25 years of applying the 3Rs principles in safety pharmacology: success stories and future perspectives

Figures

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  Figure 1. Key actions that drove the evolution of the regulatory framework on animal testing across different regions of the world (black: Europe; purple: USA; amber: Japan; blue: UK). Squares: governmental actions; circles: drug agencies actions; diamonds: industry actions; triangles: public actions.

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  Figure 2. Comprehensive In Vitro Proarrhythmia Assessment (CiPA) paradigm consists of three non-clinical pillars complemented by robust ECG monitoring in Phase 1 clinical trials. Created with BioRender.com.

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  Figure 3. Relationship between model complexity and human translatability of ex vivo and in vitro methods used in preclinical development. The lowest complexity is observed with 2D cultures derived from animal or human sources. Human translatability represents the extent to which a model reflects human physiological conditions and is generally regarded to be higher in models based on human-derived material due to species equivalence. Created with BioRender.com.

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  Figure 4. Progressive refinement of the in vivo methods used in safety pharmacology core battery studies. Created partly with Canva.com.

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  Figure 5. Alternative in vitro and ex vivo approaches for the assessment of drug-induced changes in respiratory function have the aim of creating human relevant systems that may replace animal use whilst balancing cost, complexity/laborious nature, clinically/physiological relevance and regulatory ambition. Created with BioRender.com.

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  Figure 6. Temporal evolution of the poster categories presented at the Safety Pharmacology Society (SPS) annual meetings. A regular increase in the percentage of in silico and in vitro topics is noted. Adapted from (Valentin et al., 2023).