Reprint
TGN1412 victims given drug ‘too quickly’
The Sunday Times
September 24 2006
Brian Deer
A “RECKLESS” mistake apparently overlooked by government regulators lay behind the drug trial disaster that saw six young volunteers badly injured by an experimental medicine.
Confidential documents obtained by The Sunday Times and Channel 4’s Dispatches programme reveal the drug was administered on average 15 times more quickly to the volunteers than to monkeys in earlier safety studies.
The possibility that such a crude error led to the disaster is likely to raise questions over whether the government’s Medicines and Healthcare products Regulatory Agency (MHRA) scrutinises trials adequately and protects the public from the risks of new medicines.
After the “Elephant Man” trials at Northwick Park hospital, London, in March, which left two men fighting for their lives and all six in intensive care, the agency said the reactions resulted from an “unexpected biological effect”.
However, experts say the drug, TGN1412 — one of a new generation of “magic bullet” treatments targeting the immune system — was infused so quickly into the volunteers that the potential for life-threatening problems was foreseeable.
“When you give an antibody . . . the quicker you put it in, the more likely you are to get an infusion reaction,” said Professor Terry Hamblin of Southampton University, a leading authority on monoclonal antibodies, the family of drugs to which the trial medicine belonged.
The volunteers were given TGN1412 in only three to six minutes. “To quickly infuse it over three to six minutes in six individuals I think is . . . reckless,” said Hamblin.
Ryan Wilson, 20, a former apprentice plumber, who suffered total organ failure, was the most seriously injured. He was given the drug in just four minutes. The monkeys, by contrast, received the antibody by a one-hour “slow infusion”.
Hamblin’s judgment is backed by other experts, including Dr David Glover, formerly chief medical officer of Cambridge Antibody Technology. He concludes: “The drug was given too quickly.”
The speed at which the monkeys received TGN1412 was set out in the application to the MHRA for permission to carry out the trial. This was submitted by Parexel International, a contract research company, on behalf of TeGenero, a tiny German drug developer. But the paperwork did not explicitly detail how quickly the volunteers would be given the drug, although this could be calculated from the information given.
Professor Kent Woods, the agency’s chief executive, said this weekend the results of the monkey trial had reassured his staff that the human project should be allowed to go ahead. “They did not show toxicity and the dose was 500 times higher on a weight-for-weight basis than that first used at Northwick Park,” said Woods. “That is the key issue.”
There was another apparent oversight in the agency’s scrutiny. Parexel’s paperwork did not include data on test-tube experiments designed to show the drug’s effect on human cells. One specialist said she was “pretty astonished” this was left out, although it is unlikely the data could have predicted the disaster.
This omission was only revealed after an appeal by The Sunday Times and Dispatches under the Freedom of Information Act for the reinstatement of paragraphs cut from documents released by the MHRA.
While the agency suggests in its assessment of the trial that the problems could not have been foreseen, experts say the reactions to TGN1412 — pain, vomiting and organ failure — have long been linked to first doses of monoclonal antibodies, and in previous incidents infusion time has been a critical factor.
Parexel declined to comment, and in Thursday’s Dispatches the company’s chairman, Josef von Rickenbach, takes refuge in a hotel lavatory.
Wilson has severe injuries. He has had his toes and sections of his feet amputated. Parts of his fingers have dropped off; others have died and are hard as wood to the touch where the blood supply was cut off as his body reacted to the drug.
He is the worst afflicted of the victims from the tests on March 13, but all suffered life-threatening injuries. For development of new medicines, it was the worst calamity since the 1960s Thalidomide disaster.
In the space of one hour, Wilson and five other healthy young men, aged from 19 to 34, were all infused with the drug through tubes. All were soon in agony. Their blood pressure collapsed. Their hearts raced. They struggled to breathe. Their bodies and heads swelled to grotesque proportions and [redacted 9/16], the girlfriend of one victim, [redacted 9/16], 28, described him as looking like “the Elephant Man”.
“It started off with a lower back pain,” Wilson recalls. “I just remember it getting worse and worse, and then I remember vomiting, and then just too much pain and I just blacked out. And that was it. Gone.”
Wilson’s deterioration is shown in the documents obtained by The Sunday Times. They include adverse event forms filled in at Wilson’s bedside: “09.38 feeling cold”, “09.40 headache”, “10.00 lower back pain”, “10.10 nausea and vomiting”, “10.16 pressure on chest”, “10.22 vomiting (two episodes)”, “10.40 breathing difficulty”, “10.50 diarrhoea”, “11.40 vomiting”, “12.48 pyrexia” (fever).
“Between 7.30 and 7.40 in the evening, the phone went,” said Wilson’s mother, Marion Flanagan. “Somebody said, ‘Your son took part in a drug trial today.’ I just knew. It might be a mother’s sixth sense but the hairs on the back of my neck stood up and, before he could say another word, I was screaming down the phone at him, ‘Is my son all right?’”
At 9.30pm Wilson was admitted to intensive care, vital organs all supported by machines. For 16 days he was on a ventilator and in hospital until the end of June. “It’s like I took a bungee jump into hell,” Wilson said. “All of them thought I’d die.”
The TGN1412 trials had been vital for TeGenero, based in Würzburg, near Frankfurt. The firm had no other products and its fortunes depended on this drug. It was being tested in Britain because in 2001, in response to lobbying, Tony Blair backed moves to encourage foreign drug trials and attract “big pharma” investment.
The MHRA is regarded as Europe’s most business-friendly regulator. It gave TeGenero the green light on January 27, just six weeks before the trial began. Its target, announced last year, is to approve projects in just 14 days.
TeGenero’s plan was for TGN1412 to boost part of the immune system, and so be useful in Aids or radiation therapy for cancer. If this did not work, plan B was for it to damp down a different part and so be good for rheumatoid arthritis or leukaemia.
Professor Jürgen Drews, former chairman of TeGenero, said the trial was “the right thing to do”.
A legally required dossier submitted to the MHRA describes the firm’s tests on monkeys. Ten cynomolgus macaques were infused with 50mg of TGN1412 per kilo of body weight, and another six with one-tenth of this. Their blood levels were then measured for six cytokines, a kind of protein. Some levels remained unaltered, while others rose noticeably. These included IL-6, a key inflammatory protein.
“The results weren’t dramatic,” said a senior immunologist who knows Dr Thomas Hünig, TeGenero’s chief scientist. “They showed some kind of effect but it didn’t forewarn in any way of what followed.”
What followed was the disaster: a “cytokine storm” in the human volunteers. In the monkeys, the IL-6 was measured at 390. In Wilson it touched 5,000.
The MHRA was baffled. “The adverse incidents did not involve errors in the manufacture of TGN1412 or in its formulation, dilution or administration to trial participants,” was its verdict. “An unpredicted biological action of the drug in humans is the most likely cause.”
Documents, however, suggest the reactions might have been foreseeable. They do not set out clearly the speed at which the drug was to be administered but this came to light when Hamblin performed calculations based on papers submitted to the agency and later released under the Freedom of Information Act. His calculations have since been confirmed in a confidential Parexel document.
Experts believe MHRA assessors could have spotted the difference if they had taken more time to scrutinise the project.
“I usually give it over about six hours,” said Hamblin. “If you give it in less than an hour you get horrific reactions.”
The MHRA denies it missed warning signs. “There was no reason to believe that the administration rate proposed for TGN1412 would present as a foreseeable hazard to the subjects,” it stated.
The case has highlighted concerns over biotechnology. “Clinical trials in general have an excellent safety record,” said Professor Gordon Duff, head of molecular medicine at Sheffield University, who chairs a government inquiry into the Northwick Park incident. “But in light of the TGN1412 incident there is a need to look at future safety of clinical trials with novel and potentially higher-risk drugs.”
Some observers are worried that, if the MHRA gave the go-ahead in the absence of important information, there may be room for future mistakes. “It’s a wake-up call,” said Glover. “We need to redouble efforts to ensure we don’t have the same disaster in the future.”
Brian Deer investigates the TGN1412 incident in Dispatches, Channel 4, Thursday at 9pm.
Countdown to disaster
January 27 2006 Medicines and Healthcare products Regulatory Agency (MHRA) gives permission for human trials of antibody drug TGN1412
February 22 volunteers selected for trial
March 13 TGN1412 administered in trials at Northwick Park hospital, London. The six men’s immune systems react to drug with disastrous “cytokine storm”, resulting in agonising, life-threatening injuries
May 25 MHRA inquiry finds “unexpected biological effect” most likely cause of incident
June 27 Ryan Wilson, most seriously injured victim, leaves hospital
July 19 Wilson returns to hospital to have toes amputated