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
New Statesman, 3rd April 2006
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
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.
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