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[SANET-MG] science in socieity 31
ISIS Press Release 29/08/06
Announcing Science in Society #31, Autumn 2006
The Only Radical Science Magazine on Earth
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From the Editor
It is five months since the catastrophic clinical trial of the drug
TGN1412 in London. All six victims have survived so far, but their
future is bleak. According to laboratory tests and medical reports seen
by the International Herald Tribune, they have severely damaged immune
systems and are likely to suffer immune problems for the rest of their
lives. One is showing early signs of cancer.
This would be a tragic situation however it came about, but there is
overwhelming evidence that it could and should have been avoided. Two
major investigations and statements made by many scientists with
experience in monoclonal antibody drugs have confirmed our initial
suspicion that a cytokine storm, which caused the violent illnesses, was
by no means totally unforeseeable as has been claimed (see London Drug
Trial Catastrophe – Collapse of Science and Ethics; Warnings on FDA
Approved Monoclonal Antibody Drugs; Post Mortem on the TGN1412 Disaster;
Science in Society 30). It was a risk that ought to have been
anticipated, and the body responsible for regulating drug trials, the
Medicines and Healthcare products Regulatory Agency (MHRA) has shown
itself to have a dangerously limited view of its responsibilities.
In the light of what was known at the time of the drug trial, we need to
ask some serious questions.
The role of the company that developed the drug
Why did TeGenero, the company that developed TGN1412, not realise this
was a potentially hazardous trial and ensure that it was carried out
under conditions that would reduce the risk to an acceptable level?
There is nothing in the protocol for the trials or in the information
given to the volunteers to suggest they did.
It’s not that they didn’t know about cytokine storms. On the contrary,
they state on their website: “A pronounced T-cell activation and
expansion mediated by CD28-SuperMAB(®) in animal models is accompanied
by the expression of anti-inflammatory cytokines, like IL-10, rather
than by the toxic cytokine storm of pro-inflammatory mediators induced
by other agents that address the TCR complex.”
In other words, it is not at all unexpected that a drug of this kind
should cause a cytokine storm. The special feature of CD28-SuperMAB is
that it does not, at least not in the animals it was tested on. Like all
monoclonal antibodies, however, it cannot be used in humans in its
original form. It has to be genetically modified to make it
immunologically acceptable to humans, which means that the drug used in
the trial is inevitably different from the one that was tested on animals.
Thus, when the trials began, TGN1412 was known to be one of a class of
drugs that can cause cytokine storms. The drug it was derived from did
not do this in the animal tests and TGN1412 had not done it when tested
in monkeys; if it had there would have been no question of testing it in
humans. In the light of this, it is astonishing that TeGenero did not
feel the need to be especially cautious, especially in view of the
recognized species specificity of such drugs.
Parexel did not even follow the simple and relatively common practice of
giving the drug to only one volunteer first and waiting long enough to
see there were no untoward reactions before proceeding. And the doctors
in the intensive care unit at Northwick Park have said that it was hours
after the volunteers reached them before the Parexel team informed them
of the possibility of a cytokine storm. Only then did they begin to
treat their patients with high doses of steroids to blunt the immune
Other companies have been more prudent. In May this year, the BBC
reported that Dr Harsukh Parmer, the Director of Discovery Medicines for
AstraZeneca had said his company is also developing drugs of this kind.
He had added that when working with monoclonal antibodies, the company
carries out a wider range of tests than normal before proceeding to
human trials. Even then, they begin by putting ultra low concentrations
just under the skin, rather than straight into the blood stream.
The role of UK drug trials watchdog
What exactly is the role of the UK Watchdog MHRA (Medicines and
Healthcare products Regulatory Agency)? In its investigation, it found
no errors in the manufacture of the drug or in the way it was given to
the trial participants. It concluded that, “an unpredicted biological
action of the drug in humans is the most likely cause of the adverse
reactions in the trial participants.” It said that the agreed protocol
had been followed, but made no comment about whether the protocol had
been appropriate for a trial of this sort of drug.
The MHRA does make some criticisms, but none that it considers material
to the disastrous outcome. It found that Parexel, the company that
carried out the trial, had failed to check that TeGenero’s insurance
actually covered the volunteers. The MHRA does not, however, explain why
it did not verify this as part of its approval of the protocol, as one
would expect. The counter clerk at my local Post Office, for example,
demands to see my third party liability insurance when I pay the annual
tax on my car. In fact, the volunteers were insured but only for a total
of £2 million, which may well be considerably less than the compensation
they will be awarded. Someone should have checked this before the trial;
Damning reports by Expert Scientific Group and by drug industry
There have been two substantial reports since that produced by the MHRA.
One is by an Expert Scientific Group (ESG) set up by the UK Department
of Health, and the other is by a joint task force of the UK BioIndustry
Association (BIA) and the Association of the British Pharmaceutical
Industry (ABPI). These reports are comprehensive and damning, in
complete contrast to that of the MHRA.
The BIA/ABPI report states:
“…there are sufficient signals in the publicly available data, and in
historical precedents, to indicate that a very cautious approach is
appropriate when assessing the risk, the starting dose and the study
design with first-in-human studies with a potent agonist antibody such
What they are saying is that it was obvious to many scientists both in
universities and in industry that special care is required in clinical
trials using any drug like TGN1412.
The ESG report contains a list of 19 recommendations. Some, such as
being far more careful in trials of novel drugs, are already “best”, if
unfortunately not universal practice. They also recommend far more
transparency and the sharing of information on the results of phase one
clinical trials in general and Suspected Unexpected Serious Adverse
Reactions (SUSARs) in particular.
Fragmentation of the pharmceutical industry a factor not considered
One factor not considered by these Reports is that the pharmaceutical
industry, like other industries, has become fragmented. The major
companies do not carry out all their research in house. Many new
products originate in small firms and are only taken up by the big
companies when they are past the early stages of development.
There are some advantages to this, but it has meant that the clinical
trial of TGN1412 involved four companies: TeGenero, who developed it,
Boehringer, who produced the samples used in the trial, Parexel, who
conducted the trial, and an unnamed company that had carried out the
trials on monkeys. As with the British railway system after
privatisation, it appears there was no one with an overview of the
entire process, no one with overall responsibility. Were the people at
Parexel who designed the trial fully aware of the nature of the drug
they were testing? If they were, they said nothing about it in the
information they gave to the volunteers.
It also makes it harder for the victims to get adequate compensation.
TeGenero has filed for insolvency; whereas a major pharmaceutical
company would have the resources to pay whatever damages are awarded.
Merck may be badly hurt by the Vioxx scandal but it is highly unlikely
to go under.
A new regulatory body needed
As we write, six previously healthy young men are facing lifetimes of
immune-related illness and the distinct possibility of early death.
Despite what the experts in the field are saying, those responsible for
the trials insist that they did everything properly, that what happened
was completely unforeseeable. The regulatory body that should have
intervened continues to back them up, also in the face of all the evidence.
The regulation of drug trials in the UK is clearly inadequate, and the
problem is made worse as the pharmaceutical industry becomes
increasingly international. The Food and Drug Administration in the USA
is currently embroiled in several drug trial scandals amid widespread
accusations of conflicts of interests in a high proportion of its
scientific advisory panels (this issue). More and more trials are being
carried out in third world countries where regulation is less stringent;
Parexel, for example, is expanding its operations in Latin America.
The World Health Organisation is in the process of setting up an
International Clinical Trials Registry so that the information from
trials anywhere in the world can be accessed (WHO Registry of Clinical
Trials, SiS30). There must also be internationally agreed standards for
trials. And as a first step, the UK must get its own house in order.
The MHRA sees its task only as verifying that the right boxes have been
ticked on a standard protocol, and it doesn’t do even that very well.
After the incident, it had nothing to say beyond that what had happened
had been unpredicted, when there is a consensus among the experts that
it should have been anticipated.
Clinical trials are too important and potentially too hazardous to be
regulated in such a casual manner. We need a new regulatory body with
the scientific expertise to look critically and independently at all the
trials that are submitted to it and the authority to reject any that do
not satisfy the strict requirements.
All SiS articles cited can be accessed on ISIS members website:
Transgenic Maize with Monoclonal Antibodies Grown in France
USDA Proposes to Deregulate Its Own Transgenic Plum
GM Protein in Ice Cream
GM Egg Plant Contains Bt Toxin Linked to Hundreds of Allergy Cases and
Thousands of Sheep Deaths
Save Our Oceans Save Our Planet
Oceans in Distress
Oceans and Global Warming
Oceans Carbon Sink or Source?
Shutting Down the Oceans Act I: Acid Oceans
Shutting Down the Oceans Act II: Abrupt Plankton Shifts
Shutting Down the Oceans Act III: Snuffing out the Green Fuse
Global Warming Is Happening
Gene Therapy Nightmare for Mice: Could Humans be Next?
GM Probiotic Bacteria in Gene Therapy
Letters to the Editor
Parliament Launch of Which Energy?
Which Energy? Gets High Praise At Launch
ISIS Energy Report Gets Cross Party Support
v Nuclear Power: A Leap into the Dark Energy Chasm
The Slow Burning Fuse of Sustainability
How to be Food and Fuel Rich Under Climate Change
Recycling All Resources for Sustainability
Dream Farm 2 - Story So Far
Science and Government
FDA in Third World Drug Trial Scandals
FDA Under Fire for Corporate Links that Compromise Science
Beauty and the Beast - Flowers can Pollute
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