The 1st CHIASMA Risk Assessment Summit was organised and led by CHIASMA’s regulatory science partner, the Medical University of Innsbruck (MUI), Austria. With the Summit, CHIASMA aimed to collect input on the current regulatory-science needs for the transition towards a sustainable, animal-free regulatory system and how CHIASMA can best contribute to this. Therefore, MUI reached out to regulatory experts from national and international regulatory agencies, OECD, and industry, as well as experts for method standardisation and validation, non-governmental organisations, and other experts for One Health, animal welfare, environmental, and human health protection. Furthermore, MUI targeted scientists working on Non-Animal Methods (NAMs), Next Generation Risk Assessment, Safe and Sustainable by Design, and Life Cycle Assessment, as well as social scientists working on the societal challenges for change.
For setting the scene, Georg Streck from the European Commission DG Grow explained the motivation and practical development of the European Roadmap towards, and animal free regulatory system. Ingrid Visseren-Hamakers from Radboud University (Netherlands) discussed the societal hurdles on this road. Andrew Worth and Joao Barroso, both from the European Joint Research Centre, presented the ongoing change management, including the collection of transitional scientific initiatives and the status of the OECD work on rendering the validation process for NAMs more efficient and effective.
These introductory talks were followed up by Tommaso Serchi the CHIASMA Coordinator, from the Luxemburg Institute for Science and Technology (LIST), explaining which new NAMs are being progressed and pre-validated in CHIASMA. Finally Roland Hischier from EMPA in St. Gallen (Switzerland) and Martin Paparella from the Medical University of Innsbruck (MUI, Austria) outlined CHIASMAs Next Generation concepts for a NAM based risk-, life cycle- and safe & sustainable by design assessment.
Building on this thought stimulating introduction, breakout groups were formed, discussing three questions:
- What are the further needs for CHIASMA’s experimental method validation? (chaired by Pamina Weber, LIST)
- What are the further needs for the advancement/specification of the NGRA & LCA? (chaired by Martin Paparella, MUI and Roland Hischier, EMPA)
- What are the societal hurdles for the reduction & replacement of animal tests and how could CHIASMA help to overcome them? (chaired by Angela Barth, HF partners)
From the summary reports of the break out group chairs and the subsequent plenary discussion (chaired by Steffi Friedrichs, AcumenIST, BE) the following main take home messages were extracted:
1. Further Needs for experimental Methods Validation
The RA summit supported the CHIASMAs validation strategy as a FAIR, modular, step-wise generation of data for assessing the NAMs relevance and reliability, including lab-transferability. It was noted that also the training of new colleagues is part of the achievements of any transferability assessment and the related discussions can improve the SOPs, including the identification of SOP elements that need more or less specification so support both, low data variability as well as practicability.
However, NAM validation work is resource intensive and cannot be easily covered by research projects like CHIASMA. Further collaboration between industry, contract research organizations and policy makers are needed to support the continued funding needed in the field.
To ultimately agree on a sufficiently comprehensive set of NAMs for regulatory purposes, a common understanding is needed of whether NAMs addressing key events (KEs) at the cellular level are likely to be more conservative than animal tests, considering only the cell biology and AOPs covered by the KE-based NAM testing. Upon reaching consensus on this understanding , the discussion can move towards the question of which model combination provides sufficient coverage of relevant biology and mechanisms. Notably, high model complexity, like multi-organ-on-chip models, may not be the optimal goal, since one specific complexity may not necessarily represent real world biological variability and the testing throughput is more limited. Moreover, testing many chemicals with a limited number of biological models and mechanisms may be more comprehensive in terms of environmental health protection compared to the current approach to test few chemicals with a possibly more comprehensive but still uncertain animal testing strategy.
It was also noted that full biological and mechanistic coverage is neither practically possible nor necessary for the following reasons:
- full biological and mechanistic coverage can neither be achieved with animal methods,
- functional readouts differ between different cell types used in NAMs but early pathways are shared,
- focusing on providing safe doses or concentrations rather than predicting all possible organism level outcomes may be sufficient for effective risk management and
- covering extrapolation uncertainties probabilistically can effectively ensure protection goals.
2. Further Needs for the Advancement of the NGRA & LCA
For achieving such sufficient coverage, a tiered approach might be suitable. In silico methods including AI could serve as a first step, followed by increasingly more complex experimental NAMs. Yet, this requires an agreement on complex decision trees and on when an adequate level of protection or prediction is achieved. It might be more efficient to include more complex models into the first tier, like tissuelike in vitro models and including multi-omics readouts representing the major target organs, which might be more comprehensive and already conclusive as such. For any NAM-based IATA, an uncertainty characterization is needed, which shall be as quantitative as possible and consider uncertainties of the current animal-based system with an equal level of detail and attention, with the aim to help risk managers to make decisions on the acceptability of data.
Besides (eco)toxicological impacts in the future, societal and socioeconomic impacts shall also be assessed. The outcome shall be used by the industry for designing sustainable innovation and by regulators to consider them for future regulatory frameworks.
These expectations outlined in the RA summit are well covered with the CHIASMA strategy to develop case studies for a NAM based IATA including an enhanced uncertainty characterization.
However, based on the messages received within the RA summit, we will consider if CHIASMA could also address the cost- implications from IATA concepts with more or less complex/tiered decision trees, as indicated above. This may support the selection of the most efficient and practical approach(s). We will stay in dialogue and have a constant exchange with DG Grow and EURL ECVAM, considering also the notification system for transitional activities, to ensure efficient integration of our validation efforts with other ongoing activities for the roadmap towards the animal-free regulatory system.
3. Societal Hurdles for the Reduction & Replacement of Animal Tests (and how to overcome them)
Besides toxicologists, biologists, and other STEM researchers, social scientists demand attention and are included in the process to achieve regulatory acceptance of NAMs . To this end, there were a number of suggestions made to improve and complement the regulatory process:
- Recognition of different publics, such as consumers, citizens, and patients, is the first step to implement public engagement for the transition towards an animal-free regulatory system. Social scientists are necessary to accompany the process and stay in close interaction with STEM researchers.
- It appears that essential hurdles are often firmly established societal values and norms, e.g., a) on relationships between human to non-human beings, b) on freedom of science to research and economy to produce without societal agreement on the necessity of the product, c) on goals for health and safety. Related norms may be legally enshrined. Ideally, these values and norms would be governed by an honest policy for sustainability.
- The acceptable levels of safety, uncertainty, ethical implications, and public expenditure required to achieve these goals need to be discussed and agreed upon at the societal level.
- This requires a carefully tailored communication of scientific knowledge and probabilities with the public, while scientists need to understand and consider the potentially unintended effects of such system changes.
- However, readiness for change is driven much more by societal role models and personal interactions rather than recognition of scientific facts by a broad group of people.
- From all this the role of policy makers appears very important.
- Such understanding and learnings may be shared and mutually enforce action within different societal fields like the struggle for action against climate change.
For translating these messages received at the CHIASMA’s RA summit into action, CHIASMA will seek to identify synergies with societal scientists and their related projects, like SAFE. The output may be the identification of a specific pathway to societal acceptance of the CHIASMA results, which may include another workshop specifically targeting policy makers and scientists for a discussion of science-policy needs for the acceptance of NAMs.
