Licensing Requirements for Avian Vaccines Within the European Union.

Avian vaccines are a key factor when it comes to ensuring the availability of products derived from healthy poultry and preventing the transmission of infections from domestic and wildlife birds to humans. A marketing authorization for veterinary vaccines is granted after the product's quality, safety, and efficacy have been confirmed. During the licensing procedure, the manufacturing process is assessed to guarantee consistent quality and stability of the vaccine components. Furthermore, both the safety for the target species and the risk for the user, the consumer, and the environment must be demonstrated. In addition, specific tests and studies are required to support the efficacy of the vaccine. The authorization procedures and related licensing requirements for avian vaccines to be marketed in the European Union (EU) based on the requirements of Regulation (EU) 2019/6 Article 8 and the Commission Delegated Regulation (EU) 2021/805 amending Annex II to Regulation (EU) No. 2019/6 are explained in the paper.

Requisitos de licencia para vacunas aviares dentro de la Unión Europea. Las vacunas aviares son un factor clave a la hora de garantizar la disponibilidad de productos derivados de aves sanas y prevenir la transmisión de infecciones de aves domésticas y silvestres a los humanos. La autorización de comercialización de vacunas veterinarias se concede una vez confirmada la calidad, seguridad y eficacia del producto. Durante el procedimiento de concesión de licencia, se evalúa el proceso de fabricación para garantizar una calidad y estabilidad constantes de los componentes de la vacuna. Además, se debe demostrar tanto la seguridad para las especies a las que dicha vacuna está destinada, así como el riesgo para el usuario, el consumidor y el medio ambiente. Además, se requieren pruebas y estudios específicos que respalden la eficacia de la vacuna. En este documento se explican los procedimientos de autorización y los requisitos de licencia relacionados para las vacunas aviares que se comercializarán en la Unión Europea (U.E.) con base en los requisitos de la Regulación (U.E.) 2019/6 Artículo 8 y la Regulación Delegada de la Comisión (U.E.) 2021/805 que modifica el Anexo II del Reglamento. (U.E.) No. 2019/6.

We Know What You Agreed To, Don't We?-Evaluating the Quality of Paper-Based Consents Forms and Their Digitalized Equivalent Using the Example of the Baltic Fracture Competence Centre Project.

INTRODUCTION: The informed consent is the legal basis for research with human subjects. Therefore, the consent form (CF) as legally binding document must be valid, that is, be completely filled-in stating the person's decision clearly and signed by the respective person. However, especially paper-based CFs might have quality issues and the transformation into machine-readable information could add to low quality. This paper evaluates the quality and arising quality issues of paper-based CFs using the example of the Baltic Fracture Competence Centre (BFCC) fracture registry. It also evaluates the impact of quality assurance (QA) measures including giving site-specific feedback. Finally, it answers the question whether manual data entry of patients' decisions by clinical staff leads to a significant error rate in digitalized paper-based CFs. METHODS: Based on defined quality criteria, monthly QA including source data verification was conducted by two individual reviewers since the start of recruitment in December 2017. Basis for the analyses are the CFs collected from December 2017 until February 2019 (first recruitment period). RESULTS: After conducting QA internally, the sudden increase of quality issues in May 2018 led to site-specific feedback reports and follow-up training regarding the CFs' quality starting in June 2018. Specific criteria and descriptions on how to correct the CFs helped in increasing the quality in a timely matter. Most common issues were missing pages, decisions regarding optional modules, and signature(s). Since patients' datasets without valid CFs must be deleted, QA helped in retaining 65 datasets for research so that the final datapool consisted of 840 (99.29%) patients. CONCLUSION: All quality issues could be assigned to one predefined criterion. Using the example of the BFCC fracture registry, CF-QA proved to significantly increase CF quality and help retain the number of available datasets for research. Consequently, the described quality indicators, criteria, and QA processes can be seen as the best practice approach.

A systematic review to assess the evidence-based effectiveness, content, and success factors of behavior change interventions for enhancing pro-environmental behavior in individuals.

To reduce global greenhouse gas emissions in order to limit global warming to 1.5°C, individuals and households play a key role. Behavior change interventions to promote pro-environmental behavior in individuals are needed to reduce emissions globally. This systematic literature review aims to assess the a) evidence-based effectiveness of such interventions and b) the content of very successful interventions without limiting the results to specific emitting sectors or countries. Based on the "PICOS" mnemonic and PRISMA statement, a search strategy was developed, and eligibility criteria were defined. Three databases (Embase, PsycInfo, and Web of Science) were searched to retrieve and review potential literature. As a result, 54 publications from 2010 to 2021 were included in the analysis. The results show that most interventions only have small positive effects or none at all. A total of 15 very successful interventions focused on the sectors of mobility, energy, and waste and incorporated improved (infra-) structures, education, feedback, enablement or made the sustainable option the default. Six evidence-based recommendations for content, timing, and setting are deducted and given for interventions on enhancing pro-environmental behavior (PEB). In summary, although the various interventions and intervention types to promote PEB differ in their effectiveness, very successful interventions have common elements. Future research should focus on high-/low-impact and high-/low-cost behavior to develop interventions that aim at high-impact but low-cost behavior changes, or avoid low-impact but high-cost behavior.

[Position paper of the German Network for Health Services Research (DNVF) on application-related data collection according to Social Code Book V]. / Positionspapier des Deutschen Netzwerk Versorgungsforschung (DNVF) zur anwendungsbegleitenden Datenerhebung nach Sozialgesetzbuch V.

Within the framework of the early benefit assessment, the Federal Joint Committee (G-BA) has been authorised since 2019 by the law for more safety in the supply of pharmaceuticals GSAV to request additional application-related data capture for certain pharmaceutical drugs. This results in certain challenges, especially in the area of conflict between methodological requirements and practical feasibility. The position paper provides an overview and takes up the general regulations defined by the Federal Ministry of Health (BMG) as well as the process defined by the G-BA. Subsequently, possible solutions are discussed and recommendations for implementation are given from the perspective of health care research.

Designing and piloting a generic research architecture and workflows to unlock German primary care data for secondary use.

BACKGROUND: Medical data from family doctors are of great importance to health care researchers but seem to be locked in German practices and, thus, are underused in research. The RADAR project (Routine Anonymized Data for Advanced Health Services Research) aims at designing, implementing and piloting a generic research architecture, technical software solutions as well as procedures and workflows to unlock data from family doctor's practices. A long-term medical data repository for research taking legal requirements into account is established. Thereby, RADAR helps closing the gap between the European countries and to contribute data from primary care in Germany. METHODS: The RADAR project comprises three phases: (1) analysis phase, (2) design phase, and (3) pilot. First, interdisciplinary workshops were held to list prerequisites and requirements. Second, an architecture diagram with building blocks and functions, and an ordered list of process steps (workflow) for data capture and storage were designed. Third, technical components and workflows were piloted. The pilot was extended by a data integration workflow using patient-reported outcomes (paper-based questionnaires). RESULTS: The analysis phase resulted in listing 17 essential prerequisites and guiding requirements for data management compliant with the General Data Protection Regulation (GDPR). Based on this list existing approaches to fulfil the RADAR tasks were evaluated-for example, re-using BDT interface for data exchange and Trusted Third Party-approach for consent management and record linkage. Consented data sets of 100 patients were successfully exported, separated into person-identifying and medical data, pseudonymised and saved. Record linkage and data integration workflows for patient-reported outcomes in the RADAR research database were successfully piloted for 63 responders. CONCLUSION: The RADAR project successfully developed a generic architecture together with a technical framework of tools, interfaces, and workflows for a complete infrastructure for practicable and secure processing of patient data from family doctors. All technical components and workflows can be reused for further research projects. Additionally, a Trusted Third Party-approach can be used as core element to implement data privacy protection in such heterogeneous family doctor's settings. Optimisations identified comprise a fully-electronic consent recording using tablet computers, which is part of the project's extension phase.

The generic Informed Consent Service gICS®: implementation and benefits of a modular consent software tool to master the challenge of electronic consent management in research.

BACKGROUND: Defining and protecting participants' rights is the aim of several ethical codices and legal regulations. According to these regulations, the Informed Consent (IC) is an inevitable element of research with human subjects. In the era of "big data medicine", aspects of IC become even more relevant since research becomes more complex rendering compliance with legal and ethical regulations increasingly difficult. METHODS: Based on literature research and practical experiences gathered by the Institute for Community Medicine (ICM), University Medicine Greifswald, requirements for digital consent management systems were identified. RESULTS: To address the requirements, the free-of-charge, open-source software "generic Informed Consent Service" (gICS®) was developed by ICM to provide a tool to facilitate and enhance usage of digital ICs for the international research community covering various scenarios. gICS facilitates IC management based on IC modularisation and supports various workflows within research, including (1) electronic depiction of paper-based consents and (2) fully electronic consents. Numerous projects applied gICS and documented over 336,000 ICs and 2400 withdrawals since 2014. DISCUSSION: Since the consent's content is a prerequisite for securing participants' rights, application of gICS is no guarantee for legal compliance. However, gICS supports fine-granular consents and accommodation of differentiated consent states, which can be directly exchanged between systems, allowing automated data processing. CONCLUSION: gICS simplifies and supports sustained IC management as a major key to successfully conduct studies and build trust in research with human subjects. Therefore, interested researchers are invited to use gICS and provide feedback for further improvements.

MAGIC: once upon a time in consent management-a FHIR® tale.

BACKGROUND: The use of medical data for research purposes requires an informed consent of the patient that is compliant with the EU General Data Protection Regulation. In the context of multi-centre research initiatives and a multitude of clinical and epidemiological studies scalable and automatable measures for digital consent management are required. Modular form, structure, and contents render a patient's consent reusable for varying project settings in order to effectively manage and minimise organisational and technical efforts. RESULTS: Within the DFG-funded project "MAGIC" (Grant Number HO 1937/5-1) the digital consent management service tool gICS was enhanced to comply with the recommendations published in the TMF data protection guideline for medical research. In addition, a structured exchange format for modular consent templates considering established standards and formats in the area of digital informed consent management was designed. Using the new FHIR standard and the HAPI FHIR library, the first version for an exchange format and necessary import-/export-functionalities were successfully implemented. CONCLUSIONS: The proposed exchange format is a "work in progress". It represents a starting point for current discussions concerning digital consent management. It also attempts to improve interoperability between different approaches within the wider IHE-/HL7-/FHIR community. Independent of the exchange format, providing the possibility to export, modify and import templates for consents and withdrawals to be reused in similar clinical and epidemiological studies is an essential precondition for the sustainable operation of digital consent management.

Toolbox for Research, or how to facilitate a central data management in small-scale research projects.

BACKGROUND: In most research projects budget, staff and IT infrastructures are limiting resources. Especially for small-scale registries and cohort studies professional IT support and commercial electronic data capture systems are too expensive. Consequently, these projects use simple local approaches (e.g. Excel) for data capture instead of a central data management including web-based data capture and proper research databases. This leads to manual processes to merge, analyze and, if possible, pseudonymize research data of different study sites. RESULTS: To support multi-site data capture, storage and analyses in small-scall research projects, corresponding requirements were analyzed within the MOSAIC project. Based on the identified requirements, the Toolbox for Research was developed as a flexible software solution for various research scenarios. Additionally, the Toolbox facilitates data integration of research data as well as metadata by performing necessary procedures automatically. Also, Toolbox modules allow the integration of device data. Moreover, separation of personally identifiable information and medical data by using only pseudonyms for storing medical data ensures the compliance to data protection regulations. This pseudonymized data can then be exported in SPSS format in order to enable scientists to prepare reports and analyses. CONCLUSIONS: The Toolbox for Research was successfully piloted in the German Burn Registry in 2016 facilitating the documentation of 4350 burn cases at 54 study sites. The Toolbox for Research can be downloaded free of charge from the project website and automatically installed due to the use of Docker technology.

Healthcare utilization and costs in primary care patients with dementia: baseline results of the DelpHi-trial.

The objectives of this cross-sectional analysis were to determine healthcare resource utilization and cost for community-dwelling patients with dementia (PWD) from a payer's and societal perspective, and to analyze the associations between costs and sociodemographic and clinical variables. Analysis of healthcare costs from a payer's perspective was based on a sample of 425 PWD, analysis of healthcare costs from societal perspective on a subsample of 254 PWD and their informal caregivers. Frequency of healthcare resource utilization was assessed by means of questionnaires. Informal care and productivity losses were assessed by using the Resource Utilization in Dementia questionnaire (RUD). Costs were monetarized using standardized unit costs. To analyze the associations, multiple linear regression models were used. Total annual costs per PWD valued 7016€ from a payer's and 25,877€ from a societal perspective, meaning that societal cost is approximately three and a half times as much as payer's expenditures. Costs valuated 5456 € for medical treatments, 1559 € for formal care, 18,327€ for informal care. Productivity losses valued 1297€ for PWD caregivers. Informal care could vary substantially (-21%; +33%) concerning different valuation methods. Medical care costs decreased significantly with progression of dementia and with age. Costs of care double over the stages of dementia. Formal care costs were significantly higher for PWD living alone and informal care costs significantly lower for PWD with an employed caregiver. For all cost categories, deficits in daily living activities were major cost drivers.

mosaicQA - A General Approach to Facilitate Basic Data Quality Assurance for Epidemiological Research.

BACKGROUND: Epidemiological studies are based on a considerable amount of personal, medical and socio-economic data. To answer research questions with reliable results, epidemiological research projects face the challenge of providing high quality data. Consequently, gathered data has to be reviewed continuously during the data collection period. OBJECTIVES: This article describes the development of the mosaicQA-library for non-statistical experts consisting of a set of reusable R functions to provide support for a basic data quality assurance for a wide range of application scenarios in epidemiological research. METHODS: To generate valid quality reports for various scenarios and data sets, a general and flexible development approach was needed. As a first step, a set of quality-related questions, targeting quality aspects on a more general level, was identified. The next step included the design of specific R-scripts to produce proper reports for metric and categorical data. For more flexibility, the third development step focussed on the generalization of the developed R-scripts, e.g. extracting characteristics and parameters. As a last step the generic characteristics of the developed R functionalities and generated reports have been evaluated using different metric and categorical datasets. RESULTS: The developed mosaicQA-library generates basic data quality reports for multivariate input data. If needed, more detailed results for single-variable data, including definition of units, variables, descriptions, code lists and categories of qualified missings, can easily be produced. CONCLUSIONS: The mosaicQA-library enables researchers to generate reports for various kinds of metric and categorical data without the need for computational or scripting knowledge. At the moment, the library focusses on the data structure quality and supports the assessment of several quality indicators, including frequency, distribution and plausibility of research variables as well as the occurrence of missing and extreme values. To simplify the installation process, mosaicQA has been released as an official R-package.

Potency testing of veterinary vaccines: the way from in vivo to in vitro.

Current quality control of inactivated animal vaccines still focuses on the potency of final products in a batch-wise manner. Animal welfare concerns as well as scientific considerations have led to the '3Rs-concept' that comprises the refinement of animal procedures, the reduction of animal numbers, and the replacement of animal models. Although the 3Rs-concept has been widely accepted as a fundamental principle, the number of approved alternatives for in vivo tests is still limited. To promote further progress, the international scientific workshop 'Potency Testing of Veterinary Vaccines: The Way from in vivo to in vitro' was held at the Paul-Ehrlich-Institut in Langen, Germany, on 01-03 December 2010. More than 130 participants from industry, academia and regulatory authorities discussed the current state of the 3Rs-concept, examples of its successful implementation as well as still existing hurdles. Special emphasis was laid on the 'consistency approach' that aims to ensure relevant quality attributes of vaccine batches by in vitro analyses during production rather than by in vivo potency tests on the final product. This report provides an overview of the insights gained, including the recommendations produced at the end of the workshop.

Influence of carvacrol on proliferation and survival of porcine lymphocytes and intestinal epithelial cells in vitro.

Carvacrol, an essential oil compound of oregano and thyme, has potential applications as an alternative to antibiotic growth promoters in pig nutrition. Carvacrol is well known for its antibacterial effects, but it is unclear whether there are additional effects on the porcine immune system. In the present study, the influence of carvacrol on porcine blood lymphocytes was examined. The porcine enterocyte cell line IPEC-1 was examined for comparison. Carvacrol inhibited the proliferation of purified lymphocytes with an IC50 of 182+/-67 microM in MTT assays. This was confirmed by CFSE assay. The presence of monocytes in carvacrol-treated lymphocyte preparations had a protective effect on the lymphocytes, significantly raising the IC50 to 516+/-87 microM. FACS analysis of CFSE labelled lymphocyte subsets revealed that gammadelta T cells were less susceptible to carvacrol toxicity than CD4 and CD8 T cells. The reduced lymphocyte proliferation measured after carvacrol exposure was shown to be due to apoptotic cell death, as determined by annexin-V binding and caspase-3 activation. The observed effects were not specific for lymphocytes, since carvacrol similarly induced apoptosis and suppressed proliferation in the porcine enterocyte cell line IPEC-1.

The Fusarium toxin deoxynivalenol disrupts phenotype and function of monocyte-derived dendritic cells in vivo and in vitro.

The trichothecene mycotoxin deoxynivalenol (DON) causes systemic immuno-suppression in pigs and possibly also in humans after chronic dietary exposure. Since the outcome of every immune response is largely controlled by dendritic cells (DC), we hypothesised that a direct influence of DON on DC function might play a role in mediating DON immunotoxicity. To test this hypothesis, a 2x2 factorial design study was performed. Pigs were fed a control diet or a diet containing DON (DON-diet); monocyte-derived DC (MoDC) from these pigs were then treated with DON in vitro or left untreated. Phenotype and function of the MoDC were analysed. In vitro DON-treatment of MoDC from pigs fed the control diet resulted in a down-regulation of CD80/86 and CD40. This was associated with an activation of the mitogen-associated protein kinases ERK1/2 and JNK. The endocytic activity of MoDC was decreased after in vitro DON-exposure while their T cell stimulatory capacity was not altered. MoDC derived from pigs that had been fed the DON-diet failed to up-regulate MHC-II in response to LPS/TNFalpha. Dietary exposure of pigs to DON inhibited endocytosis of FITC-dextran by MoDC, but did not influence T cell stimulatory capacity. ERK1/2 and JNK were constitutively activated in MoDC from pigs fed the DON-diet. If MoDC derived from pigs fed the DON-diet were exposed to DON in vitro, this resulted in an up-regulation of MHC-II and CD80/86, but not CD40. In comparison to untreated MoDC from pigs fed DON-diet, endocytic capacity was further down-regulated, whereas mitogen-activated protein kinase activation was increased. In summary, DON disrupts porcine DC function in vitro and in vivo, which might contribute to the immunosuppressive effects of this mycotoxin.

Cholera toxin promotes the generation of semi-mature porcine monocyte-derived dendritic cells that are unable to stimulate T cells.

Cholera toxin (Ctx) is a powerful mucosal adjuvant with potential applications for oral vaccination of swine. Dendritic cells (DC) play a key role in the decision between immunity and tolerance, and are likely target cells for mediating Ctx functions in vivo. Therefore, we examined the capacity of Ctx to enhance stimulatory activity of porcine monocyte-derived DC (MoDC). Ctx promoted the development of a semi-mature DC phenotype, with decreased levels of MHC class II and CD40, but increased CD80/86 expression. These changes were associated with activation of extracellular signal-regulated kinase (ERK), but not NFkappaB or c-Jun N-terminal kinase (JNK). Functionally, Ctx-priming greatly diminished T cell stimulatory capacity both in antigen-specific and superantigen-induced proliferation assays. The lower proliferation rate was not due to increased apoptosis of either DC or T cells. Ctx suppressed TNFalpha secretion by MoDC, but induced IL-10 production. The observed effects on T cell proliferation could only be partially mimicked by IL-10 alone. However, addition of recombinant TNFalpha to co-cultures of Ctx-primed MoDC and lymphocytes restored lymphocyte proliferation in a concentration-dependent manner. Ctx-primed DC were not actively tolerogenic, since they could not suppress proliferative T cell reactions induced by untreated DC.

Efficacy and functionality of lipoprotein OprI from Pseudomonas aeruginosa as adjuvant for a subunit vaccine against classical swine fever.

Bacterial lipoproteins are potent stimulators of innate immune responses and can mediate humoral and cytotoxic T cell responses without additional adjuvants. OprI derived from Pseudomonas aeruginosa was tested in vitro and in vivo for its adjuvant potential in the context of a classical swine fever (CSF) subunit vaccine. OprI activated porcine monocyte-derived dendritic cells (MoDC), upregulating CD80/86 and MHC class II expression, as well as pro-inflammatory cytokines. OprI enhanced CSFV-antigen-specific lymphocyte proliferation and IFN-gamma release. An E2/NS3-based subunit vaccine adjuvanted with OprI stimulated specific immune responses and partial protection against CSFV infection. Although, a water-oil-water adjuvanted vaccine was more potent at protecting animals, this study demonstrates that OprI has immunostimulatory properties for porcine DC, and has potential as vaccine immunostimulant. Further studies are necessary to optimize antigen formulation enabling to translate the in vitro efficacy into a potent vaccine in vivo.

Immunological properties of recombinant classical swine fever virus NS3 protein in vitro and in vivo.

Classical swine fever (CSF) is a highly contagious and often fatal disease of pigs characterised by fever, severe leukopenia and haemorrhages. With vaccines having an importance in disease control, studies are seeking improved protein-based subunit vaccine against the virus (CSFV). In this respect, recombinant viral NS3 protein was analysed for its immunopotentiating capacity, particularly in terms of cytotoxic immune responses. NS3 was effective at inducing in vitro responses, quantified by lymphoproliferation, IFN-gamma ELISPOT, flow cytometric detection of activated T cell subsets, and cytotoxic T cell assays. Peripheral blood mononuclear cells from CSFV-immune pigs could be stimulated, but not cells from naïve animals. In addition to the IFN-gamma responses, induction of both CD4+ T helper cell and CD8+ cytotoxic T cells (CTL) were discernible--activation of the latter was confirmed in a virus-specific cytolytic assay. Attempts were made to translate this to the in vivo situation, by vaccinating pigs with an E2/NS3-based vaccine compared with an E2 subunit vaccine. Both vaccines were similar in their abilities to stimulate specific immune responses and protect pigs against lethal CSFV infection. Although the E2/NS3 vaccine appeared to have an advantage in terms of antibody induction, this was not statistically significant when group studies were performed. It was also difficult to visualise the NS3 capacity to promote T-cell responses in vivo. These results show that NS3 has potential for promoting cytotoxic defences, but the formulation of the vaccine requires optimisation for ensuring that NS3 is correctly delivered to antigen presenting cells for efficient activation of CTL.

Fc gamma RII-dependent sensitisation of natural interferon-producing cells for viral infection and interferon-alpha responses.

Natural interferon-producing cells (NIPC), also called plasmacytoid dendritic cells, are the most potent producers of IFN-alpha in response to viral and bacterial components, serving an important function in innate immune defences. The present work demonstrates that NIPC responsiveness can be primed by immunisation, increasing their capacity to produce IFN-alpha after viral infection. NIPC isolated from pigs immunised against classical swine fever virus (CSFV), a member of the Flaviviridae, were more receptive to viral infection and produced higher levels of IFN-alpha than NIPC from immunologically naive animals. This sensitisation of NIPC was maintained for at least 8 months after immunisation. IFN-alpha production was dependent on live virus and required replication, and the "immune" NIPC responded to lower infectious doses of virus. Co-localisation of the virus with Fc(gamma)RII (CD32) in polarised structures was observed with "immune" NIPC only. This Fc(gamma)RII-dependent virus capture and sensitisation of NIPC, evidently mediated through cytophilic CSFV-specific antibodies, was inhibited by non-specifically aggregated immunoglobulin as well as by pre-formed virus-antibody complexes. In conclusion, these results demonstrate that NIPC not only represent a major player in innate immunity but are also functionally linked to the immunological memory of the adaptive immune system.