Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database

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Abstract

The contribution of animal testing in drug development has been widely debated and challenged. An industry-wide nonclinical to clinical translational database was created to determine how safety assessments in animal models translate to First-In-Human clinical risk. The blinded database was composed of 182 molecules and contained animal toxicology data coupled with clinical observations from phase I human studies. Animal and clinical data were categorized by organ system and correlations determined. The 2 × 2 contingency table (true positive, false positive, true negative, false negative) was used for statistical analysis. Sensitivity was 48% with a 43% positive predictive value (PPV). The nonhuman primate had the strongest performance in predicting adverse effects, especially for gastrointestinal and nervous system categories. When the same target organ was identified in both the rodent and nonrodent, the PPV increased. Specificity was 84% with an 86% negative predictive value (NPV). The beagle dog had the strongest performance in predicting an absence of clinical adverse effects. If no target organ toxicity was observed in either test species, the NPV increased. While nonclinical studies can demonstrate great value in the PPV for certain species and organ categories, the NPV was the stronger predictive performance measure across test species and target organs indicating that an absence of toxicity in animal studies strongly predicts a similar outcome in the clinic. These results support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials and provide context for emerging alternate models.

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