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Journal - Animal studies: a good guide for
clinical trials?
From News @ nature.com (Science
Journal)
Animal studies: a good guide for clinical trials?
Study reveals animal experiments often fail to predict outcomes
in humans.
Jim Giles
Just how useful are animal
experiments in predicting the outcome of human trials of new
medicines?
Animal-rights activists have long claimed that
differences between humans and animals make experiments in species
such as rats of little use. Most scientists disagree, saying that
drug development would be impossible without initial tests in
animals (see our Animal research special).
http://www.nature.com/news/specials/animalresearch/index.html
Now
a team of medical researchers has published in the BMJ1 results from
what they say is the first attempt to produce a scientific,
quantitative answer to this question. The results provide food for
thought for any scientist who works with animals.
The
authors say they have highlighted serious problems with the way in
which animal research is translated into human trials. Only half of
the small sample of tests analysed by the team so far produced the
same results in animals as they did in people.
The team
stresses that this is not an argument against doing animal studies.
Even so, the paper is likely to be seized on by
activists.
Data match
The researchers started by
taking six sets of clinical trials that had produced definitive
answers as to whether specific treatments for conditions such as
stroke and head injury are useful or not. They then assessed whether
the prior animal research had given similar results to the human
trials. The results, published today, say that the sets of data
matched in only three of the six cases.
When the team
investigated the reasons for this, they exposed a series of problems
with the animal data. Many studies did not allocate animals randomly
to control and treatment groups, a problem that is known to
introduce bias into clinical trials. Comparison of experiments on a
stroke treatment also suggested that studies showing negative
effects are more likely to go unpublished, skewing impressions of
efficacy.
Work on a model of head injury was undermined by
the use of a model that did not match the later clinical trials.
Rodents were injured and then treated five minutes later, says Ian
Roberts, an author on the study and an epidemiologist at the London
School of Hygiene and Tropical Medicine. In the clinical trials,
which are based on hospital admissions, patients are typically
treated within three hours of being injured.
Design
challenge
Although the results could be seen as evidence that
animal work does little to inform clinical studies, the authors
stress that their results show only that more time needs to spent
thinking about how to translate research between the two spheres.
Better-designed models and an awareness of publication bias are two
priorities, they say.
Other researchers question whether the
results are really as alarming as they sound. Robert Lechler, an
immunologist at Kings College London, says that designers of
clinical trials are already well aware of limitations in animal
models. He says that scientists apply an "intelligent filter" when
looking at such tests, and that crude comparisons between the
outcomes of animal and human studies do not capture this.
But
Peter Sandercock, a neurologist at the University of Edinburgh and
an author on the study, says the paper shows that more needs to be
done on this front. If such a filter was applied, he points out, the
animal models of head injury would have been repeated using a better
design before human studies started. "This is not a polemic against
animal research," stresses Sandercock. "But we need to be aware that
there are biases in the animal trials."
Visit our newsblog
http://blogs.nature.com/news/blog/2006/12/animal_research.html to
read and post comments about this story.
Oxford Vivisectionists are Swimming Against
the Tide
[ http://www.vero.org.uk/press7.asp
]
Vero. 24 December 2006.
Oxford Vivisectionists are Swimming
Against the Tide.
Marius Maxwell
Marius
Maxwell
As a neurosurgeon and neuroscientist with two decades
of
research experience, I feel qualified to contribute to
the
debate on non-human primate vivisection. The arguments of
the
Weatherall Committee defy much current scientific
evidence,
and have served only to confirm my view that the
data
supporting non-human primate vivisection are
profoundly
flawed and together with the moral case are
indefensible.
I concur with the findings of the crucial Perel
study in the
December 15th (2006) issue of the British Medical
Journal
(www.bmj.com ), which represents a comprehensive
and
quantitative statistical meta-analysis to test the
usefulness
of a broad spectrum of animal based drug testing
in
predicting human outcomes. This analysis, which
undermines
the conclusions of the Weatherall Committee, found
that only
three of the six categories actually succeeded in
predicting
the results of subsequent human trials and that in all
animal
experimentation studied "the quality of the experiments
was
poor." No better than the toss of a coin in other words.
The
predictive power may actually be even worse, since the
study
found evidence of broad publication bias in those
experiments
that did predict human outcome. They concluded
that
"Discordance between animal and human studies may be due
to
bias or to the failure of animal models to mimic
clinical
disease adequately."
It is important to bear in mind
that these six areas
represent a vast cross section of animal
based drug studies
including stroke, head injury, systemic
haemorrhage, neonatal
respiratory distress and osteoporosis. A
total of 228
published animal studies were scrutinized
representing many
thousands of animal test subjects including
non-human
primates. This is only the last in a long series of
studies
critical of the predictive ability of animal
experimentation
to human health care with some yielding
predictive
concordance rates as abysmally low as 5 per
cent.
The ultimate effect of such imprecise animal-based
research
is reflected in tens of thousands of unnecessary human
deaths
before the responsible drugs are finally withdrawn.
Examples
include: the use of steroids in human head and spinal
cord
injury; drugs such as rtPA in stroke treatment;
hormone
replacement therapy (HRT); Vioxx; TG1412 at Northwick
Park
hospital; amrinone for heart failure; an Alzheimer's
vaccine
in 2001; and 80 HIV/Aids vaccines which have have failed
in
over 100 clinical trials, despite testing in
non-human
primates on a massive scale. The gratuitous use of
non-human
primates in much psychological and behavioural
laboratory
experimentation does, based on my review, infrequently
fall
short of scandalous. Alternative, state of the
art
non-animal-based methods of accurately predicting drug
safety
include microdosing and in vitro assays, human DNA chips,
and
virtual human organs.
The Weatherall Committee stated that
research on animals,
including non-human primates, might
alleviate "continued
suffering to very large numbers of
humans..." But it is now
clear that the use of animals in drug
screening is actually
endangering countless human lives.
Extensive, unbiased, and
dispassionate meta-analyses of the
accuracy and validity of
animal research should be the only
yardstick employed in this
debate.
Doctors, pharmacists, and
patients groups in the Netherlands
are now demanding government
action after a national study
has found that drug related
problems caused twice as many
hospital admissions as motor
vehicle accidents (www.bmj.com ,
15th December 2006).
The December 13th (2006) issue of Nature
(www.nature.com ) also has a timely but troubling review of
animal research and
demonstrates that the tide is changing
inexorably against animal
vivisection. There is discussion of
the recent (December 2005)
Swiss reform of an animal welfare
law to protect the "dignity of
creation" of animals. This
rightly has had the effect of
progressive denial of funding
for non-human primate
research.
Many are fond of claiming the importance of animal
research
to early scientific discoveries as if the same
historical
models bear any relevance at all to contemporary
science.
Obviously animal research in the past century, in the
absence
of better alternatives, has benefited mankind as did
ancient
studies of human anatomy. Michelangelo's anatomical
drawings
and William Harvey's description of human circulation
spring
to mind, but who would seriously argue that
cadaveric
dissection represents cutting-edge science
today?
The field of Parkinson's Disease (PD) research was
greatly
stimulated by the therapeutic attempts of neurosurgeons
using
dopaminergic brain transplantation in animals and
humans
which came to the fore in the 1980's and have since
largely
receded. There have been too many false positives to
record
here. Many possible false negatives may also have
been
ignored as part of widely documented publication bias.
The
most common non-human primate model of PD results
from
monkeys being poisoned with the neurotoxin MPTP. It is
widely
acknowledged that profound disparities
(anatomical,
physiological, neurochemical, pathological, and
temporal)
exist between the MPTP non-human primate model and
humans
with idiopathic PD. Despite these paramount concerns of
human
reproducibility, hundreds of studies involving thousands
of
animals have followed with conflicting and
non-predictive
results. There is no evidence to suggest that
their overall
predictive concordance with human PD treatment, if
subjected
to the meticulous quantitative analysis of Perel
and
co-workers above, would exceed the best case 50:50 coin
toss
probability established.
Neurosurgeons have employed
precise coordinated stereotactic
techniques in the treatment of
PD, with subtle variations in
deep brain nuclear targets, since
the 1950's based on human
observation. The technique of deep
brain stimulation (DBS)
was discovered through experimentation in
patients with PD
(not in animals) in 1987. Though not a cure for
PD, it does
ameliorate some of the symptoms and is accompanied by
a
troubling incidence of depression, often suicidal. It
is
important to understand that ethical clinical research
of
actual consenting end stage human PD patients themselves
has
been conducted now for decades. Those are precisely
the
results that can be accurately translated to other
human
sufferers. Although researchers have rushed to duplicate
and
extend these studies in the neurotoxin non-human
primate
models, I am not persuaded that the nuances in deep
brain
nuclear therapeutic identification could not have been
more
accurately identified in the very PD patient cohorts
which
gave rise to the technique of DBS itself.
As an Oxford
graduate I am appalled by the decision of Oxford
University to
proceed with the construction of the animal
research laboratory
on South Parks Road. They are swimming
against the tide of
international medical and ethical
opinion. I fear that history
will judge their animal rights
opponents as less extreme than the
very scientists who
persist in non-human primate research in the
face of an
increasing body of consistent and compelling evidence
that
the resulting data has and will continue to
endanger
countless human lives.
The spectacle of a minority of
Oxford animal researchers
tirelessly promoting their claimed
achievements before the
media has caused me deep unease. They
have surprisingly gone
on record in backing the use of animals in
cosmetic testing
and urging the return to the use of great apes
in
experimentation, activities which have been illegal in the
UK
for many years. In my experience, the humility and
reticence
characteristic of truly eminent scientists
reflexively
precludes such behaviour and the protagonists
should
understand that because of obvious bias they should be
the
very last people to loudly judge the merits of their
own
work. The recent BBC2 documentary (Monkeys, Rats and Me,
27th
November, 2006) on non-human primate vivisection was
wholly
emotional and lacking in any truly scientific balance
or
objectivity. I found the images of severely affected
patients
being presented to back their doctor's various
therapeutic
assertions to be regrettable. This is not the way to
present
a controversial scientific case for critical
public
evaluation. Many of my Oxford colleagues in
world-class
scientific laboratories, and in the humanities, are
privately
aghast at the ability of a small group of
media-savvy
vivisectionists to hold the debate hostage and
thereby
besmirch the international reputation of their
University.
They are unwilling to broadcast their opinions
because of the
perceived danger of recrimination by the
University and
funding bodies.
The techniques and language of
frontier-breaking molecular
genetic technology, for example, are
largely unintelligible
to those unschooled in their use and
therefore pose hurdles
to inter-disciplinary scientific
understanding. This may be
an explanation for why many
vivisectionists are not fully
aware of all the applicable
developments in other facets of
enquiry into the same disease and
seem overly anxious to
declare emphatically and prematurely that
no alternatives to
non-human primate research can conceivably
exist in the
foreseeable future. You may add to this the natural
human
reluctance of animal researchers to turn their back on
many
years of endeavour and learn anew contemporary
scientific
protocols.
British neurosurgical colleagues of mine
have expressed
concerns that the acrimonious debate over
non-human primate
vivisection and functional neurosurgery (such
as DBS) at
Oxford has begun to detract from and overshadow many
other
achievements of their profession. DBS is an important
and
successful adjunct to the treatment of PD, is derived
from
experimentation on human subjects, and helps less than 1%
of
all neurosurgical patients. They are also worried about
the
wisdom and balance of allocation of precious
financial
resources within the cash-strapped NHS and medical
research
sectors.
The 'spin' perpetuated by overly credulous
and biased media
reporting that opponents of animal
experimentation are
'anti-science Luddites' is hollow. How on
earth can an animal
researcher still claim to be pro-science
while wilfully
ignoring the vast body of current evidence
undermining broad
swathes of animal research? It is extraordinary
how many
media reports of the significance of recent studies
casting
doubt upon the accuracy and reliability of animal
research
are casually undermined by the irrelevant assertion that
they
will only serve as grist to the mill for "animal
rights
activists." Surely the end-point of the debate should
be
human safety. Simply stated, the fact of the matter is
that
animal research in general has now been revealed to be
dodgy
science which ultimately endangers human lives.
The
debate is further muddied by the strident claims of
dubious
'citizens' groups. Their sources of funding should be
scrutinised
before their claims of legitimacy can be
believed. This activity
is reminiscent of the tactics
employed by tobacco companies to
cast doubt and aspersions
upon the vital causal link established
between cigarette
smoking and lung cancer by the Oxford
epidemiologist Sir
Richard Doll in 1950. By deliberately delaying
the societal
recognition of the dangers of smoking for decades,
untold
deaths were caused. Parallels with tobacco litigation
are
being developed by various plaintiffs' lawyers involved
in
class action suits against drug manufacturers and
will
demonstrate that the latter have long been aware of
the
dangerous imprecision of animal drug testing models to
human
outcomes thereby making them liable for much greater
damages.
History has a tendency of repeating itself, I thought,
as I
recently read the scathing report of the planning
inspector
who conducted the public enquiry into Cambridge
University's
controversial primate laboratory in 2002. He
concluded that
no national need for brain research on primates
had been
demonstrated. Cambridge University wisely cancelled
the
project. The economic reasons for non-human primate
research,
while obvious and most lucrative, are shortsighted
and
damaging, and are no more compelling now than they were
in
2002. Research and development of more accurate and
more
ethical alternatives will easily fill the income shortfall
to
the University following a much-needed moratorium
on
non-human primate research.
I would urge that the South
Parks Road building be made into
a world-class medical imaging
and research centre. The
explosion of imaging techniques over the
past decade
(functional MRI being but one) has alone obviated the
need
for non-human primate vivisection especially in
the
neurosciences. Humans can and are being studied in ways
that
would have been unimaginable only ten years ago. The
eighteen
million pounds for the animal research building could
be
better spent by Oxford University with a more
inspired,
rational and forward-looking appreciation of the
trajectory
of medical research technology.
It is clear to
anyone who cares to study the matter closely,
honestly and
objectively that the scientific justification
for non-human
primate vivisection is unsound. I cannot accept
that its
practitioners really believe it to be morally or
ethically
defensible either. The argument that supports
non-human primate
experimentation because of close kinship to
humans but, blind to
their moral worth, denies them ethical
rights, is sinister and
repugnant. The resigned and credulous
"Nasty but necessary"
defence of non-human primate research
coined by a Guardian Leader
(13th December, 2006) is
simplistic, naive, and selectively
ignores the mountain of
conflicting scientific data.
Sadly,
history reminds us that doctors and scientists have
often been
blind to the moral dimensions of their work. It is
instructive to
recall that only little more than sixty years
ago, unspeakable
and nightmarish forced human vivisection was
performed by the
notorious Unit 731 of the Japanese Army
during development of
their wartime chemical and biological
weapons programmes (The
Guardian, 27th November, 2006).
The general public, a clear
majority of whom is opposed to
animal research, deserves to be
educated about the dangers of
and protected from adverse drug
reactions stemming from weak
and outdated animal research
protocols. If scientists as a
group fail to serve society by
adequately and transparently
policing the dangers and
inconsistencies of their own
research, parliament will have to
step in to insist upon a
rigorously objective assessment of all
aspects of the drug
safety testing process.
Indeed, the
Toxicology Working Group of the House of Lords
Select Committee
on Animals in Scientific Procedures in 2002
recommended that "the
reliability and relevance of all
existing animal tests should be
reviewed as a matter of
urgency."
Following the recent
catastrophic Northwick Park clinical
study, 250 MPs (a clear
majority of those eligible to do so)
signed Early Day Motion 92:
"That this House, in common with
Europeans for Medical Progress,
expresses its concerns
regarding the safeguarding of public
health through data
obtained from laboratory animals,
particularly in light of
large numbers of serious and fatal
adverse drug reactions
that were not predicted from animal
studies; is concerned
that the Government has not commissioned or
evaluated any
formal research on the efficacy of animal
experiments, and
has no plans to do so; and, in common with 83
per cent of
general practitioners in a recent survey, calls upon
the
Government to facilitate an independent and
transparent
scientific evaluation of the use of animals as
surrogate
humans in drug safety testing and medical
research."
This issue fundamentally turns upon absolute
scientific
objectivity, integrity and morality. The controversy
will
continue to afflict the University, will not dissipate
and
cannot be legislated away. Scientific and
non-scientific
anti-vivisectionists alike have every right to be
heard and
to occupy the moral high ground of their esteemed
Oxford
forebears Johnson, Ruskin and Lewis. The end of
non-human
primate experimentation is nigh and I suspect that its
few
remaining adherents well know it. The construction of
the
South Parks Road animal facility will continue to fester
like
a "carbuncle on the face of an old friend" until
the
University finally comes to its senses and has it
excised.
"I know not by doing any living dissection any
discovery
[that] has been made by which a single man is more
easily
cured," wrote Samuel Johnson, the eighteenth century
Oxford
lexicographer who condemned doctors who "extend the art
of
torture" by performing research on animals. Time has
finally
proven the good Doctor right.
Marius Maxwell MBBChir,
DPhil
mariusmaxwell1@gmail.com |
