significant concerns no or very low predictive power

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2 Your feedback Citizens concerns should be considered How to ensure ethical concerns are harnessed to drive change? Don t separate Non-animal and animal approaches they are integrated Avoid overstating results Need integrity on both sides of the debate We can all identify something to work on Funders, researchers and journals to come together and create the right incentives and sticks Designate 2020 as the year of systematic reviews Alternatives available to male white speakers

3 Session 1 Animals are still necessary to understand basic physiology and pathophysiology, and to reproduce cause and biology of disease But there are significant concerns over how animal research is designed and how data is analysed Some analysis shows that experimental animals have no or very low predictive power of drug effects in humans

4 Session 1 Recommendations Conduct a thorough gap analysis of alternatives that are still lacking Improve study design and data analysis (also for non-animal studies) Invest higher proportion of funding in non-animal alternatives Need for systematic use of ARRIVE guidelines Scientific peer review of methodology before starting the project Need to publish negative results systematically - start with all publicly funded studies using animals More human testing using cell-based systems or humans on a chip? Support conclusions by evidence More standardisation, e.g. in design, analyses, statistics and publication Funding should be dependent on quality of process, not just results

5 Session 2 Human cell based models and organs on a chip have great potential, but still need an in vivo test to confirm if 3D cell simulation reflects in vivo Repeated dose toxicity and repro or developmental toxicity still a challenge Human genomics helps to use animal models wisely, and reduce use of larger species. Targeted gene editing of animal helps to exactly model a human disease Safety studies to investigate severe adverse effects could be replaced by in vitro methods Metabolism info and computer modelling can help bridge differences between species

6 Session 2 Recommendations Need a coordinated research strategy / agenda (more top down, like the US). When identifying which animal model is useful, a metaanalysis by a large consortium could be useful Short-term: use more in-silico predictions and in vitro cell systems Long-term: human-on-a-chip model of choice Still need more research into tissue biology: we don t understand cell interactions well enough yet Development of patient DNA databases for research purposes

7 Session 3 Need a paradigm change, moving away from 1:1 replacement of animal test with a non-animal one to integration of information and prediction of human effects Could it help to set a date when animal testing for environmental and safety testing should be phased out? One forecast from the USA predicts animal testing could be phased out in certain areas in 10 years Regulators and scientists should work together more More international organisations should be involved in the cooperation, e.g. WHO International acceptance of alternatives is paramount Need for political will

8 Session 3 Recommendations Need to carefully map uncertainties with animal tests Need to define how an adverse reaction in an organism can be defined at organ or cellular level Regulators globally need to agree on acceptable risk Revisit regulatory information requirements Need a new baseline and classification systems to 'validate' new methodologies Wider engagement on validation frameworks Need a new, collaborative approach between all players Veterinary vaccines: animal tests for safety should be deleted from pharmacopoeia

9 Session 4 Many knowledge sources exist, but lack of coordination and connection and no quality control Information written by and for science experts, often not for broad user base information needed for citizens New info not reaching approvers, funders & company owners fast enough There is enough money to share knowledge, just need to coordinate its use! Could the Commission help? Data repository and encouraging publication of negative data. Who can house and maintain the repository? Attitude is important in education & training, with the right attitude you'll find the right alternative

10 Session 4 Recommendations Need 1-stop-shop with information on which alternative is accepted by which regulatory authority Make regulatory jungle more accessible for companies Need more Member State support e.g. through National Committees Reinforce 3Rs in publications, especially refinement Need to assess quality of knowledge and agree on standards

11 Session 5 Need to understand and then remove bias in publications and reporting Embedding and ensuring implementation of ARRIVE guidelines throughout whole process Experimental Design Assistant resource Editorial policy should encourage re-use of data and transparency

12 Session 5 Recommendations Peer reviews should not be anonymous The value of Science Media Centres Need different ways to assess research and researchers Journal review panels should involve more people with experience in NAMs Include ethics in the review process Withhold last part of funding until research is published

13 Session 6 Need for cultural change Metabolomics will provide knowledge to support toxicity prediction Metabolomics will need greater international harmonisation Multi-organ chips offer possibility for mode of action, safety assessment and disease modelling

14 Session 6 Recommendations Need to harmonise these methods Must validate methods like humans on a chip Develop international guidelines for metabolomics in regulatory toxicology Conduct large scale project to demonstrate proposed strategy for risk assessment Need to change the way we measure impact

15 Session 6 / part 2 Non-invasive imaging Non-invasive imaging can help reduce animal use and offer new ways of demonstrate treatment efficacy Molecular imaging can link live cell systems with animal and with human models to increase research quality and efficiency

16 Session 6 / part 2 Stem cells Adult stem cells recently can be reprogrammed to form any cell of our body (induced pluripotent stem cells), and organoids as model of our organs can be built Such organoids are useful for safety pharmacology, drug repurposing and development of new drugs FDA is adopting this type of assay for safety pharmacology of heart drugs (CiPA initiative 2017) Limited availability of human model systems for pre-clinical research, need for human organ models for toxicity screening and safety pharmacology: - organs on chip from induced pluripotent stem cells can fill that gap, can be used already to model asthma or intestinal diseases or be used to study toxicity from e.g. nanoparticles - brain on chip built from stem cells of patients have huge potential to study complex neurological diseases Still impossible to model with stem cell models: pharmacokinetics, reproductive toxicology, effects on cognition Only need for animals in stem cell research is still in stem-cell therapy of human diseases

17 Session 6 / part 2 Virtual Physiological Human Animals (as well as in vitro models) are only models! Need to establish analogy with the human. Need to be clear about assumptions of the model. Laboratory test combined with imaging information can be used to model effects in humans that cannot be directly measured. Virtual Physiological Human can replace preclinical animal models

18 Recommendations Patients perspective: need to keep the research machinery running to develop cures for many rare diseases, if possible with nonanimal methods of course. Regulatory requirements need to adapt to allow human testing faster where risk is acceptable (e.g. diseases without cure today)