Scoring the Culture of Care as a key performance indicator in a global pharmaceutical company.

Culture of Care has been an integral part of Sanofi's policy on animal protection for more than 15 years. Culture of Care goes beyond compliance with regulations and standards, since it relates to the attitudes of staff and to caring for research animals, as well as to the company's commitment to an active animal protection policy. However, the concept of Culture of Care remains subjective. Via two anonymous and voluntary surveys conducted in 2018 and 2021, it was possible to understand the level of staff engagement and the perception of company efficiency. Based on key questions, it was possible to assess individual engagement (animal welfare knowledge, pride, engagement, recognition) and company commitments (oversight body efficiency, level of transparency, Sanofi policy on animal protection). The institutional scores were 7.7/10 and 7.9/10 obtained in 2018 and in 2021, respectively. The individual score obtained for 2018 was 6.7/10 compared to 6.9/10 obtained in 2021. The combination of these two criteria helps to determine a Culture of Care score and thus make it a performance indicator. The scores are CoC2018 (7.7; 6.7) and CoC2021 (7.9; 6.9). Being able to quantify this level of engagement and the perception that employees have of the company encourages the organisation of an improvement programme and helps measure the benefits.

The European Federation of the Pharmaceutical Industry and Associations' Research and Animal Welfare Group: Assessing and benchmarking 'Culture of Care' in the context of using animals for scientific purpose.

The European Federation of Pharmaceutical Industries and Associations' Research and Animal Welfare group members reflected on the concept of a Culture of Care in relation to animal care and use and on differences in its understanding and application across European pharmaceutical companies. The term 'Culture of Care' is used across different regions and organizations but rarely with any defined indicators to support working practice. The European Federation of Pharmaceutical Industries and Associations' Research and Animal Welfare group has developed a framework to help organizations identify gaps or potential areas for improvement in support of a positive Culture of Care. The framework is a tool that identifies five areas of focus for a Culture of Care: company values; strategic approach at establishment level; implementation structures; staff support; and animal care and procedures. The framework is intended as an aid for continuous improvement, highlighting where indicators of good practice are present. We expect it to provide points of reflection and ideas for those looking to implement a Culture of Care in a structured way, while facilitating a professional and strategic approach. To prevent it supporting a 'tick-box' exercise, the framework must not be used as an auditing tool, but as a starting point for consideration and discussion about how care manifests within the context and constraints of individual establishments.

Current concepts of Harm-Benefit Analysis of Animal Experiments - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 1.

International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm-benefit analysis (HBA) and deemed the project to be appropriate. Although the process for conducting HBAs may not be new, the relevant factors and algorithms used in conducting them during the review process are deemed to be poorly defined or lacking by committees in many institutions. This paper presents the current concept of HBAs based on a literature review. References on cost or risk benefit from clinical trials and other industries are also included. Several approaches to HBA have been discovered including algorithms, graphic presentations and generic processes. The aim of this study is to better aid and harmonize understanding of the concepts of 'harm', 'benefit' and 'harm-benefit analysis'.

Recommendations for Addressing Harm-Benefit Analysis and Implementation in Ethical Evaluation - Report from the AALAS-FELASA Working Group on Harm-Benefit Analysis - Part 2.

International regulations and guidelines strongly suggest that the use of animal models in scientific research should be initiated only after the authority responsible for the review of animal studies has concluded a well-thought-out harm-benefit analysis (HBA) and deemed the project to be appropriate. The AALAS-FELASA working group on HBA has performed a literature review and based on this review, proposed a method for HBA. Examples of the working group's approach are included in this report.

Approaches to animal research project evaluation in Europe after implementation of Directive 2010/63/EU.

Directive 2010/63/EU requires the evaluation and authorization of all research projects and training activities involving the use of animals and defines some components and expertise necessary for the evaluation process. Adoption of Directive 2010/63/EU provided an opportunity to harmonize project evaluation processes across Europe, but thus far, member states have used a variety of approaches in the transposition and implementation of Directive 2010/63/EU. The authors discuss and compare the project evaluation systems being implemented in five European Union member states (France, Germany, Spain, the Netherlands and the UK).

Recombinant chimeric virus with wild-type dengue 4 virus premembrane and envelope and virulent yellow fever virus Asibi backbone sequences is dramatically attenuated in nonhuman primates.

Candidate vaccine ChimeriVax viruses are attenuated, efficacious, safe, and highly unlikely to be transmitted by arthropod vectors. Nevertheless, concerns have been raised about the use of these vaccines because of the potential for recombination between vaccine and wild-type (WT) strains. To evaluate the vertebrate pathogenicity of such a worst-case recombinant, ChimeriVax-dengue (DEN) 4 virus was chimerized with the WT Asibi yellow fever virus. In this worst-case scenario, chimeric viruses remained fully attenuated in nonhuman primates. We therefore conclude that, even in the highly unlikely event of "virulent" backbone reversion, the safety of ChimeriVax-DEN vaccines would not be compromised.

Substitution of wild-type yellow fever Asibi sequences for 17D vaccine sequences in ChimeriVax-dengue 4 does not enhance infection of Aedes aegypti mosquitoes.

To address concerns that a flavivirus vaccine/wild-type recombinant virus might have a high mosquito infectivity phenotype, the yellow fever virus (YFV) 17D backbone of the ChimeriVax-dengue 4 virus was replaced with the corresponding gene sequences of the virulent YFV Asibi strain. Field-collected and laboratory-colonized Aedes aegypti mosquitoes were fed on blood containing each of the viruses under investigation and held for 14 days after infection. Infection and dissemination rates were based on antigen detection in titrated body or head triturates. Our data indicate that, even in the highly unlikely event of recombination or substantial backbone reversion, virulent sequences do not enhance the transmissibility of ChimeriVax viruses. In light of the low-level viremias that have been observed after vaccination in human volunteers coupled with low mosquito infectivity, it is predicted that the risk of mosquito infection and transmission of ChimeriVax vaccine recombinant/revertant viruses in nature is minimal.

Host-cell interaction of attenuated and wild-type strains of yellow fever virus can be differentiated at early stages of hepatocyte infection.

Yellow fever (YF) virus is currently found in tropical Africa and South America, and is responsible for a febrile to severe illness characterized by organ failure and shock. The attenuated YF 17D strain, used in YF vaccine, was derived from the wild-type strain Asibi. Although studies have been done on genetic markers of YF virulence, differentiation of the two strains in terms of host-cell interaction during infection remains elusive. As YF wild-type strains are hepatotropic, we chose a hepatic cell line (HepG2) to study YF virus-host cell interaction. HepG2 cells rapidly produced high titres of infectious viral particles for 17D and Asibi YF strains. However, HepG2 cells were more susceptible to the attenuated 17D virus infection, and only this virus strain induced early apoptosis in these cells. Molecular markers specific for the 17D virus were identified by microarray analysis and confirmed by quantitative RT-PCR analysis. As early as 1h postinfection, three genes, (IEX-1, IRF-1, DEC-1) all implicated in apoptosis pathways, were upregulated. Later in infection (48 h) two other genes (HSP70-1A and 1B), expressed in cases of cellular stress, were highly upregulated in 17D-infected HepG2 cells. The early specific upregulation of these cellular genes in HepG2 cells may be considered markers of the 17D virus. This study on the YF attenuated strain gives a new approach to the analysis of the factors involved in virus attenuation.

Future improvements and implementation of animal care practices within the animal testing regulatory environment.

Animal welfare is an increasingly important concern when considering biomedical experimentation. Many of the emerging regulations and guidelines specifically address animal welfare in laboratory animal care and use. The current revision of the appendix of the European Convention, ETS123 (Council of Europe), updates and improves on the current animal care standardization in Europe. New guidelines from the Organisation for Economic Co-operation and Development and the European Federation of Pharmaceutical Industries Association focus specifically on safety testing. These guidelines will affect the way toxicity studies are conducted and therefore the global drug development process. With the 3Rs principles taken into account, consideration regarding animal welfare will demand changes in animal care practices in regulatory safety testing. The most significant future improvements in animal care and use practices are likely to be environmental enrichment, management of animal pain and distress, and improved application of the humane endpoints. Our challenge is to implement respective guidelines based on scientific data and animal welfare, through a complex interplay of regulatory objective and public opinion. The current goal is to work toward solutions that continue to provide relevant animal models for risk assessment in drug development and that are science based. In this way, future improvements in animal care and use practices can be founded on facts, scientific results, and analysis. Some of these improvements become common practice in some countries. International harmonization can facilitate the development and practical application of "best scientific practices" by the consensus development process that harmonization requires. Since the implementation of good laboratory practices (GLP) standards in safety testing, these new regulations and recommendations represent a new way forward for animal safety studies.