Putting animal welfare principles and 3Rs into action European Pharmaceutical Industry Report 2016 Update PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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2 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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The pharmaceutical industry is committed fully The use of animals in research remains a the lives of the people and animals that stand to the key principles of the 3Rs (Reducing the highly sensitive issue. While it is desirable to benefit from the research. number of animals used, Refining experiments to replace the use of animals in research & to minimise the impact on animals, and development, research involving animals Here we introduce you to our 4th report Replacing animal experiments wherever continues to be necessary to protect human which gives an overview of EFPIA and its possible with alternatives), and through them, and animal, and environmental health; maintain member’s activities in putting into action animal to ensuring high standards of animal welfare in the ability to respond to regulatory demands, welfare principles and the 3Rs of reduction, the research process. and; understand the causes of diseases and refinement and replacement. We give an functioning of complex biological systems in the extensive overview of the work taking place in This concept of the 3Rs was developed some body. Furthermore, Europe must remain a world the industry. With this in mind, the examples 50 years ago, and continues to be taken up leader in medical research and innovation to included in this report highlight the activities and implemented within the pharmaceutical address the unmet medical needs of its citizens going beyond compliance, and examples sector where the ongoing aim is to improve and to preserve its capacity to shape its health where we are leading on 3Rs and transparency the quality of life for people by developing strategies. through open communication. new products and services for the diagnosis and treatment of diseases, while ensuring high The pharmaceutical industry along with all welfare to the animals involved. Furthermore, stakeholders have responsibilities to play in The previous reports “Putting Animal Welfare the pharmaceutical industry strongly supports the development, uptake and dissemination of Principles and 3Rs into Action” are available the Directive 2010/63/EU on the protection work on 3Rs and those taken by industry are here. of animals used for scientific purposes which visibly highlighted in this report. We strive to has enhanced animal welfare standards go beyond what is legally required and work to and mandated the application of reduction, implement 3Rs to ensure high animal welfare refinement and replacement (‘3Rs’) across the and high quality science and ultimately improve EU.
3 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
Beyond Compliance Leading by Example Open Communications
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Beyond Compliance Leading by Example Open Communication
3Rs and welfare in everyday practice Dissemination beyond own We tell what we do and engage in department and own establishment open dialogue with interested parties drives improvement in welfare and Science and technology drive 3Rs and general quality of science welfare - We invest continuously in Communicating progress made in changing research paradigms animal welfare activities In a global world, we exchange with and learn from international partners to drive Staff training is an essential element of convergence good science and good welfare
Full and correct implementation of Directive 2010/63/EC on the protection of animals used for scientific purposes
is the responsibility and endeavor of the whole scientific community
4 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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3Rs and welfare in everyday practice: Researchers go beyond the regulatory requirements to develop systems leading to improved 3Rs and animal welfare in every day practice
Refinement model to evaluate the non- interactions occur in humans. An innovative specific side effects of anti-body drug study was conducted to show that there conjugates moving away from use of was no need to use an animal with the non-human primates (Reduction and same specific interactions as in humans. Refinement) Using rats rather than NHP is a significant refinement and substantial contribution Antibody Drug Conjugates (ADCs) are to reducing the number of NHP used in targeted antibodies that are connected to a research very potent chemotherapeutic drug that can be used in treating certain cancers. The ADC In vitro gastrointestinal in vitro allows the treatment to be delivered directly models to mimic processes in humans to the site where the tumour is. (Replacement)
ADCs are challenging to develop as they When developing human medicines, there have complex structures and are one is a need for methods to rank different of the leading causes of failure in their formulations for the medicines to be development are unexpected, non- specific delivered in clinical trials. Mostly this is TNO have developed in vitro gastrointestinal Implanted cannula for serial collection side effects. These occur when the antibody done using simple test-tube assays such as models which are multi-compartmental of cerebrospinal fluid reducing animal used in the ADC binds to healthy tissue dissolution rates. These results occasionally dynamic non-animal systems that simulate use (Reduction) also. need to be verified by assessing the the successive dynamic processes in the kinetics in a live animal. However, species stomach, small and large intestine. This The development of a serial collection To overcome this challenge, a model in rats differences in the gastrointestinal tract in vitro system allows the testing of of cerebrospinal fluid (CSF) and plasma was developed to evaluate the non-specific are well known (e.g. differing pH, gastric formulations being developed for human samples via implanted cannula in freely side effects. Normally, the complexity and emptying times), which may introduce use, in a system that mimics the human moving laboratory rats has led to a decrease specificity of ADCs necessitate the use of difficulties in interpreting results for human gastrointestinal tract instead of doing in in animal numbers. non-human primates where these specific relevance. vivo pharmacokinetic studies.
5 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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The CSF sample is a useful tool for the compound is present in the groups of bespoke studies that have illustrated that translational analysis of biological animals being tested and to understand micro-sampling has no or negligible impact efficacy markers and pharmacokinetic how the degree of systemic exposure on the parameters assessed across many drug exposure. It shows how the drug may be linked to any toxicological effects study types. Many of these have been candidate that is developed for treating observed. The blood (plasma or serum) published enabling a broader uptake of the brain diseases produces desired effects in concentration data generated from each technique and the pharmaceutical industry the brain, such as elevation of dopamine sample is used to derive toxicokinetic (TK) has contributed to a regulatory question in Parkinson’s disease. Up to six samples data and regulatory guidance dictates and answer document to encourage the use of CSF at different time points can be generally how and when these data are of micro-sampling where possible. collected from the same animal, which needed during compound development. reduces significantly the number of animals Change in housing conditions to allow needed, as compared with terminal CSF The information is used to establish safety urine samples to be taken in own cages sampling, which requires an animal per margins for human clinical trials. The reducing stress (Refinement) time point. This new technique improves largest influence on animal numbers used the quality of data because baseline and in safety assessment, particularly rodents, In many studies, e.g. safety studies, urine treated CSF samples are collected in the is the collection of samples for TK analysis. is collected so that urine concentration same animal and can be compared with the However, advances in bio-analytical of specific parameters can be measured, corresponding plasma levels. techniques have opened up the potential to which may indicate alterations, e.g. kidney use smaller sample volumes to assess drug function change. Traditionally, rodents have Decrease in number of toxicokinetic exposure in blood, plasma or serum. The been housed singly in glass metabolism sampling through micro-sampling use of micro-samples holds exciting promise cages with no food, to allow the collection (Reduction and Refinement) from business, scientific and animal welfare of uncontaminated urine samples. perspectives. Some companies have trialed the use of Generally, blood samples are taken hydrophobic sand as an alternative to from animals during general toxicology, The pharmaceutical industry has addressed housing in metabolism cages for urine reproductive toxicology and safety the concerns of barriers to using micro collection from mice. As a result of pharmacology studies to demonstrate that sampling by conducting a number of this work mice can be housed in their
6 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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home cage with sand substrate for urine unable to determine the potency of that collection thus reducing the stress for the irritancy response. animals of being moved. Data have shown that samples collected are of high quality. The Ocular Corrosion/Severe Irritant Test uses ex-vivo tissue (cow’s eyes) where Numerous replacement methods the cornea is used as a biological barrier developed for skin and eye irritation between the test article and a nutrient and corrosion testing, and skin medium. If the test article is corrosive or sensitisation a severe irritant, it will damage visibly the cornea and maybe even penetrate it. Pharmaceutical companies have For Skin Sensitisation testing, 3 methods implemented and perform regularly a have been accepted internationally as number of in vitro alternative assays that in vitro alternatives for determining skin were put in place as prescreens for in vivo sensitisation. testing of skin corrosion/skin irritation and ocular corrosion/irritation. Implementation Welfare assessment framework for dogs of these tests have led to an end of to produce reliable results (Refinement) extensive rabbit use for these methods. The Skin Corrosion test can be either a Stress can cause a variety of different colourmetric test which changes colour if responses in different animals, increasing animals. One organisation has supported Read also: the test sample is corrosive or a 3D in vitro variation in results between animals and a PhD project developing a welfare * New methods for monitoring and skin model in which if the test article kills reducing confidence in the data produced. assessment framework for dogs, which has improving the welfare of laboratory dogs the cells within a defined time period it is Ensuring animals are fit and well, and been used to measure refinements. Some of * The National Centre for the Replacement, considered corrosive. The Skin Irritation test making sure all their behavioural needs are these resources have been made available Refinement, and Reduction of Animals in uses different commercially- available 3D in met reduces stress, reduces variation and in an NC3Rs resource on dog housing and Research vitro skin tissue models, however they are produces better quality data from fewer husbandry.
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Non-invasive dog model for bile Understanding behavioural needs * Enhance dog well-being by organising collection (Refinement) of pigs and dogs to improve welfare periods of play with volunteer employees and produce better quality results who do not work routinely with dogs. A new dog model for non-invasive bile (Refinement) * Introduction of a new toy consisting collection has been developed. In vivo of small rubber tires for newly-weaned models for metabolite identification play Companies continue to apply refinements to minipigs. The tyre can hang from above an important role because they give an their animal care and welfare programmes, or simply be placed on the floor. The integrated picture of the total metabolic in the development of non- or less- invasive inside of the tyre can be filled with food fate and provide information on the extent techniques and also in considering the pellets making it even more interesting. of direct elimination of the unchanged drug. fate of animals at the completion of their * Older minipigs tend to show less In this context, a non-invasive dog model experimental life. interest in rubber toys, for them large ice for the collection of bile was established Companies also collaborate and share good cubes layered with ice, straw and chow in order to obtain metabolism data for practice to further enhance animal care diet keep them highly interested for potential drug candidates at an early stage ProgrammesCollaboration with consultant several hours. of drug development. The procedure used behaviourists helps enhance the use of * Development of a LABgility programme, until now for bile collection from dogs positive reinforcement training to refine for dogs and minipigs which is a includes surgical bile duct cannulation handling, restraint and technical procedures modified form of agility training. Like with a risk of infection and a prolonged in both dogs and pigs to better understand agility, animals negotiate different recovery period. The new model operates the behaviour of the animals and build an obstacles to enhance their intelligence with a commercially- available device that is enhanced and specific training regime for and agility”. Enrichment plays a vital applied in humans for non-invasive sampling animals prior to studies. This consistent role in reducing animal boredom and of upper gastrointestinal content. With this approach to training has refined greatly enhancing their well-being in what is model the laparotomy could be replaced by procedures and has had a positive impact on inevitably a restricted environment. a non-invasive procedure involving no pain animal welfare: LABgility was developed and is tailored and no recovery times. to meet the special needs of laboratory
8 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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animals, with a focus on body awareness, and ultimately to improvements in animal coordination and flexibility with the welfare. Whilst recognising the individuality aim of providing physical and mental of each facility, the participating CROs stimulation, promoting the animal- valued, for example, the opportunity to human relationship, where the level of discuss the welfare needs of primates within excitement is controlled. This ensures a laboratory setting or to benchmark their that animals do not over stimulate procedures with similar laboratories. By and the training of basic behaviours is respecting each other’s positions, the group maintained, such as sit, walking on the was able to identify ways in which they leash etc., to refine animal husbandry, could further refine animal and technician handling and experimental protocols. welfare at their respective facilities, for * Introduction of a dog rehoming example, positive reward training or sharing programme, which allows dogs above details of protective clothing used during a certain age to lead a life embedded procedures. By developing a peer-to-peer in a family. Prerequisites for rehoming expert network the group demonstrated the of animals include the careful selection commitment and passion for animal welfare of animals with regard to their health within the contract research industry. and behavioural attitudes as well as the careful selection of the new owners.
Open dialogue amongst CROs leads to improved animal welfare (Refinement)
Open dialogue and a strong commitment to animal welfare amongst several CROs led to sharing knowledge and expertise
9 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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Science and technology drive 3Rs and welfare We invest continuously in changing research paradigms
Impact of science and widely and have now been adopted within technology European regulations for PBT assessments.
Replacing animal tests in persistent, Introduction of a fully automated system bioaccumulation and toxicity studies of to perform behavioural tests decreasing chemicals (Replacement) stress on animals and making results more reliable (Refinement) In collaboration with academic scientists, better test methods were found to assess Behavioural analyses in animal disease models Persistence, Bioaccumulation and Toxicity are a major challenge for the development (PBT) studies required for the environmental of new drugs. Besides being time consuming registration of all chemical products. and labour intensive, first and foremost Advanced in vitro or other tests not using behavioural tests are heavily observer- and vertebrate animals allow for a more environment-dependent, and frequently realistic assessment of chemical properties stressful for the animals making results from and propensity to degrade, meaning less behavioural analyses often inconclusive, due compounds progress through reliance on to high variability, lack of reproducibility, animal tests, sparing thousands of fish from and limited validity towards the investigated the high severity tests. Through scientific behavioural phenotype. publications, communications and training workshops these new tests are available
10 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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The OptiMan (Operator-independent Motor backward translation of these findings, to model for inflammatory bowel disease led the study showed a high correlation between analysis) System has been designed to improve animal models. Furthermore, the non- to a reduction of animals in drug research. colonoscopy as a gold standard in clinics and overcome these issues by means of a fully- invasive nature of imaging leads to a major Here, imaging helped to reduce the MRI. automated behavioural testing system for reduction in the number of animals used. number of animals by two-thirds, including rats. It combines three manually-operated An example is a recent in-house-established colonoscopy and MRI exams. The findings in Human skin models as replacements behavioural tests into the fully automated to animals for understanding skin platform. Thus addressing key shortcomings of infections and mode of action of vaccines conventional behavioural readouts in animal (Replacement) research and contributing to improving animal welfare by reducing stress and animal use by Human skin equivalents and skin explants limiting variability. from clinical samples represent a valid alternative to animal models for studying skin Advancements in use of non-invasive infections and the mode of action of vaccine imaging technologies (Refinement and formulations. Generally, skin equivalents are Reduction) amenable to extensive manipulation, whilst explants provide a closer representation of During the last decade, some companies have the human skin. Both models have been fostered the implementation of non-invasive characterised extensively and data generated imaging technologies like MRI, US, CT, SPECT, suggest that the skin equivalent closely PET and optical imaging into animal studies resembles human skin characteristics. The two covering a broad range of applications. Non- models have been used successfully to study invasive imaging offers the unique opportunity host-pathogen interaction of Staphylococcus to observe and measure anatomical, aureus. pathological and metabolic changes within the same animal over time. This helps to refine animal experiments by getting a better understanding of the human pathology and
11 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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Supporting R&D for better science and more welfare – examples of national and European initiatives supported and/or funded by industry
Collaborations funding work on 3Rs in Berlin prize for 3R research pharmaceutical safety testing The German pharmaceutical industry trade The British pharmaceutical industry association (VFA) and some of its member trade association (ABPI) has an ongoing companies, in collaboration with the local collaboration with the UK National Centre for animal welfare consortium, are funding the Replacement, Refinement and Reduction the Berlin prize for 3R research. The prize of Animals in Research (NC3Rs), which is now focusses on 3R methods/projects developed/ in its 11th year. The collaboration, funded located in Berlin and Brandenburg (academia by ABPI members, supports a programme and industry). The winner project receives a manager working on disease models, efficacy monetary award for further work to lead to a and safety assessment. The collaboration reduction in animal numbers. The award for has been extended to support an additional 2015 was for the development of cell-based programme manager post for a two-year assays to measure botulinum neurotoxin period, working on activity. 3Rs in pharmaceutical safety testing. The extension of this highly-productive collaboration demonstrates the ongoing commitment of the UK industry to work collaboratively to address challenges and bottlenecks in the application of the 3Rs to the development of new medicines.
Read more here.
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Innovative Medicines Initiative - world’s are contributing to a better understanding of Resources: A drug and disease model library experimental models, human volunteers largest public-private partnership in the the challenges faced in using animal models will be developed, as well as modelling and and clinical data of pain life sciences driving animal welfare and and what impact their results are having on simulation solutions for better prediction ◊ IMIDIA - Improving beta-cell function 3Rs the use of laboratory animals in research and the reduction of animals used and identification of diagnostic biomarkers and development. Through the unique ◊ EBiSC - European Bank for induced For treatment monitoring in diabetes: The Innovative Medicines Initiative (IMI) is approach and collaborative platform of IMI, pluripotent Stem Cells: iPS cells help to pancreatic β-cell line for drug efficacy a public-private partnership between the the 3Rs are addressed on multiple different reduce the use of animals in research. testing in diabetes R&D as well as for a European Union and EFPIA. IMI is pursuing levels such that the selection of models to ◊ EMTRAIN - European Medicines preclinical model for cell replacement the goal of developing the next generation be tested, protocols to be followed and the Research Training Network: pan-European therapy of vaccines, medicines and treatments by interpretation of results generated are being platform for education and training. In this ◊ iPiE - Intelligent Assessment of improving research practice; getting new optimised, reducing the use of animals overall. framework SafeSciMET - European Modular Pharmaceuticals in the Environment: based healthcare solutions to patients faster; and Examples of such projects from the 100 Education and Training Programme in on existing data help identify which ‘legacy’ improving health outcomes thanks to new project IMI portfolio include: Safety Sciences for Medicines: implements APIs are most likely to pose a risk to the tools, methodologies, research infrastructure training for a new generation of safety environment and so should be prioritised and big data. ◊ ABIRISK - Anti-Biopharmaceutical specialists for testing – reduction of overall number of Immunisation - Prediction and Analysis of ◊ eTOX - Integrating bioinformatics and animals used Established in 2009, and further expanded in Clinical Relevance to Minimise the Risk: chemoinformatics for the development ◊ MIP-DILI - Mechanism-Based Integrated 2014, the IMI consortia (involving industry, develops tools for determining patient of Expert systems allowing the in silico Systems for the Prediction of Drug-Induced academia, SMEs, patients, regulators, etc.) response directly, i.e. without the use of prediction of toxicities: combination of this Liver Injury: develop new tests that will help have a direct or indirect impact on the use animals knowledge will enable them to create more researchers detect potential liver toxicity, of animals and IMI projects are contributing ◊ COMPACT - Collaboration on reliable computer models including combinations of non animal enormously to the 3Rs. the optimisation of macromolecular ◊ EU-AIMS - European Autism models IMI successes have brought results in 3Rs pharmaceutical access to cellular targets: Interventions - a Multicentre Study for ◊ NEWMEDS - Novel methods leading or new research paradigms (different ways sets up sophisticated in vitro models of Developing New Medications: construct for to new medications in depression of addressing scientific challenges) or more biological barriers and appropriate animal the first time cellular models of ASD with and schizophrenia: develop improved predictive testing tools that do not require – models to identify and exploit novel construct validity experimental models that mimic or require fewer – animals by removing from cell pathways for effective delivery of ◊ EUROPAIN - Understanding chronic schizophrenia or depression in humans pipelines harmful molecules before animal biopharmaceuticals pain and improving its treatment: elucidate ◊ Pharma-Cog - Prediction of cognitive studies are conducted. IMI funded projects ◊ DDMoRe - Drug Disease Model the mechanisms of pain, using novel properties of new drug candidates for
13 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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neurodegenerative diseases in early clinical to develop and validate quality testing After a first decade, during which the EPAA development: development of experimental approaches for both human and veterinary started to deliver tangible results (see 2015 human models for the study of drugs vaccines using non-animal methods activity report), the Commission and the ameliorating cognitive impairment industry decided to prolong the partnership ◊ Predect - New models for preclinical In 2015, IMI launched several new calls for for the new five-year term. evaluation of drug efficacy in common solid proposals with new topics with 3Rs impact, tumours: focus on complex but transferable such as translational imaging methods in ◊ In 2015 and 2016, the pharmaceutical next generation in vitro and in vivo models safety assessment or quantitative systems sector led the industry delegation at the ◊ PreDiCT-TB - Model-based preclinical technology. In 2016 additional topics with Steering Group. development of anti-tuberculosis drug direct 3Rs impact were launched such as on ◊ EFPIA and its members play important combinations: in silico modelling for data quality and reproducibility in Central roles on the EPAA Project Platform focusing the prediction of efficacy of novel drug Nervous System research or on preclinical data their work on skin sensitisation, vaccines regimens for tuberculosis sharing. and other biologicals as examples. ◊ SAFE-T - Safer and Faster Evidence- ◊ A successful project identified based Translation: focus on measuring sets Approaches to Animal Testing – from differences in legal requirements for of safety biomarkers across a variety of bench to industrial application vaccines testing between different regions patient populations (Europe, US, China, Japan, Brazil, etc) and ◊ STEMBANCC - Stem cells for biological EFPIA and a number of its members are brought together regulators from these assays of novel drugs and predictive founding members of the EPAA (European regions to align views on usefulness of toxicology: supply of cells that mimic more Partnership for Alternative Approaches alternatives to four safety tests and kick accurately what happens in the human to Animal Testing) – a cross-sectoral and off actions to remove obsolete tests from body multidisciplinary partnership between national and international guidance. Two ◊ U-BIOPRED - Unbiased biomarkers five European Commission services and in vivo safety tests were recognised as for the prediction of respiratory disease seven industry sectors. The mission of obsolete by 12 regulators from 4 regions outcomes: will be linked to results of the EPAA is to promote 3Rs in regulatory who committed (and started the relevant preclinical models, in order to facilitate testing, and facilitate the development and processes) to kick off deletion in European future drug development implementation/regulatory acceptance of Pharmacopoeia, WHO and OIE guidelines, VAC2VAC – Vaccine batch to vaccine batch alternative testing strategies. and national legislation as appropriate. comparison by consistency testing: aims
14 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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Staff training is an essential element of good science and good welfare
Training courses external experts in this field. The goal was to assess technology and scientific strengths and To further strengthen the knowledge sharing weaknesses, as well as practical applications and application of global standards, a global and future roadmaps within the field of laboratory animal sciences course is provided in silico toxicology. Several examples were at all sites and covers animal ethics, 3Rs provided of how in silico modelling provided considerations in research, as well as rules/ useful alternatives to in vivo testing and in regulations (company policies, local laws and some instances, impacted the design of future the EU Directive), welfare and husbandry. safety studies.
Workshops
In silico (or computational) toxicology is a sub-discipline of toxicology that uses data and mathematical/statistical modelling to generate knowledge. A workshop was held in one company, which included both internal and
15 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
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Dissemination beyond own department and own establishment drives improvement in welfare and general quality of science.
Determining the most effective Sharing experiences to improve anaesthesia for fish (Refinement) knowledge on compound administration in minipigs (Reduction) Fish are used to assess the potential impact of new medicines on the environment, but Minipigs are increasingly being used in pre- surprisingly little is known about appropriate clinical testing as an alternative to dogs. anaesthesia in fish. For some studies, fish need To administer compounds in fluid form, a to be anaesthetised to minimise pain and vehicle (compound suspending agent) has distress. This is done by flowing anaesthetic to be identified. The vehicle needs to have a into the fish tank. However, some chemical good safety profile, showing little or no side substances in the water can be unpleasant effects for the intended species. However, only for the fish. A study has shown that zebrafish few vehicles are cited on publically available detect and actively avoid seven of nine databases for use in mini-pigs. A collaborative most commonly used anaesthetics, however project was conducted with the purpose of Etomidate appears to be the most effective summarising the experience of numerous anaesthetic. Industry has shared this work laboratories in a review paper. The paper through publication and is working with other reports tolerability and compositions used laboratories and groups to broaden the use of in minipigs for dermal, oral, subcutaneous Etomidate in work with adult zebrafish. and intravenous routes of administration.
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By sharing these data, testing of inadequate knowledge within the 3Rs. Some companies Exploring changes with using 3Rs in safety encouraging and highlight the advances the formulations and studies to qualify these also help sponsor external 3Rs awards e.g. assessment over the past 30 years pharmaceutical industry has made in this area. vehicles in minipigs can be minimised or NC3Rs, IQ/AAALAC e.g. in the first year of This also builds on a previous publication avoided, thereby contributing to reduced the IQ/AAALAC awards, scientific papers from A peer-reviewed study was published exploring showing the pharmaceutical industry is animal usage. Switzerland, the United States and Brazil were how the use of in vitro alternatives in the increasingly working in collaboration on 3Rs chosen. safety assessment of new medicines has research. Driving 3Rs within pharmaceutical changed over the last 30 years, to determine companies (Refinement, reduction and Rehoming Policies patterns, drivers and challenges in uptake. replacement) The British Pharmaceutical Industry Trade Read more: Some companies have rehoming policies. Association conducted a survey looking at how * Development and use of in vitro alternatives Some companies have established 3Rs Prerequisites for rehoming of animals include many in vitro assays were used in different to animal testing by the pharmaceutical departments or introduced 3Rs leaders in order the careful selection of animals with regard to areas of safety assessment between 1980 and industry 1980–2013 to take a more strategic approach to driving their health and behavioural attitudes as well 2013. Responses were collected from four * Quantifying the pharmaceutical industry’s 3Rs innovation within their company. as careful selection of the new owners. For pharmaceutical companies and three contract contribution to published 3Rs research Many companies run an annual 3Rs award example within the framework of the « live research organisations. There was a large and 2002–2012 process often with external judges included. saving products » production the use of horses steady increase in the use of in vitro tests by These awards not only recognise and reward is required as plasma donors. At the end of companies between 1980 and 2013; more innovative new science that has 3Rs benefit, their donor “career”, these horses cannot be than 20% of all in vitro tests reported were as well as care and welfare, but also help re-used. As the horses are often healthy young conducted in 2013, the last year of the survey promote the importance of the 3Rs in animal and well socialized, rehoming is conceivable. period, and over 70% were conducted since research within individual companies. These To study the feasibility, a partnership with the 2010. In vitro assays were most widely used in awards are often recognised at the most senior GRAAL association (Group of Reflection and genotoxicity, safety pharmacology, and drug levels within companies. Actions for Animals: an animal protection metabolism studies. The survey highlighted association involved in rehoming program of periods of step change in the uptake of in vitro Many companies enter into collaborations animals used by the biomedical research) was assays, which may have been linked to the (e.g. with other stakeholders such as national set up. This project permits horse lovers to adoption of relevant international guidelines 3Rs centres/ platforms) to share and gain adopt young and healthy horses. or EU legislative decisions. These results are
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Leading by Example
Full and correct implementation of Directive 2010/63/EC on the protection of animals used for scientific purposes is the responsibility and endeavor of the whole scientific community
Activities of EFPIA and its good practice and recommend a course this, a workshop was organised bringing also work closely with the EU institutions and members of action to enable progress. The recent together numerous people who had views on have participated in the European Parliament’s 2 workshops focused on ‘Enhancing 3Rs implementing a Culture of Care in a “thought- Intergroup for the Welfare and Conservation of EPFIA and its members remain committed to provisions’ and on ‘Culture of Care’. The first starter” workshop. animals. full and correct implementation of Directive mentioned workshop led to the discussion * Guidance and trainings: To ensure proper * Scientific input: The European Commission 2010/63/EU and enhance the cultures of care, evaluating opportunities to enhance the implementation of the provisions laid out in will report in 2016 on the impact of Directive challenge and openness for research involving implementation of selected welfare and 3Rs the Directive, it is essential guidance is taken 2010/63/EU in advancing the 3Rs and welfare animals. They have undertaken numerous provisions of Directive 2010/63. up, best practices are shared and trainings of animals and creating level playing field. activities on this regard recently: * Culture of Care: Establishing, promoting take place. EFPIA are recognized expert The Directive is delivering benefits for animal and maintaining a good ‘culture of care’ is stakeholders by the EU institutions and have science in Europe, which remains critical * Supporting Directive 2010/63/EU: a fundamental requirement if legal, ethical been involved in numerous expert working for the discovery and development of new EFPIA and its members signed the statement and animal welfare obligations, along with groups organized by the Commission. These medicines. Given the state of science, and supporting European Directive 2010/63/EU wider responsibilities towards employees working groups have led to the development importance of ensuing animal welfare, access (“Directive”) on the protection of animals used and the public, are to be met. Defining of endorsed guidance documents which EFPIA to medicines, and retention of biomedical for scientific purposes following the European culture of care across Europe remains diverse. and its members support and promote. Further research and drug development in Europe, Citizen’s Initiative Stop Vivisection which was In early 2016, the EFPIA Research and to this they support trainings for example on EFPIA do not recommend amendments to seeking to repeal the Directive and ban animal Animal Welfare Working Group started a understanding and implementing severity the directive at this stage. Attention should research. The Directive is vital to ensure that reflection on the concept of culture of care assessment of animal tests correctly. remain focused on properly implementing and necessary research involving animals can (referred to as ‘climate of care in recital * Joining forces: EFPIA remains open to a enforcing the current Directive, advancing the continue whilst requiring enhanced animal 31 of the Directive and covered in most of constructive dialogue and engagement of 3Rs, and delivering on the concrete actions welfare standards. (read more) the guidance documents developed) and all stakeholders who are committed to share identified at the Commission’s recent scientific * Working with the User community: how it is understood and applied across experiences and expertise on the requirements conference on ‘non-animal research – the EFPIA organizes annually “users workshops” research institutions/companies in Europe and laid out in the directive and disseminate these way forward, which EFPIA and its members to allow experts from industry, academia and conducted a survey that offered insights into in best practices. Consortia have been formed attended and provided expertise. research funding organisations to exchange good practice and areas for improvement with diverse stakeholders on focusing on within the user community. Following areas to bring about positive change. EFPIA
18 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
Beyond Compliance Leading by Example Open Communications
Practice Science Training Sharing Enforcing Dialogue Reporting
Leading by Example
Global collaborations has been the global regulatory agreement for a suitable harmonized replacement test. An Directive 2010/63/EU sets a high scientific International Working Group for Alternatives to standard of good quality science, good animal HIST was formed in 2010 involving regulators, welfare and implementation of the 3Rs as a control laboratories, industry, 3Rs groups (6 bench mark for global harmonization. There workshops, 2 collaborative studies). This finally are a number of challenges with regulatory culminated in consensus at a workshop in requirements differing internationally, making 2015 that a modified in vitro cell approach was global collaborations necessary to lead towards an acceptable alternative. This method have improved animal welfare and implementation been very recently optimized and validated. of 3Rs: Worldwide laboratory animal population, this could prevent undue suffering and death to an Replacing batch testing of animals for estimated 84,000 mice every year. quality control safety testing of vaccine Cell lines to replace animal use for Polio Currently, regulations worldwide require vaccine that acellular pertussis vaccines are tested in mice to ensure the safety of every batch, The Polio Eradication plan engages all 145 and especially the lack of residual toxin countries that currently use OPV Oral Polio (HIST test). HIST tests have been employed Vaccine in their routine immunization for quality control safety testing of pertussis programs. It includes the introducing at least 1 line L20B (full in vitro model) for the control critical test for ensuring the safety of the IPV. combination vaccines for many years. The dose of Inactivated Polio Vaccine IPV into the IPV inactivation. The current IPV inactivation This project initiated 15 years ago encountered level of distress of these tests are considered routine immunization schedule globally and test is used since 1959, the beginning of the many challenges: adherence to the new as severe, using large numbers of mice with a ultimately stopping OPV use in 2019-2020. The IPV manufacture. This test has been critical method worldwide except in US&CA who lethal endpoint. A lot of work was done on in kidney cells from monkeys were used to ensure all along the history of the IPV since the requested additional evidences of equivalence. vitro alternatives since the early 2000s in close the full inactivation of the vaccine doses. Cutter incident in US (lack of reliability of the collaboration with national control laboratories The goal of the project was to replace cells inactivation test & process causing 204 cases Read more: and regulators. The most challenging aspect from monkeys by cells from a continuous cell of polio and 11 deaths in 1955). This test is the Polio Global Eradication Initiative
19 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
Beyond Compliance Leading by Example Open Communications
Practice Science Training Sharing Enforcing Dialogue Reporting
Open Communications
We tell what we do and engage in open dialogue with interested parties.
Openness on animal research public dialogue. This includes expanding their the housing of different species and learn this project for years. The Basel Declaration Animals in Research materials, explaining how about the multiple efforts of Swiss industry to Society organizes an international congress Over 100 UK companies are signatories and why animals are used in the development enhance the 3Rs in daily practice. every two years. In 2016 it was held in Rome to the Concordat on Openness on Animal of new medicines, examples and descriptions at the beginning of October. The venue was research. They have hosted open days for of projects involving animals including the Transatlantic publications specifically chosen because the research staff and family, community science fairs harms to the animals, and examples of how community had recently had to battle with and visits around their facilities. In addition the 3Rs are applied. They also produced EFPIA members contributed to a special edition radical opponents of animal experiments they have contributed to blogs externally a Members’ Guide to the Concordat on of the Journal of the American Association for who, amongst other things, had destroyed on 3Rs award process and progress towards Openness on Animal Research, highlighting Laboratory Animal Science (JAALAS) focusing at a stroke many years of research on mental openness to ensure greater transparency and examples and advice to support our member on the 3Rs. disorders. The main focus of the congress understanding of animals used in research. companies in being more open on this topic. discussed how the research community was The Basel Declaration Society to cope with such attacks and how the public Read more: Read more: can be better informed about the benefits of * Great progress in openness on animal * Members’ guide to the Concordat on The aim of the Basel Declaration Society is animal experiments both in basic research and research Openness on Animal Research in the UK to reinforce the public’s trust in biomedical in applied research. The discussions considered * Recognising and rewarding 3Rs research when using animal experiments, to how to deal with misinformation on animal developments at AstraZeneca Visits to research facilities foster communication between researchers experiments, what strategy to adopt in the and the public and to increase acceptance of event of a crisis and how transparency can Disseminating an encouraging openness To enhance the communication and the Basel Declaration. Like the Declaration of be improved on the subject of research with on work using animals transparency of the industry with policymakers Helsinki, in which the basic ethical principles of animals. from Switzerland and abroad, member clinical research in humans are formulated, the The British Pharmaceutical Trade Association companies offer policymakers from Bern and Basel Declaration Society aims to help ensure has undertaken a number of activities to be, Brussels the opportunity to visit their facilities that ethical principles such as the 3Rs are and to support and encourage our members in Basel. In 2015 several of these visits took applied in research using animal experiments to be, increasingly open about their use of place. Members of the European Parliament worldwide. Interpharma and two member animals in research, to facilitate informed and their staff had the opportunity to see companies have provided financial support for
20 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
Beyond Compliance Leading by Example Open Communications
Practice Science Training Sharing Enforcing Dialogue Reporting
Open Communications
Communicating progress made in animal welfare activities
In addition to participating in international events and platforms, the pharmaceutical industry is communicating on the 3Rs through Corporate Social Responsibility (CSR) reports. Each pharmaceutical company has a website where CSR reports are available. A dedicated section on animal welfare and the 3Rs are included in these reports. A few examples can be found here:
* AstraZeneca * GlaxoSmithKline * Interpharma * Novartis * Novo Nordisk * Merck * Sanofi * UCB
EFPIA have produced three previous reports on Putting animal welfare principles and 3R into action since 2011 (available on EFPIA’s website). Furthermore, some of its member companies produce their own annual 3Rs report illustrating industry’s commitment to applying the 3Rs principles in animal research and to enhancing scientific advances leading to the implementation of one of the 3Rs.
21 PUTTING ANIMAL WELFARE PRINCIPLES AND 3Rs INTO ACTION - European Pharmaceutical Industry Report - 2016 Update
Beyond Compliance Leading by Example Open Communications
Practice Science Training Sharing Enforcing Dialogue Reporting
Useful Links
Accreditation of Laboratory Animal Care International (AAALAC) - www.aaalac.org
Alternatives Approaches to Animal Testing (EPAA) - www.ec.europa.eu/growth/sectors/chemicals/epaa_en
European Centre for the Validation of Alternative Methods (ECVAM) – www.eurl-ecvam.jrc.ec.europa.eu
European Commission - www.ec.europa.eu/environment/chemicals/lab_animals/home_en.htm
Federation of Laboratory Animal Science Associations (FELASA) - www.felasa.eu
Innovative Medicines Initiative (IMI) - www.imi.europa.eu
Institute for Laboratory Animal Research (ILAR) - www.dels.nas.edu/ilar
National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) -www.nc3rs.org.uk
3R Foundation - www.forschung3r.ch
For more information, contact
Kirsty Reid, Manager Science Policy and Animal Welfare [email protected] Magda Chlebus, Director Science Policy [email protected]
Photos have been sourced from a number of sources, including EFPIA and Understanding Animal Research. EFPIA would like to thank the members of the EFPIA working group on Research and Animal Welfare for the valuable contributions to this report. June 2017
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