Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Novel Pharmaceuticals

Abstract

Animal models of human disease are commonly utilized to gain insight into the potential efficacy and mode of action of novel pharmaceuticals. However, conventional (healthy) rodent and nonrodent models are generally utilized in nonclinical safety testing. Animal models of human disease may be helpful in understanding safety risks of compounds in nonclinical or clinical development, with their greatest value being in targeted or hypothesis-driven studies to help understand the mechanism of a particular toxicity. Limitations of animal models of disease in nonclinical safety testing include a lack of historical control, heterogeneity in disease expression, a limited life span, and confounding effects of the disease. In most instances, animal models of human disease should not be utilized to supplant testing in conventional animal models. While of potential benefit, testing in an animal model of human disease should only be taken after adequate consideration of relevance along with benefits and limitations of the proposed model.

Regulatory acceptance of animal models of disease to support clinical trials of medicines and advanced therapy medicinal products

“…In addition, the potential for significant inter-individual variation in primary or secondary disease-associated pathology poses additional challenge sin interpretation. Thus, discerning whether clinical and anatomic pathology findings are attributable to incidental age-related or background changes, anticipate primary or secondary disease manifestations, and reconcile test article-related adverse vs. non adverse effects, will require additional experience and data accumulation specifically with each model system (Morgan et al, 2013).…”

“…While animal models of disease may result in improved safety assessment of human relevance, in many instances, even the optimal use of animal models of disease in preclinical testing will not result in an absolute predictability or understanding of toxicities that may be encountered in a clinical setting, in large part because of limitations in any animal model (Morgan et al, 2013). Table 2 provides a summary of advantages and limitations of using animal models of disease for assessing safety.…”

“…Will incorporation of safety endpoints in proof-of-concept studies help to better predict the safety aspects of the medicine in the disease condition? (Morgan et al, 2013).…”

Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities

“…While disease models are not routinely used in the safety assessment of drugs in development, this approach can provide additional information that can augment the results from toxicity studies with healthy animals. Morgan et al (2013) and Boelsterli (2003) provide additional discussion concerning the value of disease models in toxicity testing. Finding at the end of 1-mo dosing period Stomach (glandular) Degeneration/necrosis: superficial mucosa a -4 / 0 b 2 / 2 8 / 7 ----Edema, lamina propria, superficial -----1/0 2/0 2/3 Hemorrhage: superficial glandular mucosa (rat); lamina propria, superficial (dog) 3/4 8/4 8/5 7/10 -0/1 1/1 2/3 Hyperplasia/regeneration: foveolar epithelium a 10/9 10/7 10/10 10/9 ----Nerve (sciatic) Axonal degeneration -2/2 9/10 10/9 --1/0 1/2 Skeletal muscle ( …”

Guidelines for Translational Research in Heart Failure

“…This can render animal disease models not only suitable for POC testing but, in some cases, also for more reliable safety (toxicity) testing. The potential use of animal models for functional safety assessment is increasingly discussed, as new therapeutic modalities and targets are being identified and developed, especially including those for HF [87]. Moreover, histomorphological or functional safety studies performed in a disease model can provide a "veterinary" safety multiple based on the dosage that provokes histologic lesions and/or compromises cardiac function compared to a pharmacodynamic dosage.…”