Levelling the Translational Gap for Animal to Human Efficacy Data

Abstract

Reports of a reproducibility crisis combined with a high attrition rate in the pharmaceutical industry have put animal research increasingly under scrutiny in the past decade. Many researchers and the general public now question whether there is still a justification for conducting animal studies. While criticism of the current modus operandi in preclinical research is certainly warranted, the data on which these discussions are based are often unreliable. Several initiatives to address the internal validity and reporting quality of animal studies (e.g., Animals in Research: Reporting In Vivo Experiments (ARRIVE) and Planning Research and Experimental Procedures on Animals: Recommendations for Excellence (PREPARE) guidelines) have been introduced but seldom implemented. As for external validity, progress has been virtually absent. Nonetheless, the selection of optimal animal models of disease may prevent the conducting of clinical trials, based on unreliable preclinical data. Here, we discuss three contributions to tackle the evaluation of the predictive value of animal models of disease themselves. First, we developed the Framework to Identify Models of Disease (FIMD), the first step to standardise the assessment, validation and comparison of disease models. FIMD allows the identification of which aspects of the human disease are replicated in the animals, facilitating the selection of disease models more likely to predict human response. Second, we show an example of how systematic reviews and meta-analyses can provide another strategy to discriminate between disease models quantitatively. Third, we explore whether external validity is a factor in animal model selection in the Investigator’s Brochure (IB), and we use the IB-derisk tool to integrate preclinical pharmacokinetic and pharmacodynamic data in early clinical development. Through these contributions, we show how we can address external validity to evaluate the translatability and scientific value of animal models in drug development. However, while these methods have potential, it is the extent of their adoption by the scientific community that will define their impact. By promoting and adopting high quality study design and reporting, as well as a thorough assessment of the translatability of drug efficacy of animal models of disease, we will have robust data to challenge and improve the current animal research paradigm.

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician

“…It is known that some of the drugs entering clinical development do not confirm their effectiveness previously demonstrated in laboratory conditions (Pound and Ritskes-Hoitinga, 2018;Ferreira et al, 2020). This situation also applies to drugs intended for a preventive or pathogenetic effect on the course of DOX cardiomyopathy (Weidemann and Strotmann, 2006;Vincent et al, 2013;Lipshultz et al, 2014;Abushouk et al, 2017;Kim et al, 2019;Wang et al, 2019;Sharma et al, 2020).…”

Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

“…Using animals to model multifaceted human diseases that generally do not develop naturally in them and incorporate a wide variety of pathological events and outcomes, is at best complicated and at worst futile. As mentioned above, it is well-known that drugs tested in animal models of human brain diseases often fail in the clinic [ 195 , 196 , 197 , 198 ] and this is related to issues of reproducibility and validity of the models [ 199 , 200 , 201 ]. In other words, whether the model you are using is working in different labs with minor modifications, and whether the model is truly reporting what you say it is.…”

Applicability of organ-on-chip systems in toxicology and pharmacology

“…In addition, it might also lead to the identification of potential hazards that are irrelevant for humans. It is well-known that both falsenegative and false-positive results limit considerably the predictivity of animal experimentation and compromise the development of beneficial drugs for human use (Van Meer et al 2013;Van Meer et al 2015;Van Norman 2019;Ferreira et al 2020). An avenue to circumvent part of these issues is the use of micro physiological systems (MPS).…”