The future of drug development: Leveraging EMA support for use of alternative nonclinical approaches

A major nonclinical regulatory science research need identified by the European Medicines Agency (EMA) is the establishment of novel pre-clinical models to predict the safety of advanced therapy medicinal products (ATMPs).¹  More recently, the United States (US) Food and Drug Administration (FDA) also announced plans to promote the use of more clinically relevant approaches and phase out animal testing requirements during the development of monoclonal antibodies and other products.²

The EMA has already made significant strides to expand its actions and regulatory considerations regarding alternative non-clinical models in medicines development. These include: 

• Encouraging and prioritizing the use of novel non-clinical models as a key innovation action in its European Medicines Agencies Network Strategy to 2025³  
• Highlighting the strategic goals of the 3Rs Working Party (3RsWP) to support the qualification of new approach methodologies (NAMs) by way of the Scientific Advice Working Party (SAWP). In addition, the 3RsWP aims to develop a database of validated NAMs and ensure accessibility for all stakeholders as outlined in the EMA 2024 Consolidated 3-year rolling work plan for the Non-Clinical Domain⁴ 
• Providing access to proceedings from 3RsWP plenary meetings with stakeholders (including industry and trade associations) to showcase priorities to the upcoming year(s)⁵ 
• Drafting of ‘Reflection paper on the alternatives to the use of non-human primates (NHPs).⁴ to outline the key findings and recommendations for the industry
• Participating in `The International Medicines Regulators’ Working Group on 3Rs, to harmonize approaches which improve the predictive value and reduce the reliance upon animal studies.⁶ The working group includes regulators from the EMA, the Swiss Agency for Therapeutic Products (Swissmedic), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Australian Therapeutic Goods Administration (TGA), Health Canada, and the FDA
• Describing the potential of artificial intelligence (AI) and machine learning (ML) modelling approaches to replace, reduce, and refine the use of animals for absorption, distribution, metabolism and excretion (ADME) and toxicity testing as outlined by the 2023 Reflection paper on the use of AI in the medicinal product lifecycle⁷  

Both EMA and the European Commission strongly support the implementation of the 3R principles which encourage alternatives to the use of animals.^8,9 According to the Directive 2010/63/EU¹⁰, 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 the welfare of animals used in scientific research, with the final aim of replacing all animal research with non-animal methods. 

The EMA’s Innovation Task Force (ITF, a multidisciplinary group that includes scientific, regulatory, and legal competencies) encourages the prioritization and rapid integration of 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 

Alternative approaches to animal models: Established 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 nonclinical 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.⁷ 

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 an investigational 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, clinical data 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 are considered inferior in terms of precision and reproducibility. Despite these drawbacks, the use of an animal-based activity assay sometimes cannot be avoided, particularly for novel classes of drugs and during early development. In such cases, early engagement with EMA can help to identify the most acceptable options for that phase and replace 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. For developers of NAMs, it provides an early opportunity to discuss the regulatory acceptance of 3R-compliant methods which may utilize innovative technologies and their integration into the development and evaluation of medicinal products. 

• 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 voluntarily seek CHMP Scientific Advice (SA) for the qualification of novel methodologies in support of drug development. The output is a CHMP qualification opinion and scientific assessment (publicly available) or a CHMP qualification advice on future protocols and studies to be performed (confidential). 

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 the meeting.   
• 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 ATMP classification and certification, designation of orphan medicinal products and scientific advice. 
• For developers in early stages of development, new manufacturing methods, nanotechnologies, pharmacogenomics, treatments intended for antimicrobial resistance (AMR), and 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 biopharmaceutical 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 EMA ITF informal discussion meetings (such as the ITF Briefing Meeting) and when scientific advice for qualification opinion or qualification advice is more appropriate. We offer technical and regulatory support for these meetings and can assist with the preparation of documentation, drafting of reports and navigation of the process from start to conclusion.   

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

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References 

1. https://www.ema.europa.eu/en/documents/other/regulatory-science-research-needs_en.pdf 
2. https://www.fda.gov/news-events/press-announcements/fda-announces-plan-phase-out-animal-testing-requirement-monoclonal-antibodies-and-other-drugs 
3. https://www.ema.europa.eu/en/documents/report/european-union-medicines-agencies-network-strategy-2025-protecting-public-health-time-rapid-change_en.pdf 
4. https://www.ema.europa.eu/en/documents/other/consolidated-3-year-rolling-work-plan-non-clinical-domain-2025-2027_en.pdf 
5. https://www.ema.europa.eu/en/events/3rs-working-party-3rswp-plenary-meeting-public-session-2025-2027-work-plan
6. https://www.ema.europa.eu/en/documents/other/terms-reference-tor-international-medicines-regulators-working-group-3rs_en.pdf 
7. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-reflection-paper-use-artificial-intelligence-ai-medicinal-product-lifecycle_en.pdf 
8. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-principles-regulatory-acceptance-3rs-replacement-reduction-refinement-testing-approaches_en.pdf
9. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-providing-overview-current-regulatory-testing-requirements-medicinal-products-human_en.pdf 
10. https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32010L0063 

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