http://www.gmwatch.org/archive2.asp?arcid=6417

Calamitous GM drug trial raises questions about modern science
(5/4/2006)

1.Ziauddin Sardar takes a drugs trial
2.'No faults in calamitous drug trial'

The genetically engineered drug TGN1412 given to six men in a clinical
trial who subsequently suffered multiple organ failure has been found
not to have been contaminated during the manufacturing process. It also
appears to have been administered to the men according to the proper
protocols.

This suggests the adverse reactions suffered by the trial volunteers
were caused by the nature of the drug itself. (item 2)

The first article below considers how "this tragedy provides us with an
opportunity to think about the nature of science itself." (item 1)

EXCERPTS: "The researchers were ignorant of their own ignorance. But,
as a New Scientist investigation revealed, they also failed to consider
the possibility of things going wrong. In other words, ignorance was
written out of the equation. This double ignorance, or
ignorance-of-ignorance, is rapidly becoming a dominant theme in
science."

"this tragedy provides us with an opportunity to think about the nature
of science itself. How radically science has changed. How intrinsic
uncertainty has become to scientific practice."

"The only sensible way to handle risk is by learning to respect
uncertainty. The alternative is to stumble along blindly from tragedy
to disaster. This time it was a clinical trial that went wrong, with
tragic consequences for six volunteers. In the case of nanotechnology,
for instance, there could be serious repercussions for us all."
---

1.Ziauddin Sardar takes a drugs trial
Ziauddin Sardar
New Statesman, 3rd April 2006
http://www.newstatesman.com/200604030017

Science has ceased to be normal "puzzle solving". Welcome to the era of
post-normal science, writes Ziauddin Sardar

Science is not what it used to be. We tend to become aware of this
every time a disaster occurs in which science is implicated. The
tragedy of the recent drug trial at Northwick Park Hospital in London
is a good example. The six human guinea pigs suffered multiple organ
failure within hours of taking an experimental drug. Two of them are
still in a critical condition.

So what went wrong? The volunteers were given the smallest possible
dose of TGN1412, an anti-inflammatory medicine made by the German
pharmaceutical company TeGenero. Intended to fight leukaemia,
rheumatoid arthritis and multiple sclerosis, it had already been tested
on animals. TeGenero insists that it followed "best practice". The
Medicines and Healthcare Products Regulatory Agency (MHRA), which
halted the trial, is investigating whether the reaction suffered by the
men was caused by a manufacturing problem, contamination, a dosing
error, or whether it was some "completely unanticipated side effect of
the drug in humans".

The scope of the MHRA inquiry suggests we are dealing with a system
involving a range of actors and many different stages. Anything could
have gone wrong at any, or all, of these stages; and any one or all of
the actors involved could have botched things unwittingly. This is not
"textbook" science, where everything is arranged so that nothing goes
wrong and there is only one answer to every problem. Science in the
real world is a dirty, highly complex business.

But the MHRA's brief tells us something more. "Completely unanticipated
side effect" is a euphemism for ignorance. In the real world, science
and ignorance go hand in hand. There are two aspects to this ignorance.
The testers assumed that we know enough about the immune system to
proceed confidently. But the immune system is mind-bogglingly complex
and our understanding of it is rather limited. The researchers were
ignorant of their own ignorance. But, as a New Scientist investigation
revealed, they also failed to consider the possibility of things going
wrong. In other words, ignorance was written out of the equation. This
double ignorance, or ignorance-of-ignorance, is rapidly becoming a
dominant theme in science.

Normally, such testing is done with full awareness of its risks. That
is why we have the whole machinery of prior checks and approvals to
ensure safety, or, in other words, quality. Frequently, when something
goes drastically wrong, it turns out that the quality-control machinery
was not operating well: that is, the quality-of-quality was defective.
This may turn out to have been the case with the Northwick Park trials.
What this implies is that regulatory checks were either bypassed or
rubber-stamped. Most of the time, it doesn't matter - but sometimes it
does.

It mattered in the fatal case of Jesse Gelsinger. In 1999, 18-year-old
Gelsinger volunteered to take part in gene therapy trials at the
University of Pennsylvania. To get the corrective genes into his
system, he was injected with the common-cold virus, laced with copies
of the genes. Doctors had calculated that he required a huge dose, but
no one had done the maths which would have shown that the virus itself
could kill him. Is this what happened in the TGN1412 trial - no one had
worked out that super-stimulating the immune system could lead just as
easily to a catastrophe as to a cure?

We do need to develop drugs that use the immune system. But this
tragedy provides us with an opportunity to think about the nature of
science itself. How radically science has changed. How intrinsic
uncertainty has become to scientific practice. How
ignorance-of-ignorance is inherent in all scientific endeavour. How
every advance in science brings its own risks. In other words, science
has ceased to be normal "puzzle solving". Welcome to the era of
post-normal science.

The man who has pioneered our understanding of post-normal science just
happens to be my best friend. Way back in 1971, Jerry Ravetz
established himself as one of our most prominent philosophers of
science with his book Scientific Knowledge and Its Social Problems. In
the 1980s, he highlighted the benefits and risks of genetically
engineered organisms - that work remains unsurpassed. In the 1990s, he
developed a whole new mathematics for dealing with scientific risk and
uncertainty. Now, once again, he is venturing where most scientists and
philosophers fear to tread.

Scientists don't like their critics; they are even less keen on
philosophers of science. But we ignore Ravetz at our peril. Science has
become a multidimensional process, says Ravetz, now at the James Martin
Institute for Science and Civilisation in Oxford. We need new ideas to
understand it and new tools to manage the risks involved. The only
sensible way to handle risk is by learning to respect uncertainty. The
alternative is to stumble along blindly from tragedy to disaster. This
time it was a clinical trial that went wrong, with tragic consequences
for six volunteers. In the case of nanotechnology, for instance, there
could be serious repercussions for us all.

I think it's time we paid attention. Ravetz's ideas about risk,
ignorance and quality may just hold the key to our survival.

The No-Nonsense Guide to Science by Jerry Ravetz is published by
Verso/New Internationalist (GBP7)
---

2.'No faults in calamitous drug trial'
Staff and agencies
Wednesday April 5, 2006
http://www.guardian.co.uk/medicine/story/0,,1747611,00.html?gusrc=rss

There is "no evidence" that an experimental drug given to six men in a
clinical trial who subsequently suffered multiple organ failure was
contaminated during the manufacturing process, the government's
medicines watchdog said today.

The Medicines and Healthcare Products Regulatory Agency (MHRA) said it
appeared that the drug TGN1412 did not contain "anything other than the
correct ingredients".

The regulator, which is responsible for the safety of medicines, also
found no evidence that the trial was run in a way that may have
contributed to the serious reactions suffered by the volunteers.

An interim report by the MHRA cautioned that it could not be certain
about its findings yet, but it seemed TGN1412 produced adverse
reactions in humans that were not picked up by earlier animal testing
of the drug.

The medicines watchdog said the trial, which was carried out by the US
company Parexel, was run according to approved protocol with the
correct dose of TGN1412 given to the volunteers.

"If these findings were to be confirmed, it would indicate that this
product showed a pharmacological effect in man which was not seen in
pre-clinical tests in animals at much higher doses," the regulator's
chief executive, professor Kent Woods, said.

TGN1412 is one of a class of drugs known as monoclonal antibodies. They
are genetically engineered versions of antibodies, the body's natural
immune defences against infections.

Unlike traditional chemically-engineered compounds, monoclonal
antibodies are designed to be accepted by the human body, which experts
say makes it difficult to determine through animal testing what dose
would be toxic to humans.

The health secretary, Patricia Hewitt, today announced the
establishment of a group of international experts to investigate
whether trials of monoclonal antibodies may need to be revised.

Five of the six volunteers have already been discharged from Northwick
Park hospital in north-west London, with the latest allowed home today.
The remaining volunteer is still undergoing treatment but is no longer
in intensive care.

Two of the men, aged between 18 and 40, became critically ill and
another four were left in a serious condition after receiving the drug
during the trial last month.

The drug, developed by German pharmaceutical company TeGenero, was
being trialled for the treatment of leukemia, multiple sclerosis and
rheumatoid arthritis. The trial, carried out at an independent centre
at Northwick Park, was the first time it had been tested on humans.

The MHRA's initial findings appear to confirm speculation by
pharmaceutical experts that the adverse reaction suffered by the trail
volunteers were caused by the nature of the drug itself.