Pursuing alternative approaches to animal models in drug development: EMA innovation task force and scientific advice opportunities

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

A major nonclinical regulatory science research need identified by the European Medicines Agency (EMA) is the establishment of novel pre-clinical models, including new models for assessment of safety of the predictivity of advanced therapy medicinal products (ATMPs).¹   

• EMA has significantly expanded its actions and regulatory considerations recently regarding alternative nonclinical testing models in medicines development. These include: 
• Encouraging and prioritizing use of novel pre-clinical models as a key innovation action in its European Medicines Agencies Network Strategy to 2025²  
• Highlighting the identification of alternatives to the use of nonhuman primates and promoting acceptance of animal-free innovations as strategic goals in the 2023 Consolidated 3-year Work Plan for the Non-Clinical Domain³  
• Describing the potential of artificial intelligence (AI) and machine learning (ML) modelling approaches to replace, reduce, and refine the use of animals for ADME and toxicity testing in the 2023 Reflection paper on the use of Artificial Intelligence (AI) in the medicinal product lifecycle⁴  
• Recent EMA webinars held to discuss alternatives to animal testing 

Both EMA and the European Commission strongly support the implementation of the 3R principles (replace, reduce, and refine) which encourage alternatives to the use of animals.^5,6 According to the Directive 2010/63/EU⁷, in order to increase competitiveness of research and industry in the European Union (EU) and to replace, reduce and refine the use of animals in procedures, the Commission and the Member States should contribute through research and by other means to the development and validation of alternative approaches. This directive aims to protect animals in scientific research, with the final aim of replacing all animal research with non-animal methods. 

The EMA’s Innovation Task Force (ITF) encourages the prioritization and rapid integration of new approach methodologies (NAMs) into the regulatory framework for nonclinical drug development. Drug developers, and particularly those developing ATMPs, are encouraged to explore novel and non-animal assessments of their products’ effects.  

Alternative approaches to animal models 

New approach methodologies (NAMs): Alternative approaches to animal models, also known NAMs include improved tests based on human and animal cells, organoids, organ-on-chips, and in silico modelling. They provide opportunities for developers to work with more predictive scientific tools to protect human and animal health as well as the environment. AI and ML applications in non-clinical development aim to improve performance and robustness in data analysis but could potentially also include AI and ML modelling approaches to replace, reduce, and refine the use of animals.4 

Leveraging clinical data: When a product class has been studied extensively in clinical trials for a particular indication, there may be a strong case to leverage clinical data for a study product in that class when it is used for a new indication. This requires a biologically plausible, shared mechanism of action for the product class. In combination with in vitro data for the new indication, this could be used to reduce or eliminate the need for new animal data. 

Animal-based assays: It is well recognized in the EU that animal-based assays should be used as a last resort. For safety assays, some tests such as the abnormal toxicity test in mice, have been withdrawn from the European Pharmacopoeia, while in other cases more suitable in vitro assays are strongly encouraged and are being increasingly phased in. 

For assays testing potency or used for the characterization of a drug’s mechanism of action, in vitro assays have long been the preferred option, since animal-based assays tend to be inferior, at minimum in terms of precision and reproducibility. Despite these drawbacks, the use of an animal-based activity assay sometimes cannot be avoided, in particular for novel classes of drugs and during early development. In such cases, early engagement with EMA can help to identify the fastest acceptable options for phase and replacement out of animal-based assays in routine testing and characterization. 

Early advice for developers of NAMs 

• Secure briefing meetings with the EMA ITF 

Through the ITF, EMA offers dedicated support to micro, small and medium-sized enterprises (SMEs), academics and researchers to replace, reduce and refine animal use for the development, manufacturing and testing of human medicines. The ITF is a multidisciplinary group that includes scientific, regulatory, and legal competencies. For developers of NAMs, it provides an opportunity to discuss 3R-compliant methods and to facilitate their integration into the development and evaluation of medicinal products. By engaging with the ITF, NAM developers have a forum for early dialogue to discuss innovative aspects such as emerging therapies, methods, and technologies and to discuss the regulatory acceptance of new methodologies as alternatives to animal testing.  

• Seek EMA scientific advice (SA) on qualification of novel methodologies  

NAMs should be accepted at the regulatory level through a qualification process before being used in medicine development. NAM developers can seek CHMP Scientific Advice (SA) for qualification of novel methodologies for drug development. This EMA qualification process is a voluntary, scientific pathway leading to either a CHMP qualification opinion or qualification advice on innovative methods or drug development tools. The advice is based on the evaluation of the scientific rationale and the preliminary data submitted to the Agency. The output is a CHMP qualification opinion and scientific assessment (public document) or a CHMP qualification advice on future protocols and studies to be additionally performed for qualification purposes in the form of a confidential document. 

• Important considerations for EMA ITF and SA meetings: 
  • Ensure an informed position on the acceptability of available data and robust preparation of nonclinical documentation and submissions ahead of any meetings.   
  • Apply for an ITF briefing discussion meeting to facilitate informal exchange of information and guidance in the development process. These discussion meetings can complement and reinforce existing formal procedures such as advanced-therapy-medicinal-product (ATMP) classification and certification, designation of orphan medicinal products and scientific advice. 
  • If you are in early stages of development, new manufacturing methods, nanotechnologies, pharmacogenomics, treatments intended to tackle antimicrobial resistance (AMR), platform technologies for new medicines and digital technologies including AI/ML may all be viable routes to pursue.  

Parexel’s Regulatory Consulting experts partner with small to medium-sized pharmaceutical companies and academics who are working to implement NAMs as alternatives to animal testing. This includes technologies using human and animal cells, organoids, organ-on-chips and AI/ML. Our regulatory experts can help navigate the regulatory pathways and offer guidance about when to seek for EMA ITF informal discussion meetings (ITF Briefing Meeting) and when scientific advice for qualification opinion or qualification advice is more appropriate. We offer practical support for these meetings including applying, preparing documentation, drafting reports and guiding all processes to conclusion.   

Ready to discuss your alternative approaches to animal models? Our regulatory strategy experts are always available for a conversation. 

References 

1. https://www.ema.europa.eu/en/documents/other/regulatory-science-research-needs_en.pdf 
2. https://www.ema.europa.eu/en/documents/report/european-union-medicines-agencies-network-strategy-2025-protecting-public-health-time-rapid-change_en.pdf 
3. https://www.ema.europa.eu/en/documents/other/consolidated-3-year-work-plan-non-clinical-domain-including-priorities-2023_en.pdf 
4. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-reflection-paper-use-artificial-intelligence-ai-medicinal-product-lifecycle_en.pdf 
5. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-principles-regulatory-acceptance-3rs-replacement-reduction-refinement-testing-approaches_en.pd
6. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-providing-overview-current-regulatory-testing-requirements-medicinal-products-human_en.pdf 
7. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32010L0063 

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