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Is animal research sufficiently evidence based to be a
cornerstone of biomedical research?
Public acceptance of the use of animals in biomedical research is conditional on it producing benefits
for humans.Pandora Pound and Michael Bracken argue that the benefits remain unproved and
may divert funds from research that is more relevant to doctors and their patients
Pandora Pound medical sociologist 1, Michael B Bracken Susan Dwight Bliss professor of
epidemiology 2
1Bath, UK; 2Yale University Schools of Public Health and Medicine, New Haven CT, USA
Proponents of animal research claim that the benefits to humans
are self evident.1However, writing in The BMJ 10 years ago
we argued that such uncorroborated claims were inadequate in
an era of evidence based medicine.2At that time over two thirds
of UK government and charitable investment was going into
basic research,3perhaps creating an expectation that such
research was highly productive of clinical benefits. However,
when we searched for systematic evidence to support claims
about the clinical benefits of animal research we identified only
25 systematic reviews of animal experiments, and these raised
serious doubts about the design, quality, and relevance of the
included studies. As our colleagues had done earlier,4we argued
the case that systematic reviews should be extensively adopted
within animal research to synthesise and appraise findings, just
as they are in clinical research.
Poor quality and reporting of animal
studies
The overall number of systematic reviews of animal studies
remains lamentably low, with the ratio of reviews to total
number of publications being about 10-fold higher in human
studies.5In 2011 Korevaar and colleagues identified 244
systematic reviews of preclinical studies up until 2010,
estimating that the number was doubling every three years.6
As the number of systematic reviews increased, the poor quality
of much preclinical animal research became increasingly
apparent.7Evidence accumulated that many animal studies failed
to address important threats to internal and external validity,
making prediction to humans tenuous at best.8 9 For example,
the National Centre for the Replacement, Refinement and
Reduction of Animals in Research (NC3Rs) surveyed 271
animal studies conducted between 1999 and 2005 and found
that only 32 (12%) reported using random allocation to treatment
or control and that investigators were blinded to the allocation
in only 14% (5/35) of studies that used qualitative scoring.10
Systematic reviews of animal studies also revealed evidence of
selective analysis and outcome reporting bias11 as well as
publication bias12 leading to overstatement of the validity of
entire bodies of research.13
The Collaborative Approach to Meta-Analysis and Review of
Animal Data from Experimental Studies (CAMARADES) has
been at the forefront of conducting systematic reviews of animal
studies. Initially focusing on stroke, it later expanded to include
neurological disease, bone cancer, multiple sclerosis, and
Parkinson’s disease. By 2012 John Ioannidis, professor of health
research and policy at Stanford, concluded that CAMARADES
had found consistent suggestions of serious bias in animal
studies, making it: “nearly impossible to rely on most animal
data to predict whether or not an intervention will have a
favourable clinical benefit-risk ratio in human subjects.”14
Lack of benefit for humans
Concerns have been raised that compounds with little or no
therapeutic potential could proceed to clinical trials because
overoptimistic conclusions are drawn about their efficacy as a
result of flaws in experimental design and inadequate control
of bias.15-19 Several studies have shown that even the most
promising findings from animal research often fail in human
trials and are rarely adopted into clinical practice.20-22 For
example, one study found that fewer than 10% of highly
promising basic science discoveries enter routine clinical use
within 20 years.23 In stroke medicine, despite decades of
immense human, animal, and financial investment, animal
models have failed to yield a single neuroprotective treatment
for humans.24 25 Similarly, none of more than 100 drugs studied
in an established mouse model of amyotrophic lateral sclerosis,
many of which had been reported to slow down the disease, was
ultimately found to be beneficial after more rigorous
experiments. Eight of these drugs had been used in thousands
Correspondence to: P Pound pandorapound@gmail.com
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BMJ 2014;348:g3387 doi: 10.1136/bmj.g3387 (Published 30 May 2014) Page 1 of 3
Analysis
ANALYSIS
of patients who participated in failed clinical trials.26 A similar
lack of translation has become apparent in inflammation.27
Falling investment in basic and animal
research
Public funding bodies are becoming aware of the lack of return
on investment, and public and charitable spending on basic
research has decreased in the UK from 68.3% in 2004-5 to
59.4% in 2009-10.28 This seems wise since retrospective analysis
of the payback from research is beginning to suggest that it is
clinical rather than basic research that has most effect on patient
care.29 30 Almost half of all research involving animals in the
UK in 2012 was conducted by universities (48%), the remainder
occurring in commercial organisations (27%), public bodies
(13%), and non-profit organisations (9%).31 The drug industry
is also beginning to decrease its reliance on animal research
because each translational failure represents huge losses of
invested capital.21 32 In Europe drug companies have reportedly
decreased their use of animals by more than 25% from 2005 to
2008.33
A broken model?
The animal research community continues to cite selected
instances of how research on animals has resulted in medical
advances, or will one day do so (see www.
understandinganimalresearch.org.uk/resources/animal-research-
news-feed/). However, these convey little confidence about the
overall reliability and success of animal models, taking into
account the total evidence. Given the large amount of animal
research being undertaken, some findings will extrapolate to
humans just by chance. Understanding Animal Research, a
British organisation financed mainly by those conducting or
funding animal research, highlights four reports purporting to
support the validity of animal research,34 all of which rely solely
on expert opinion, one of the weakest forms of evidence
according to widely agreed standards.35
Would improvements in preclinical experimental procedures
and research reporting enhance the prediction from animals to
humans and provide greater benefits for humans? In an article
reviewing developments in the field of stroke, Sutherland and
colleagues note that despite researchers adhering to
recommendations intended to improve the quality of preclinical
stroke studies for over 10 years, there is no evidence of an
increased rate of successful translation.25 Others argue that
animal models will always fail to predict human outcomes
reliably because humans and animals are such complex
interactive systems with different evolutionary trajectories that
even small differences between species could be important.36
The genomic and inherent differences between rodent and
human physiology are increasingly acknowledged,37 and even
non-human primates have many differences in the epigenome
that fundamentally affect the functionality of the genome38 and
may account for their lack of success in predicting clinical
response.39-41 Even if the research was conducted faultlessly,
animal models might still have limited success in predicting
human responses to drugs and disease because of inherent
inter-species differences in molecular and metabolic pathways.42
The use of transgenic animals, in which the genome has been
changed by insertion of foreign genetic material, attempts to
increase the validity of animal models by making them more
closely resemble human phenotypes of interest. Yet transgenic
models, where genes are regarded as operating largely
independently of each other, have been criticised as limited,43
oversimplistic, and, at least to date, as contributing more to an
idea of therapeutic promise than actual clinical outcomes.21 36
Furthermore, it has been observed that transgenic animals do
not always produce the desired phenotype after cross breeding
several generations, thereby undermining the rationale for this
research strategy.26
Attempts to improve animal research and
reporting
In response to the serious deficiencies found in the conduct and
reporting of animal studies the ARRIVE (Animal Research:
Reporting In Vivo Experiments) guidelines 44 were produced in
2010. Over 300 journals and the major UK funding agencies
have endorsed these guidelines, but a recent survey of papers
published in Nature and PLoS found little improvement in
reporting standards.45 A Gold Standard Publication Checklist
has also been developed by SYRCLE (Systematic Review
Centre for Laboratory Animal Experimentation) in the
Netherlands to encourage more rigour in the conduct, not just
reporting, of animal research.46
Michael Festing, a retired Medical Research Council scientist,
recently acknowledged that few basic scientists receive any
formal teaching, most relying on what they learn from their
supervisor.47 Similarly, the leadership of the National Institutes
of Health in the US recognises that poor training may in part
be responsible for the lack of reproducibility of animal models.48
The UK Fund for the Replacement of Animals in Medical
Experiments now offers voluntary workshops in experimental
design and statistical analysis, and an online course in
experimental design (www.3rs-reduction.co.uk) has been
developed. Training is also available for preclinical investigators
to learn how to conduct systematic reviews (www.syrcle.nl).
In 2008 the Medical Research Council (MRC) funded a pilot
“research translator” at an English university hospital site to try
to facilitate the translation of findings from bench to bedside.
One of the findings from a qualitative study investigating this
initiative was that basic scientists’ motivation came from
scientific discovery rather than the application of their findings
to medicine.49 Recent attempts to improve translation within the
animal research community include the “co-clinical trial” in
which preclinical trials explicitly parallel ongoing human phase
I and II trials50 and the development of a scoring system to
identify biomarkers that better predict therapeutic success.51
Time for change
The culture within research is shifting, and animal research is
no longer as immune from challenge or criticism as it once was.
Nonetheless, although science is more self critical, in practice
it can be difficult to achieve change because stakeholders
(governments, funders, universities, allied research industries,
and researchers) may all have interests, not infrequently
financial,52 in continuing to do things as they have always been
done. Although there are also valid criticisms of clinical
research,53 urgent attention needs to be paid to the quality of
animal research for important reasons.
Much clinical research follows on from animal research. If the
foundations of the biomedical research enterprise are unsound,
then whatever is built on these foundations will be similarly
precarious.
The current situation is unethical. Poorly designed studies and
lack of methodological rigour in preclinical research may result
in expensive but ultimately fruitless clinical trials that needlessly
expose humans to potentially harmful drugs or may result in
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BMJ 2014;348:g3387 doi: 10.1136/bmj.g3387 (Published 30 May 2014) Page 2 of 3
ANALYSIS
other potentially beneficial therapies being withheld. Moreover,
if poorly conducted studies produce unreliable findings, any
suffering endured by animals loses its moral justification because
their use cannot possibly contribute towards clinical benefit.
Non-publication of animal studies is similarly unethical because
the animals involved cannot contribute towards the accumulation
of knowledge and because non-publication may result in further,
unnecessary animal and human experiments. 13
In addition to intensifying the systematic review effort,
providing training in experimental design and adhering to higher
standards of research conduct and reporting, prospective
registration of preclinical studies,54 and the public deposition of
(both positive and negative) findings would be steps in the right
direction.18 Greater public accountability might be provided by
including lay people in some of the processes of preclinical
research such as ethical review bodies55 and setting research
priorities.28 However, if animal researchers continue to fail to
conduct rigorous studies and synthesise and report them
accurately, and if research conducted on animals continues to
be unable to reasonably predict what can be expected in humans,
the public’s continuing endorsement and funding of preclinical
animal research seems misplaced.
We thank SABRE Research UK (www.sabre.org.uk) for the use of its
archive.
Contributors and sources: PP has conducted research in the sociology
of medicine for over two decades and has a particular interest in
evidence based medicine in animal research. MB is an epidemiologist
who teaches and has considerable experience in evidence based
medicine. He has been an active member of the Cochrane Collaboration
from its inception and has a particular interest in research methods. PP
conceived the idea for this article and wrote the first draft. MB contributed
his knowledge, expertise, and critical eye to subsequent drafts. PP is
the guarantor.
Competing interests: We have read and understood BMJ policy on
declaration of interests and have no relevant interests to declare.
Provenance and peer review: Not commissioned; externally peer
reviewed.
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Cite this as: BMJ 2014;348:g3387
© BMJ Publishing Group Ltd 2014
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BMJ 2014;348:g3387 doi: 10.1136/bmj.g3387 (Published 30 May 2014) Page 3 of 3
ANALYSIS
Key messages
The conduct, reporting, and synthesis of much animal research continues to be inadequate
This current situation is unethical since animals and humans participate in research that cannot produce reliable results
There is insufficient systematic evidence for the clinical benefits of animal research
Greater rigour and accountability is needed to ensure best use of public funds
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BMJ 2014;348:g3387 doi: 10.1136/bmj.g3387 (Published 30 May 2014) Page 4 of 3
ANALYSIS
