In-Silico Breakthrough: EMA’s Shift from Animal Testing

The DIA Europe 2024 conference brought together leading experts to discuss groundbreaking innovations and regulatory strategies in clinical trials. Key topics included the implementation of the 3Rs (reduction, replacement, and refinement of animal testing), the potential of organ-on-chip (OOC) technologies, and the need for collaborative regulatory advice. The conference emphasized the importance of early dialogue, international collaboration, and the adoption of advanced in vitro models to improve the efficiency and accuracy of drug development while adhering to ethical standards.

Embracing the 3Rs: Reduction, Replacement, and Refinement

Sonja Beken, Chair of the 3Rs Working Party at EMA and Coordinator of Non-Clinical Evaluators at the Belgian Federal Agency for Medicines and Health Products opened the discussion by emphasizing the significance of the 3Rs—reduction, replacement, and refinement of animal testing. Beken highlighted the evolving landscape since 2010, noting the establishment of the 3Rs Working Party in 2023 to spearhead strategic initiatives aimed at minimizing animal use in preclinical testing.

Beken pointed out that while traditional animal testing has been the cornerstone of preclinical safety assessment, it has limitations. The paradigm shift towards investigative toxicology, integrating in silico models, AI, and organ-on-chip technologies, aims to predict human toxicities more accurately. The goal is to move from descriptive to predictive toxicology, reducing reliance on non-human primates, especially given their scarcity and ethical concerns.

Industry Perspectives on 3Rs Implementation

Natasa Zamurovic, Head of Immunology Preclinical Safety at Novartis, discussed practical ways the industry incorporates the 3Rs in preclinical testing, focusing on monoclonal antibodies and teratogenicity. For monoclonal antibodies, she explained that regulatory guidelines often require testing in non-human primates due to their physiological similarities to humans. However, advancements have allowed for a reduction in animal use through a robust weight-of-evidence approach. Zamurovic illustrated this with examples where a single, well-designed study in non-human primates can meet regulatory requirements. This approach leverages existing data and shared knowledge and integrates in vitro studies and computational models, enhancing the reliability of safety assessments while minimizing animal use.

Zamurovic also addressed the complexities of teratogenicity testing, particularly for drugs like thalidomide, known for severe developmental abnormalities. Traditional animal models often fail to predict human responses due to species-specific differences. Novartis advocates for human-relevant in vitro models using human-induced pluripotent stem cells (iPSCs) to study early developmental processes. By validating these models with known teratogens and comparing their predictions with clinical outcomes, researchers can improve the predictive accuracy of teratogenicity testing. These efforts and collaborative data sharing across the industry aim to enhance ethical and scientific rigor in preclinical testing.

Advancing Organ-on-Chip Technologies

The potential of OOC technologies was a focal point of the DIA Europe 2024 session. These advanced in vitro models simulate human organ functions, offering a promising alternative to animal testing. Beken emphasized that OOC technologies can predict human drug responses more accurately, particularly for liver and heart tissues. She discussed examples such as liver-on-chip systems used to predict drug-induced liver injury and heart-on-chip models for assessing cardiovascular safety. Beken stressed the importance of establishing clear qualification criteria and regulatory pathways to ensure their acceptance.

Beken highlighted recent initiatives under the Belgian Presidency of the Council of Europe aimed at qualifying these microphysiological systems. These efforts include multi-stakeholder workshops that bring together industry experts, regulators, and academics to define the standards and requirements for OOC technologies. By fostering collaboration and setting clear guidelines, these initiatives aim to accelerate the adoption of OOC models. Specific examples discussed included liver-on-chip systems being tested for their ability to replicate human liver responses to various drugs and heart-on-chip models evaluating the impact of new pharmaceuticals on cardiovascular health. These advancements aim to reduce reliance on animal testing and improve the efficiency and accuracy of drug development.

Collaborative Regulatory Advice: A Path Forward

Christophe Lahorte, Head of the National Innovation Office at the Belgian Federal Agency for Medicines and Health Products, introduced the concept of simultaneous national scientific advice (SNSA) at DIA Europe 2024. This initiative streamlines regulatory advice by involving multiple national competent authorities (NCAs) in a single, coordinated procedure, reducing divergent opinions and saving time for applicants. For example, companies can now receive harmonized guidance instead of seeking separate feedback from each NCA, making the drug development process more efficient.

Lahorte highlighted the success of SNSA pilots, which have seen increased participation from NCAs and improved convergence of regulatory opinions. One pilot involved regulatory advice for new cancer therapy, with coordinated input from NCAs across several EU countries, leading to a more cohesive regulatory pathway. He emphasized that early dialogue between regulators and developers helps identify and resolve potential issues sooner, facilitating smoother clinical trial applications under the Clinical Trials Regulation (CTR).

Future Directions and Global Harmonization

The session concluded with a panel discussion featuring Gunilla Andrew-Nielsen, Head of Clinical Trials at the Swedish Medical Products Agency, and other experts, who emphasized the critical need for global harmonization of regulatory acceptance criteria for novel methodologies. Andrew-Nielsen highlighted that inconsistent regulatory standards across different countries could hinder the adoption of innovative tools like AI and OOC technologies, slowing down drug development. For instance, while some countries have begun integrating AI models to predict drug interactions and side effects into their regulatory frameworks, others lag due to the lack of standardized criteria, resulting in delays and increased costs for pharmaceutical companies navigating multiple regulatory environments.

A promising initiative under the Belgian Presidency of the Council of Europe aimed to qualify OOC systems for predicting drug-induced liver injury and cardiovascular safety. However, without international collaboration to harmonize acceptance criteria, the full potential of these technologies may not be realized. Andrew-Nielsen and her colleagues stressed the importance of global regulatory bodies working together to establish common standards, arguing that such collaboration would streamline the approval process for new methodologies and foster innovation. They called for more global initiatives and multi-stakeholder workshops to ensure groundbreaking tools like AI and OOC technologies can seamlessly integrate into the drug development pipeline worldwide.

Summary

This discussion at DIA 2024 highlighted significant advancements in preclinical testing methodologies and the importance of harmonizing regulatory frameworks globally. Emphasizing the 3Rs, leveraging OOC technologies, and adopting SNSA can revolutionize drug development. However, achieving these goals requires ongoing collaboration between industry experts, regulators, and academics to establish clear standards and guidelines. By fostering such partnerships, the pharmaceutical industry can reduce reliance on animal testing, streamline regulatory processes, and ultimately bring safer, more effective drugs to market more efficiently.