Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail

Pandora Pound,Merel Ritskes-Hoitinga

doi:10.1186/s12967-018-1678-1

Abstract

BackgroundThe pharmaceutical industry is in the midst of a productivity crisis and rates of translation from bench to bedside are dismal. Patients are being let down by the current system of drug discovery; of the several 1000 diseases that affect humans, only a minority have any approved treatments and many of these cause adverse reactions in humans. A predominant reason for the poor rate of translation from bench to bedside is generally held to be the failure of preclinical animal models to predict clinical efficacy and safety. Attempts to explain this failure have focused on problems of internal validity in preclinical animal studies (e.g. poor study design, lack of measures to control bias). However there has been less discussion of another key factor that influences translation, namely the external validity of preclinical animal models.Review of problems of external validityExternal validity is the extent to which research findings derived in one setting, population or species can be reliably applied to other settings, populations and species. This paper argues that the reliable translation of findings from animals to humans will only occur if preclinical animal studies are both internally and externally valid. We review several key aspects that impact external validity in preclinical animal research, including unrepresentative animal samples, the inability of animal models to mimic the complexity of human conditions, the poor applicability of animal models to clinical settings and animal–human species differences. We suggest that while some problems of external validity can be overcome by improving animal models, the problem of species differences can never be overcome and will always undermine external validity and the reliable translation of preclinical findings to humans.ConclusionWe conclude that preclinical animal models can never be fully valid due to the uncertainties introduced by species differences. We suggest that even if the next several decades were spent improving the internal and external validity of animal models, the clinical relevance of those models would, in the end, only improve to some extent. This is because species differences would continue to make extrapolation from animals to humans unreliable. We suggest that to improve clinical translation and ultimately benefit patients, research should focus instead on human-relevant research methods and technologies.

Highlights

Few would dispute that the pharmaceutical industry is in the midst of a productivity crisis [1–7] or that rates of translation from bench to bedside are dismal [8–15]
We conclude that preclinical animal models can never be fully valid due to the uncertainties introduced by species differences
We have argued that translation from animals to humans can only occur if preclinical animal studies are both internally and externally valid

Summary

Conclusion

We have argued that translation from animals to humans can only occur if preclinical animal studies are both internally and externally valid. If the aim is to improve clinical translation and address patients’ needs for safe and effective treatments, the first step is to acknowledge where current systems are failing We noted that those conducting preclinical animal research appear to downplay the problem of animal–human species differences but interestingly, other researchers and commentators in the field do . They may briefly acknowledge that species differences constitute a problem for external validity, the tendency is to focus on other, potentially modifiable, aspects of external validity [10, 26]. MR-H contrib‐ uted conceptually with ideas and comments Both authors critically revised and edited subsequent drafts before approving the final version.

Introduction

Findings