animals in research

REVIEW ARCHIVES OF HELLENIC MEDICINE 2021, 38(6):761-765

ÁÑ×ÅÉÁ ÅËËÇÍÉÊÇÓ ÉÁÔÑÉÊÇÓ 2021, 38(6):761-765

The use of animal studies in human research

Animal studies have supported our knowledge about basic mechanisms

of the human body and led to the development of greatly needed forms of

treatment. Yet, we cannot overlook the fact that the use of animals in research

has always raised controversy on ethical and technical grounds. The use of

animals in human research has long been a subject of debate in relation to its

correctness and its value to research. The aim of this review is to summarize

the special concerns in animal research, including the problem of animal-to-

human predictability, the poor methodological standards in animal research,

and the inadequate reporting of data.

...............................................

K. Giannakou,1

A. Vyrides2

1Department of Health Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus 2Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

Submitted 9.3.2021

Accepted 22.3.2021

Η χρήση των μελετών σε ζώα στην ανθρώπινη έρευνα

Περίληψη στο τέλος του άρθρου

Key words

Animal research Basic research Experimental research Pre-clinical studies

Copyright Athens Medical Society www.mednet.gr/archives

ARCHIVES OF HELLENIC MEDICINE: ISSN 11-05-3992

1. INTRODUCTION

Over the past centuries, animal research has been suc-

cessfully used in many areas of science, such as in basic

research, and has played an important role in the devel-

opment of modern medical treatments.1,2 Even though

the history of today’s therapeutic armamentarium has

always involved animal testing, we cannot overlook the fact

that the use of basic laboratory science has always raised

controversy on ethical and technical grounds, while the

successful translation of promising preclinical discoveries

into human studies is rare.3 There is ongoing debate over

the appropriateness and value of using animals in medical

and public health research.4 This review summarizes the

special concerns in animal research, including the issue

of animal-to-human predictability, the methodological

flaws in animal experimentation, and the poor reporting

of animal data.

2. UTILITY OF ANIMALS IN RESEARCH

Research based on animals has brought new and deeper

understanding about the basic mechanisms of the human

body and has provided valuable contributions to the devel-

opment of great medical advances with a profound impact

on such diseases as poliomyelitis and Parkinson’s disease.

Advances in surgical techniques and methods of treatment,

including kidney and heart transplantation, were initially

tested and perfected with the use of animals.5–7 Animal

studies provide a degree of environmental and genetic

manipulation not often feasible in humans.7 Experiments

using animals have not only supported the development

of new vaccines for the treatment of infectious diseases of

public health significance, including diphtheria, tetanus,

tuberculosis, poliomyelitis, and measles, but have also led

to the development of greatly needed forms of treatment,

such as antibacterial and antibiotic drugs.1,8 Such studies

can provide important information in terms of the patho-

physiology and the causes of disease, and can disclose

new targets for directed treatment. Pre-clinical studies in

selected animal species are also necessary for the formula-

tion of hypotheses that justify clinical trials. Without such

studies, it would be unethical to test promising but un-

proven therapies in humans and it would not be necessary

762 K. GIANNAKOU and A. VYRIDES

to allocate valuable resources to test new treatments on

humans, given that preliminary testing on animals failed to

demonstrate clinical relevance.4,9 Extensive animal testing

is also required by regulatory authorities concerned with

public protection, to screen new treatments for toxicity

and to establish safety.9

3. EFFICACY AND PREDICTABILITY

While basic research is of inherent value, decades of

animal experimentation for the investigation of specific dis-

eases such as cancer and diabetes mellitus have produced

little or nothing of value to humans, as encouraging results

in animal studies seldom translate into successful human

randomized trials with similar results.10–12 It is estimated

that around 28 billion dollars per year are invested by the

United States in basic research that cannot be reproduced.13

In addition, approximately 90% of promising discoveries

examined in clinical trials fail to obtain regulatory ap-

proval, or ultimately to improve human health, because

of inadequate efficacy and or unacceptable toxicity, and

the limited predictive ability of preclinical studies.12,14–16

For instance, the traditional mouse models for cancer have

now been widely discredited, as human cancer cell lines

are more accurate in identifying effective cancer drugs,

and in practice, the traditional mouse allograft model is

not predictive at all.17–19 Similarly, the entire field of mouse

immunology research is tainted by the recent discovery

that, unlike humans, mice have a second, functional cervi-

cal thymus gland, which raises important questions about

results from previous trials on thoracic thymectomized

mice.20 In addition, despite the use of numerous successful

animal models for the treatment of traumatic brain injury,

diabetes mellitus and stroke, each one has failed to translate

into benefits for humans.4,21,22 Previous studies investigat-

ing the issue of translation of published, highly promising

discoveries of in vivo basic science into clinical applications

found that only a minority of these (approximately 5–8%)

were ultimately translated into an approved therapeutic

method.12,15 Consequently, all these failures of translation,

expose clinical research participants to the possible danger

of discoveries that fail, for reasons of safety or efficacy, and

deprive them of funding for developing potential beneficial

interventions.23–27

The concept of animal-to-human predictability is based

on the hypothesis that animal studies are translatable to

the human situation. Due to the complexity, this statement

(or parts of it) is not always true. This can be attributed

to important differences between species, ranging from

genetics to physiology.28,29 Several analyses have set out to

understand why the extrapolation of results from animals

to human sometimes fail. One obvious reason is the dif-

ference, not so much in organ composition and functions,

but in the greater complexity of humans compared to all

other animal species. It is generally accepted that laboratory

animal models share some features with humans, argu-

ably acting as excellent representations of certain human

characteristics and attributes. The underlying reason for

the poor translation of animal model results into human

trials can be attributed to the vast anatomical, physiological,

and genetic differences between them.4,30,31 In addition, the

human organism often differs dramatically from the animal

species involved in pre-clinical studies with respect to the

absorption, distribution and excretion of substances, and

often forms very different metabolites of the same drug.4,8

Another possible explanation is that laboratory animals

are usually young, with no comorbidities, and have not

been exposed to the several competing interventions that

humans often receive. Finally, differences associated with

the formulation, route of administration and timing of an

intervention used in animal studies compared with human

studies may create problems, as these factors can influence

the pharmacokinetic properties of drug (e.g., absorption,

distribution, etc.).9,32

4. BIAS AND METHODOLOGICAL LIMITATIONS

The poor quality of preclinical animal studies is widely

acknowledged, and there is growing belief among scien-

tists that an important part of the discrepancy between

animal and human studies is due to the poor quality and

methodological biases in animal experimentation, and the

lack of adequate reporting of animal data.4,8,9,33 Bias related

to randomization, double blinding, surrogate endpoints,

calculation of sample size, statistical analysis, and nonpubli-

cation of negative results continue to limit the extrapolation

of animal findings to human.4,12,34,35 For instance, an analysis

of 76 animal studies published in leading journals between

1980 and 2000 showed that only around one third of highly

cited animal research was finally translated to the level of

human randomized trials, and only 49% was conducted

according to good methodological quality.12 In another

analysis, 290 animal studies that did not use randomization

or blinding were much more likely to report a treatment

effect than studies that were randomized or blinded.34

Similarly, in an analogous analysis of 4,445 animal studies

in 160 meta-analyses of neurological diseases, the authors

concluded that there was a possibility that most of the data

were either suppressed or recast in such a way that truly

negative studies would be published as positive results,

THE USE OF ANIMAL STUDIES 763

suggesting strong bias, and with selective analysis and

outcome reporting bias being used as a plausible explana-

tion.36 In addition, a series of systematic reviews of animal

studies revealed indications of selective analysis and out-

come reporting bias, and also publication bias, leading to

overstatement of the validity of entire bodies of medical and

public health research.10,37–41 Considering that the evidence

in clinical research and public health is hierarchical, from

animal studies to observational studies, randomized control

trials and their secondary synthesis (e.g. systematic reviews

and meta-analyses), it is possible to assume that systematic

reviews often sanctify results from poor or misleading

primary studies.42,43 Umbrella reviews, which are reviews of

multiple systematic reviews and meta-analyses, have been

developed to assess the credibility of the evidence in an

entire field, and they represent one of the highest levels

of evidence synthesis today.44–46 For instance, the risk of

reporting, selection, and other inherent biases has been

detected in umbrella reviews covering a very wide range

of topics including nutrition,47,48 psychiatry,49,50 obstetrics

and gynecology,51–53 and internal medicine,54,55 highlighting

the need for cautious interpretation of primary evidence.

5. CONCLUSIONS AND RECOMMENDATIONS

In summary, knowledge gained from individual ani-

mal studies is usually incremental, each study providing

knowledge that others continue to build upon for a deep

understanding of physiology, at both the molecular and

the macro level. To simply look at overall translation rates

from single studies is an oversimplification of the scientific

process and the ways in which interventional therapies have

been developed. Animal studies can certainly be more ben-

eficial in hypothesis generation than the direct prediction

of the human response, considering that there is room for

substantial improvement in animal research to enhance its

credibility and reproducibility. It should be noted that we

are in no way underplaying the importance and value of

animal testing, enabling, among other things, the prolif-

eration and testing of everyday surgical techniques, but at

this point in time, we believe that is necessary to address

the methodological flaws in experimental studies, such as

the lack of randomization and blinding, sample sizes that

do not permit valid statistical analysis, and insufficient

transparency in the reporting of results.

For instance, in response to the serious deficiencies

found in the conduct and reporting of animal studies the

“Animal Research: Reporting In Vivo Experiments (ARRIVE

2.0) guidelines” were formulated in 2020.56 In addition, re-

cent attempts to improve translation from animal research

also include the “co-clinical trial” in which preclinical trials

explicitly parallel ongoing human phase I and II trials.57

Likewise, a prospective registration system of animal ex-

periments, similar to that used for clinical trials, is needed

to avoid publication bias.10 Further studies are needed to

identify the prevalence of bench-to-bedside translation, to

examine current trends in translation, and to identify key

modifiable factors associated with successful translation

of preclinical research into clinical trials, using established

knowledge synthesis methods. Lastly, there is a need for

preclinical researchers to push for broader dissemination

of protocols, and techniques to improve the transparent

reporting of preclinical studies using clear definitions and

calculations. Ultimately, all these suggestions will improve

the quality and the reliability of animal studies and con-

sequently their predictive value, but they will also help

researchers to distinguish truly promising therapies from

the many false-positive or overstated leads.

ΠΕΡΙΛΗΨΗ

Η χρήση των μελετών σε ζώα στην ανθρώπινη έρευνα

Κ. ΓΙΑΝΝΑΚΟΥ,1 Α. ΒΥΡΙΔΗΣ2

1Τμήμα Επιστημών Υγείας, Σχολή Θετικών Επιστημών, Ευρωπαϊκό Πανεπιστήμιο Κύπρου,

Λευκωσία, Κύπρος, 2Barts and The London School of Medicine and Dentistry, Queen Mary University

of London, London, Ηνωμένο Βασίλειο

Αρχεία Ελληνικής Ιατρικής 2021, 38(6):761–765

Μελέτες σε ζώα έχουν υποστηρίξει τις γνώσεις μας σχετικά με τους βασικούς μηχανισμούς του ανθρώπινου οργα-

νισμού και έχουν οδηγήσει στην ανάπτυξη πολύ αναγκαίων θεραπειών. Ωστόσο, δεν μπορεί να παραβλεφθεί το γε-

γονός ότι η χρήση ζώων στην έρευνα ήταν πάντα πεδίο αντιπαράθεσης για ηθικούς και τεχνικούς λόγους. Η χρησι-

μοποίηση ζώων στην έρευνα για τον άνθρωπο αποτελεί εδώ και πολύ καιρό αντικείμενο συζήτησης σχετικά με την

764 K. GIANNAKOU and A. VYRIDES

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Corresponding author:

K. Giannakou, European University Cyprus, 6 Diogenes street,

Engomi, 2404, PO Box 22006, 1516 Nicosia, Cyprus

e-mail: [email protected]

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