Why animal model therapies usually don't work in human beings

Several times people ask me  why when several animal studies are reported in the medical field, they don't  translate into human therapies. Although I answered it several times, I now want to give a detailed analysis of it.

While there are several reasons why experimentation using animals can’t reliably predict human outcomes, the most significant issue is the vast physiological differences between species. 

A 2014 review published in the British Medical Journal found that “even the most promising findings from animal research often fail in human trials and are rarely adopted into clinical practice. For example, one study found that fewer than 10% of highly promising basic science discoveries enter routine clinical use within 20 years.” So most experiments on animals are just 'basic knowledge' that  doesn't help us much.

Not only do medications that work on animals fail in humans, there are also probably some—perhaps many—drugs that would help humans but are discarded because they fail in tests on animals.

Animal Studies Do Not Reliably Predict Human Outcomes

Both obvious and subtle differences between humans and animals, in terms of our physiology, anatomy, and metabolism, make it difficult to apply data derived from animal studies to human conditions.

Acetaminophen, for example, is poisonous to cats, but is therapeutic in humans; penicillin is toxic in guinea pigs, but has been an invaluable tool in human medicine; morphine causes hyper-excitement in cats, but has a calming effect in human patients; and oral contraceptives prolong blood-clotting times in dogs, but increase a human’s risk of developing blood clots. Many more such examples exist. Even within the same species, similar disparities can be found among different sexes, breeds, age and weight ranges, and ethnic backgrounds.

Furthermore, animal ‘models’ are seldom subject to the same causes, symptoms, or biological mechanisms as their purported human analogues. Indeed, many health problems currently afflicting humans, such as psychopathology, cancer, drug addiction, Alzheimer’s, and AIDS, are species-specific.

As a result, accurately translating information from animal studies to human patients can be an exercise in speculation. Even high-quality animal studies will replicate poorly in human clinical research.

Due to the inherent differences between animals and humans, drugs and procedures that work in animals often end up failing in humans.

Another reason to worry is drugs and procedures that could be effective in humans may never be developed because they fail in animal studies. It is difficult to know how frequently this occurs, since drugs that fail in animals are rarely tested in humans. There have, however, been some notable cases.

Although Lipitor, Pfizer’s blockbuster drug for reducing cholesterol, did not seem promising in early animal experiments, a research scientist requested that the drug be tested in a small group of healthy human volunteers. It was only then that its effectiveness was demonstrated(1).

In many instances, medical discoveries are delayed as researchers waste time, money, effort, and animal lives trying to create an animal model of a human disease. A classic example is the discovery that smoking significantly increases the risk of lung cancer. The finding was first reported in 1954 on the basis of an epidemiological study. The report was dismissed, however, because lung cancer due to inhalation of cigarette smoke could not be induced in animal models. It wasn’t until 30 years later that the U.S. Surgeon General finally issued the warning on cigarettes.

Another noteworthy example concerns the development of the polio vaccine. Researchers spent decades infecting non-human primates with the disease, and conducting other animal experiments, but failed to produce a vaccine. The key event, which led directly to the vaccine and a Nobel Prize, occurred when researchers grew the virus in human cell cultures in vitro.

We know that animals make poor surrogates for humans. On top of this, the design of animal experiments is often inherently flawed, making it that much less likely that results obtained from such studies will be useful.

Researchers from the Vanderbilt University Medical Center described some of the problems with animal ‘models’ in their 2004 article: “…[T]he design of animal studies automatically controls many variables that can confound human studies”; “…[T]he phenotypes studied in animals are not truly identical to human disease but are limited representations of them”; and “In most cases, animal studies do not assess the role of naturally occurring variation and its effects on phenotypes.”(3)

Furthermore, in their effort to secure research funds, expand the territorial boundaries and influence of their laboratories, or simply maintain their employment, it is common practice for biomedical researchers to generate an endless series of experiments. They do so by devising minor variations on a common theme, redefining previous work, subdividing one problem into multiple parts, or manipulating new technology and equipment to answer old or irrelevant questions. Such practices are endemic in such fields as experimental psychology, substance abuse/addiction, and most of the neuroscience and transplantation protocols. Yet, by their very design, these experiments do little to improve human or animal lives (4).

Although the unreliability and limitations of animal experimentation have increasingly been acknowledged, there remains a general confidence within much of the biomedical community that they can be overcome. So they continue with it. 

However, three major conditions undermine this confidence and explain why animal experimentation, regardless of the disease category studied, fails to reliably inform human health: (1) the effects of the laboratory environment and other variables on study outcomes, (2) disparities between animal models of disease and human diseases, and (3) species differences in physiology and genetics. 

Laboratory procedures and conditions exert influences on animals’ physiology and behaviors that are difficult to control and that can ultimately impact research outcomes. Animals in laboratories are involuntarily placed in artificial environments, usually in windowless rooms, for the duration of their lives. Captivity and the common features of biomedical laboratories—such as artificial lighting, human-produced noises, and restricted housing environments—can prevent species-typical behaviors, causing distress and abnormal behaviors among animals. Among the types of laboratory-generated distress is the phenomenon of contagious anxiety. Cortisone levels rise in monkeys watching other monkeys being restrained for blood collection. Blood pressure and heart rates elevate in rats watching other rats being decapitated. Routine laboratory procedures, such as catching an animal and removing him or her from the cage, in addition to the experimental procedures, cause significant and prolonged elevations in animals’ stress markers. These stress-related changes in physiological parameters caused by the laboratory procedures and environments can have significant effects on test results. Stressed rats, for example, develop chronic inflammatory conditions and intestinal leakage, which add variables that can confound data. (5). A variety of conditions in the laboratory cause changes in neurochemistry, genetic expression, and nerve regeneration. So In order to control for potential confounders, some investigators have called for standardization of laboratory settings and procedures.

The lack of sufficient congruence between animal models and human diseases is another significant obstacle to translational reliability. Human diseases are typically artificially induced in animals, but the enormous difficulty of reproducing anything approaching the complexity of human diseases in animal models limits their usefulness. Even if the design and conduct of an animal experiment are sound and standardized, the translation of its results to the clinic may fail because of disparities between the animal experimental model and the human condition (5).

Ultimately, even if considerable congruence were shown between an animal model and its corresponding human disease, interspecies differences in physiology, behavior, pharmacokinetics, and genetics would significantly limit the reliability of animal studies, even after a substantial investment to improve such studies. In spinal cord injury, for example, drug testing results vary according to which species and even which strain within a species is used, because of numerous interspecies and interstrain differences in neurophysiology, anatomy, and behavior. (5)The micropathology of spinal cord injury, injury repair mechanisms, and recovery from injury varies greatly among different strains of rats and mice. A systematic review found that even among the most standardized and methodologically superior animal experiments, testing results assessing the effectiveness of methylprednisolone for spinal cord injury treatment varied considerably among species. This suggests that factors inherent to the use of animals account for some of the major differences in results.

Even rats from the same strain but purchased from different suppliers produce different test results.

In one study, responses to 12 different behavioral measures of pain sensitivity, which are important markers of spinal cord injury, varied among 11 strains of mice, with no clear-cut patterns that allowed prediction of how each strain would respond. These differences influenced how the animals responded to the injury and to experimental therapies. A drug might be shown to help one strain of mice recover but not another. Despite decades of using animal models, not a single neuroprotective agent that ameliorated spinal cord injury in animal tests has proven efficacious in clinical trials to date. (5)

Further exemplifying the importance of physiological differences among species, a 2013 study reported that the mouse models used extensively to study human inflammatory diseases (in sepsis, burns, infection, and trauma) have been misleading. The study found that mice differ greatly from humans in their responses to inflammatory conditions. Mice differed from humans in what genes were turned on and off and in the timing and duration of gene expression. The mouse models even differed from one another in their responses. The investigators concluded that “our study supports higher priority to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory disease (5)

Wide differences have also become apparent in the regulation of the same genes, a point that is readily seen when observing differences between human and mouse livers.

Recognizing the inherent genetic differences among species as a barrier to translation, researches have expressed considerable enthusiasm for genetically modified (GM) animals, including transgenic mice models, wherein human genes are inserted into the mouse genome. However, if a human gene is expressed in mice, it will likely function differently from the way it functions in humans, being affected by physiological mechanisms that are unique in mice. 

As medical research has explored the complexities and subtle nuances of biological systems, problems have arisen because the differences among species along these subtler biological dimensions far outweigh the similarities, as a growing body of evidence attests. These profoundly important—and often undetected—differences are likely one of the main reasons human clinical trials fail (5, 6).

In practice, how does one take into account differences in drug metabolism, genetics, expression of diseases, anatomy, influences of laboratory environments, and species- and strain-specific physiologic mechanisms—and, in view of these differences, discern what is applicable to humans and what is not? 

It has been argued by some researchers that some information obtained from animal experiments is better than no information. This argument neglects how misleading information can be worse than no information from animal tests. The use of nonpredictive animal experiments can cause human suffering in at least two ways: (1) by producing misleading safety and efficacy data and (2) by causing potential abandonment of useful medical treatments and misdirecting resources away from more effective testing methods.

Humans are harmed because of misleading animal testing results. Imprecise results from animal experiments may result in clinical trials of biologically faulty or even harmful substances, thereby exposing patients to unnecessary risk and wasting scarce research resources. Animal toxicity studies are poor predictors of toxic effects of drugs in humans.

An equal if indirect source of human suffering is the opportunity cost of abandoning promising drugs because of misleading animal tests.

An editorial in Nature Reviews Drug Discovery describes cases involving two drugs in which animal test results from species-specific influences could have derailed their development. In particular, it describes how tamoxifen, one of the most effective drugs for certain types of breast cancer, “would most certainly have been withdrawn from the pipeline” if its propensity to cause liver tumor in rats had been discovered in preclinical testing rather than after the drug had been on the market for years (7).

In addition to potentially causing abandonment of useful treatments, use of an invalid animal disease model can lead researchers and the industry in the wrong research direction, wasting time and significant investment.

The opportunity costs of continuing to fund unreliable animal tests may impede development of more accurate testing methods. Human organs grown in the lab, human organs on a chip, cognitive computing technologies, 3D printing of human living tissues, and the Human Toxome Project are examples of new human-based technologies that are garnering widespread enthusiasm. The benefit of using these testing methods in the preclinical setting over animal experiments is that they are based on human biology. Thus their use eliminates much of the guesswork required when attempting to extrapolate physiological data from other species to humans. Additionally, these tests offer whole-systems biology, in contrast to traditional in vitro techniques. Although they are gaining momentum, these human-based tests are still in their relative infancy (5).

 Now an analysis finds only one in 20 therapies tested in animals reach approval for human use (2)

An analysis of reviews of translational biomedical research reveals that just 5% of therapies tested in animals reach regulatory approval for human use. The study, an umbrella review, published June 13 in the open access journal PLOS Biology, summarizes other systematic reviews and provides high level evidence that while the rate of translation to human studies is 50%, there is a steep drop off before final approval.

The authors argue that improved robustness and generalizability of experimental approaches could help increase the chances of translation and final approval.

Animal studies are used in basic research to provide insight into aspects of human diseases. They have paved the way for certain therapeutic innovations, although there are several steps that follow before a treatment can be approved for human use.

In debates about the ethics of animal research, clinical translation is one of the main justifications of such work, yet there is little evidence on how many studies make it through each step and are finally approved.

Researchers now  meta-analyzed 122 systematic reviews that evaluated the translation of therapies from animals to humans.

They assessed how many advanced to any human study, to a randomized controlled trial and to regulatory approval as well as looking at consistency between animal and human study results.

They found that of 367 therapeutic interventions tested in 54 human diseases, 50% progressed from human to animal studies, 40% to randomized controlled trials and only 5% to regulatory approval. There was a high rate—86%—of alignment between animal and human studies, and the average time periods for reaching the different stages were five years to any human study, seven years to randomized controlled trials and 10 years to regulatory approval.

Although the number of studies crossing the first stage is higher than previous evidence has suggested, the low rate of final approval suggests there could be deficiencies to address in the design of both animal and early clinical studies.

The authors add, "To improve animal-to-human translation, we advocate for enhanced study design robustness of animal and human research which will not only benefit experimental animals but also affected patients."

So it would be better to direct resources away from animal experimentation and into developing more accurate, human-based technologies.

Footnotes:

2. Ineichen BV, et al, Analysis of animal-to-human translation shows that only 5% of animal-tested therapeutic interventions obtain regulatory approval for human applications. PLoS Biology (2024). DOI: 10.1371/journal.pbio.3002667

1.  Agres, T. (2006, Mar. 9). FDA Input Aids Early Trials. Drug Discovery and Development. Retrieved March 2008, from www.dddmag.com/fda-input-aids-early-trials.aspx

3. Williams, S.M., Haines, J.L., and Moore, J.H. (2004). The use of animal models in the study of complex disease: all else is never equal or why do so many human studies fail to replicate animal findings? Bioessays, 26(2): 170-179.

4. https://aavs.org/animals-science/problems-animal-research/#:~:text=....

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594046/

6. See note 4, Wall, Shani 2008.

7. Nature Reviews Drug Discovery 2003;2:167, at 167.