How can a drug, a foreign substance, do anything
but tax the immune system?
----- Original Message -----
From: bryce_j_j
To: SSRI-Crusaders
yahoogroups.com
Sent: Sunday, September 24, 2006 7:34 AM
Subject: [SSRI-Crusaders] TGN1412 Elephant Man given drug 'too quickly'
'Reckless error' left men fighting for life
Brian Deer
http://www.timesonline.co.uk/newspaper/0,,176-2372235_1,00.html
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 Myfanwy Marshall, the girlfriend of one
victim, Mohamed Abdalla, 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 Countdown
to disaster
[Non-text portions of this message have been removed]
.