March 19

Poison Chalice–TGN1412_Sunday Times UK

Below are two important articles from Britain’s Sunday Times.,,2087-2092527,00.html
The Sunday Times – Britain
Poison Chalice
March 19, 2006
Lois Rogers, Richard Woods and Brian Deer investigate how a drug trial left six men battling for life

The sales pitch could have been written by a time-share spiv. “You’ll be paid for your time,” it reads. “Free food . . . digital TV, pool table, video games, DVD player and now FREE internet access!” An invitation to one long holiday? No, this is how Parexel, the company at the heart of a medical disaster, recruits human guinea pigs to test new drugs and brave the frontiers of modern science.
One of those lured by the prospect of £2,000 for lazing in a private clinic was David O’Donnell, a 19-year-old student. He told a friend who leapt at the opportunity.
Early last week O’Donnell arrived at the Parexel clinic attached to Northwick Park hospital, north London, to be screened for trials of a drug known as TGN1412. A first trial was just starting and his friend was taking part. O’Donnell was due to prepare for the next round.

To his surprise, researchers said the study had been cancelled and asked him to join another project. They did not reveal that down the corridor, six volunteers in the first trial were, as one witness said, “exploding”. Minutes after being given the drug they had suffered catastrophic reactions, screaming and begging for help. It was like “a living hell”, said a witness.
Among the victims was O’Donnell’s friend. He is one of four men who remain seriously ill in intensive care; they are conscious but, says the hospital, will “need specialist observation for some time”.
Two others are critical and being kept alive by life support systems. Myfanwy Marshall, a girlfriend of one of the victims, said he had swollen up “like the Elephant Man”. “Their condition remains very serious and complex,” said Ganesh Suntharalingam, clinical director of intensive care at Northwick Park. “It would not be sensible to comment on prognosis.” Medical sources say they may be in a coma for a year.

What went wrong? The authorities claim that all the proper procedures were followed; that nothing untoward showed up in earlier laboratory and animal tests of TGN1412; and that the incident was almost unprecedented.

Medical sources point out, however, that in the search for wonder drugs, scientists are now tampering with the very building blocks of life. While science outstrips regulation, commercial testers are still allowed to trawl for human guinea pigs as if they are offering a week on the beach rather than a step into the unknown.
Official guidelines state that payments to volunteers should only be for “expense, time and inconvenience”, and should not “induce people to take part in studies against their better judgment”. Yet the two men hovering between life and death this weekend are Ryan Wilson, 21, a trainee plumber who had hoped to make enough cash to take his mother on holiday, and another man referred to as “a serial human guinea pig”. In four years he is said to have earned £60,000 from drug trials.

THE maker of TGN1412, a German company called TeGenero, belongs to a new breed of small bio-tech firms hunting for miracle cures. The drug began as the brainchild of scientists at Wurzburg University who studied immune cells. They targeted a molecule called CD28, which sits on certain white “T” cells that can influence other cells involved in diseases such as leukaemia and rheumatoid arthritis.

Such research is expensive. So in 2000 the scientists set up TeGenero and raised £9m from venture capitalists and other investors. TGN1412 was the company’s lead product — and at the cutting edge of science. The researchers believed they had engineered a “monoclonal anti-body” — a product that, instead of shutting down harmful processes in the body as a traditional drug might do, actually spurred beneficial systems into action.

Where once the testing of new products was the preserve of academia, now medical research is dominated by commercial interests. When the time came for human trials on TGN1412, TeGenero contracted the task out to Parexel, a US-quoted firm that operates in numerous countries.

Parexel recruits trial volunteers by placing advertisements online or in local papers, where they catch the attention of the young and the poor. Once on the books, guinea pigs get further offers. “The offers keep rolling in via text message,” said Tom de Castella, a former Parexel volunteer at Northwick park. “£650 for three days here, £1,000 for a week there.” Recruiters favour the UK because the regulatory process here is seen as speedy. To critics, the regime is also inadequate.

The body overseeing testing and licensing is the Medicines and Healthcare products Regulatory Agency (MHRA), which is funded by the industry it is supposed to police. The MHRA has to pass judgment on an increasing number of trials that even specialists find hard to understand.

When TeGenero sought approval for human tests on TGN1412, the MHRA had concerns and asked for more information. Eventually it gave the all-clear without consulting outside specialists — which shocked some experts. “I can’t understand it. They are normally super-cautious,” said Angus Dalgleish, professor of cancer at London University and a world expert on the immune system. “I would have told the people doing this trial [on TGN1412] not to do it because the dangers were so great.”

He cited earlier studies of a similar drug that had caused severe side effects: “They should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways.”

The MHRA defended its decision. Its spokesman said: “The application in this particular clinical trial was reviewed by experienced MHRA staff including medical, toxicological and and pharmaceutical experts. From the data provided there was nothing to suggest that this product would be hazardous to man at the doses to be used in the clinical trial. In addition we know that the study was reviewed and approved by an independent ethics committee and by our German counterparts.”

Jorg Schaaber, a member of the German drug industry monitoring group Buko Pharma, said, however, that all trials of monoclonal antibodies — like TGN1412 — had shown the drugs carried “considerable risks” of side effects including fever, severe pain, limb weakness, uncontrollable tremor, vomiting and diarrhoea. “Anyone getting involved in these studies should be made aware of that,” he added.

Guinea pigs do sign “consent forms” that detail the risks; but Tom Edwards, a 21- year-old from Oxford who took part in another Parexel trial, pointed out that his form was 15-pages long. He said he felt “pressured” into signing the form and eventually did so without reading all of it “because I felt like I was slowing everyone down”.

THE TGN1412 trial began last Sunday when eight healthy young men gathered at the 36-bed Parexel centre at Northwick Park. They spent the evening playing pool and watching television. Among them was Raste Khan, a television technician.

Next morning, blood samples were taken. Then the researchers began to administer TGN1412, at one 500th of the dose used in animal experiments. Two of the eight were secretly given placebos. “A few minutes after the first patient had been given the drug he started to shake,” said Khan. “He took his top off, he looked like he was burning up. Several minutes later the third person was vomiting, he was hyperventilating. He looked like he was in the worst pain.

“Then number four, the chap on my right, a big strapping and physically fit fellow, started to react. He was sweating, eventually took his top off and then just collapsed. Everyone was vomiting, there were these big black bin liners filled up with vomit. “The chap on my left was in pain, he was screaming his back was hurting — it was like someone was punching him in the back because he kept arching forwards.”

Khan was terrified. Would he be affected too? Gradually he realised that he had received a placebo. The six victims were undergoing a massive biological reaction. Body temperatures were soaring and blood vessels dilating. Plasma was leaking into surrounding tissue. Blood pressure was dropping like a stone.

Wilson was one of the hardest hit. “His mother got a call to say his head and neck were swelling up and his legs were purple,” said a friend. The medical team responded with textbook treatment for a general anaphylactic reaction. First, a shot of epinephrine, a potent antihistamine, to try to stop the swelling; and, second, a hefty dose of a steroid. But it quickly became obvious that this was well beyond the usual range for vascular shock; the men were heading for multi-organ failure.
Once the victims had been rushed to intensive care, clinicians were so staggered by the severity of the reaction they called in murder squad detectives to investigate whether the trial had been sabotaged.

COULD there have been an accidental overdose? Or contamination during manufacture? Only detailed tests will find the answer but David Glover, an independent drug trial consultant and former chief medical officer at Cambridge Antibody Technology, suspects the drug itself.

“This drug was intended to promote production of a protein, rather than a negative blocking effect. I think it might have had a cascade effect,” he said. In other words, a chain reaction sparked by the antibody in TGN1412 may have spiralled out of control.

When tested in animals TGN1412 may have shown no side effects; but in humans it may have switched on a massive immune reaction.
“The danger is that they are messing around with T regulator cells and we don’t know what all the T regulator subsets do,” said Michael Seed, joint head of experimental pathology at the William Harvey Research Institute in London. “Some will switch things on and some will switch things off.”

Whatever the precise explanation, the system of using human guinea pigs for drugs trials is under close scrutiny. It has emerged that last year a House of Commons select committee said that some volunteers are given “limited information” and are exposed to “unacceptable risks”.

“We are pushing back the boundaries and we are going to have to think differently about the way we evaluate drugs all the way through,” said Janet Derbyshire, head of the Medical Research Council’s clinical trials unit. “I think it would be prudent to stop monoclonal antibody trials.”

O’Donnell, who could all too easily have been hit by TGN1412 himself, is not deterred, however. “I’m planning to take part in a trial in April for an anti-depressant,” he said. “If testing didn’t take place we would no longer have new medicines on the market.”

Additional reporting: Steven Swinford
The Sunday Times      March 19, 2006
Earlier trials had shown that drug group was highly toxic
Lois Rogers and Isabel Oakeshott

EXPERTS knew that drugs similar to the one that nearly killed six men at a London hospital last week could have had dangerous side effects.

Trials last year in America of a similar “monoclonal antibody” caused severe toxic reactions in patients. But the UK study went ahead after the regulatory authority failed to consult outside specialists who would have warned against proceeding.

Angus Dalgleish, a world expert on immunology, said yesterday that he was amazed the trial had been allowed to proceed. “The previous studies which caused similar severe side effects were in patients already suffering from cancer, but [the researchers] should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways,” said Dalgleish, a professor of cancer at St George’s hospital medical school, south London.

Last week six healthy young male volunteers, who were to be paid £2,000 for the trial, suffered catastrophic side effects within minutes of receiving an experimental drug called TGN1412, which was being tested as a potential treatment for leukaemia, rheumatoid arthritis and multiple sclerosis.

Yesterday two of those given the drug remained in a coma at Northwick Park hospital, northwest London. The other four had regained consciousness.

Dalgleish said the Medicines and Healthcare Products Regulatory Agency (MHRA), which approves such trials, should have consulted a specialist before approving the study. “I can’t understand it. They are normally super-cautious. I would have told the people doing this trial not to do it because the dangers were so great,” he said.

Dalgleish also criticised the way the drug was administered at the start of the study. “I am amazed they gave it to six people at once instead of waiting to observe the effects in one of them.”

The data that should have raised the alarm were presented at a meeting of the American Society of Clinical Oncology last May. Dalgleish said an engineered antibody, developed by a team led by Steven Rosenberg at America’s National Cancer Institute, and using the same pathway as TGN1412 had produced severe side effects in about half of a group of patients dying of cancer.

The MHRA defended its decision, saying: “We have [since] given the trial protocol to a new set of assessors and they came to the same conclusions. There was nothing wrong with it.”

Parexel, the American firm contracted to run the human trials for the drug firm TeGenero, said: “We believe that best practices were followed and the appropriate policies and procedures were adhered to.”

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