Why most animal models are bound to fail
Note: This post is written by the authors of a paper published in the Journal of Translational Medicine in November 2018, entitled: “Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail”. It outlines concerns with the animal model generally.
The pharmaceutical industry is in the midst of a productivity crisis, with preclinical – mainly animal - tests failing to predict whether drugs will be safe or whether they will actually help people. It’s time to question the scientific merit of using animals to cure human diseases.
At issue here is the use of animals as proxies for humans because it is not considered ethically acceptable to conduct the relevant studies on humans.
Consider stroke research, where researchers artificially induce strokes in animals, then give these animals an experimental drug. If the drug is judged to be safe and effective in animals, then it can be tested in clinical trials in the hope that it will be successful in humans too.
While that may sound straightforward enough, well over 1,000 experimental treatments for induced stroke have been tested on laboratory animals, many of which were judged to be beneficial to those animals. But only one of these treatments has been found to benefit humans with stroke, and only a very small proportion of stroke patients at that.
This pattern of poor translation of research findings from animals to humans is observed across a broad range of diseases.
Many scientists suggest the way to address the problem of animal studies not accurately predicting human health outcomes is to improve the quality of animal research. There are two basic approaches here:
The first is what’s called improving the “internal validity” of the experiments. Examples of this include reducing the possibility of bias creeping into experiments and by analysing and reporting findings more rigorously and objectively. This is well-known territory to people struggling to improve the quality of animal studies.
The second, less discussed way of addressing the low predictivity of animal studies is to improve “external validity”. This refers to the extent to which research findings produced in one setting, or one population or species, can be applied to another setting, population or species. This is extremely important in animal research, because much of this research is intended to apply to humans.
External validity is problematic
Scientists frequently conduct studies on small, single-sex samples of identical, young, healthy laboratory animals. Then they try to apply their findings to humans of different ages, sex and ethnicities, with diverse genetic profiles and health statuses. In addition, these people may already be taking medication for a variety of health problems. A common answer to this problem is to suggest that animal samples should be more like human samples.
How does this problem play out in the field of stroke?
Some scientists may suggest, for example, that research should be conducted in older animals with hypertension because many humans with stroke are elderly and hypertensive. It has also been suggested that to make animal studies more like the human situation, experimental drugs in animal studies should be administered at the same sort of time interval after stroke that humans with stroke are likely to be able to access medication, i.e. some hours after the stroke. Currently some experimental drugs are given to animals before the stroke is induced, or immediately after —neither of which have relevance to the real life situations in which humans with stroke are able to access emergency care.
“Animal models will still not be sufficiently scientifically valid and will continue to be an unreliable method for developing drugs for humans.”
While such improvements are likely to improve the external validity of animal models to some extent, this effort will take many decades, consume considerable resources and will involve the death of many thousands of animals.
Yet, in spite of such efforts, animal models will still not be sufficiently scientifically valid and will continue to be an unreliable method for developing drugs for humans. This is because they involve applying findings from one species to another.
Species differences are an insurmountable problem
Species differences are rarely adequately acknowledged within the animal research literature. In the field of stroke, for example, it is highly unusual for researchers to suggest that animal-human species differences might account for the failure to translate findings derived in animal studies into benefits for humans.
Species differences will always limit the extent to which findings from animal studies can be reliably translated to humans, meaning that animal models will never be fully scientifically valid, no matter how many ‘improvements’ are attempted. Aiming for animal-free innovations based on human-derived materials (e.g. organs-on-a-chip, organoids) may be a more successful approach because it does not involve extrapolating from one species to another. Scientific quality must remain paramount however, if valid and reliable results are to be obtained from new technologies.
The future belongs to high quality human-based research.
Explore the full paper here.
Pandora Pound, Research Consultant, Safer Medicines Trust
Merel Ritskes-Hoitinga, Professor, SYRCLE, Radboud University Medical Center