Abstract
The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.
Highlights
Interventional studies in animals are an integral component of drug development
Studies were included in the meta-analysis if they used a pharmacological class that had been used in Phase 2 or three trials for Non-alcoholic fatty liver disease (NAFLD) in humans (Supplementary file 1) and reported at least one of: hepatic triglyceride content, NAFLD Activity Score (NAS, or any of its components), portal inflammation, or fibrosis stage
After adjustments made for shared controls, 414 studies were included in the meta-analysis, comprising 603 cohorts of rodents (10,364 animals)
Summary
Interventional studies in animals are an integral component of drug development. If a disease can be suitably modelled in an animal, the therapeutic response to a treatment observed in animals should inform its potential efficacy in humans (Howells et al, 2014). Other variables of animal model design can influence the magnitude of the treatment response (Watzlawick et al, 2019) and reporting of model design is often incomplete (Florez-Vargas et al, 2016). These findings are highly relevant in the context of the ‘reproducibility crisis’ (Baker, 2016; von Herrath et al, 2019) as well as having ethical implications for the use of animals in research that is not of optimum quality (Prescott and Lidster, 2017)
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