clinical development and 40% were gene therapies. Most developers were small- or medium-sized enterprises (65%). The most often mentioned challenges were related to country-specific requirements (16%), manufacturing (15%), and clinical trial design (8%). The European ATMP field is still in its early stages, and developers experience challenges on many levels. Challenges are multifactorial and a mix of ATMP-specific and generic development aspects, such as new and orphan indications, novel technologies, and inexperience, adding complexity to development efforts.

Traceability of Biologics in The Netherlands: An Analysis of Information-Recording Systems in Clinical Practice and Spontaneous ADR Reports.

INTRODUCTION AND OBJECTIVE: Pharmacovigilance requirements for biologics mandate that EU Member States shall ensure that any biologic that is the subject of a suspected adverse drug reaction (ADR) is identifiable by brand name and batch number. Recent studies showed that brand name identification is well established, whereas batch numbers are (still) poorly reported. We evaluated information-recording systems and practices in the Dutch hospital setting to identify determinants for brand name and batch number recording as well as success factors and bottlenecks for traceability. METHODS: We surveyed Dutch hospital pharmacists with an online questionnaire on systems and practices in hospitals for recording brand names and batch numbers. Additionally, we performed an analysis of the traceability of recombinant biologics in spontaneous ADR reports (received between 2009 and 2014) from the Netherlands Pharmacovigilance Centre Lareb. RESULTS: The survey showed that brand names are not routinely recorded in the clinical practice of Dutch hospitals, whereas batch numbers are poorly recorded. Seventy-six percent of the 1523 ADR reports for recombinant biologics had a traceable brand name whereas 5% of these reports contained a batch number. The results suggest a possible relationship between the availability of brand and batch number information in clinical practice and the inclusion of this information in ADR reports for biologics. CONCLUSION: The limited traceability of brand names and batch numbers in ADR reports may be primarily caused by the shortcomings in the recording of information in clinical practice. We recommend efforts to improve information-recording systems as a first step to improve the traceability of biologics in ADR reporting.

Classification of Recombinant Biologics in the EU: Divergence Between National Pharmacovigilance Centers.

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.

[The new pharmacovigilance legislation in practice]. / Nieuwe wetgeving geneesmiddelenbewaking in de praktijk.

Recent European legislation has provided new tools to enhance the overseeing of medicinal products in the postmarketing phase. Package leaflets of newly approved medicines contain a black inverted triangle as a signal for enhanced monitoring. The leaflets also have clear instructions on how to report possible adverse drug reactions. Databases of drug reactions are accessible by the public. The most important change is the establishment of the Pharmacovigilance Risk Assessment Committee (PRAC) within the European Medicines Agency (EMA). This Committee will review safety signals of medicinal products arising in the member states of the European Union. The Committee could recommend adaptation of the package leaflet, or suspension or revocation of the marketing authorisation. The PRAC is also involved in the assessment of risk management plans for medicinal products and post-authorisation efficacy and safety studies.

Amisulpride: is there a treatment for negative symptoms in schizophrenia patients?

In this article we report on a meta-analysis of the published studies of amisulpride conducted in order to demonstrate efficacy on primary negative symptoms in schizophrenia. Four placebo-controlled studies were conducted in patients with predominantly negative symptoms. In all studies a significant improvement was observed on the Scale for the Assessment of Negative Symptoms (SANS) in the amisulpride groups (50-300 mg daily) as compared to placebo. The improvement on the SANS was not accompanied by a simultaneous improvement on the Scale for the Assessment of Positive Symptoms (SAPS) or a decrease in extrapyramidal symptoms (EPS) in three of the four studies, indicating a genuine effect on primary negative symptoms. The overall analysis shows that the improvement on the SANS was accompanied by a small simultaneous improvement on the SAPS. Moreover, in the studies where depressive symptoms were measured, a significant improvement was also shown in favor of amisulpride. However, as the SAPS and the Montgomery Asberg Depression Rating Scale (MADRS) baseline scores were rather low, the improvement on both scales in favor of amisulpride is probably not responsible for the improvement on the SANS. A positive correlation was found between the severity on the mean SANS score at baseline and mean improvement at endpoint, and a surprisingly high success rate was observed in the placebo groups, indicating either that primary negative symptoms are not as persistent as had previously been thought, or that the concept of primary negative symptoms should be reconsidered. Probably amisulpride is efficacious on these nonenduring primary negative symptoms.