British Rethinking Test Rules After Drug Trial Nearly Kills 6
- We have technology to send people to the moon and beyond but still
rely on medical "research" methods that are 200 years old. Is it
because the inexactness of results gives the drug companies cover?
For more information, visit: http://www.curedisease.com/Harms.html
British Rethinking Test Rules After Drug Trial Nearly Kills 6
By ELISABETH ROSENTHAL (International Herald Tribune) 1704
wordsPublished: April 8, 2006In February, when Rob O. saw the text
message from Parexel International pop up on his cellphone in London
-- ''healthy males needed for a drug trial'' for £2,000, about $3,500
-- it seemed like a harmless opportunity to make some much-needed
cash. Parexel, based in Waltham, Mass., contracts with drug makers to
test new medicines.
Just weeks later, the previously healthy 31-year-old was in intensive
care at London's Northwick Park Hospital -- wires running directly
into his heart and arteries, on dialysis, his immune system, liver,
kidneys and lungs all failing -- the victim of a drug trial gone
One of six healthy young men to receive TGN1412, a novel type of
immune stimulant that had never before been tried in humans, Rob O.
took part in a study that is sending shock waves through the research
world and causing regulators to rethink procedures for testing certain
powerful new drugs.
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Although tests of TGN1412 in monkeys showed no significant trouble,
all six human subjects nearly died. One is still hospitalized and the
others, though discharged, still have impaired immune systems, their
future health uncertain.
On Wednesday, after releasing its interim report on the trial as well
as previously confidential scientific documents that were part of the
application for a trial permit, the British government announced it
was convening an international panel of experts to ''consider what
necessary changes to clinical trials may be required'' for such novel
compounds. The outcome ''could potentially affect clinical trials
regulation worldwide,'' the announcement said.
In statements this week, both Parexel and the drug's manufacturer,
TeGenero, emphasized that they had complied with all regulatory
requirements and conducted the trial according to the approved
protocol. But they declined to answer questions e-mailed to them about
the specifics of the science involved.
''The companies have worked according to strict standards applicable
for such type of studies,'' said Kristin Kaufmann, a spokeswoman for
Within an hour of receiving the milky white drug in a Parexel research
ward in the hospital on March 13, the volunteers were racked with
chills, pain and nausea, said Rob O., who asked that his last name not
be used, for fear that he might be hurt professionally. A doctor
informed him he was ''seriously ill.''
''But no one's going to die?'' Rob O. recalled saying, believing he
was participating in a fairly standard trial of a painkiller for
arthritis. The chilling response: ''Two of you might. Who's your next
of kin?'' In fact, TGN1412 is anything but standard. The first product
of TeGenero, a tiny German company with just 15 employees, TGN1412
belongs to a completely novel class of manufactured antibodies that
researchers thought could revolutionize the treatment of leukemia and
Now, TGN1412 seems poised to go down in medical history as a
pharmaceutical lemon, its disastrous trial raising serious questions
about whether patient safety is adequately protected in the lucrative
race to get products to market.
The British Medicine and Healthcare Products Regulatory Agency, which
approved the trial at Northwick Park, announced Wednesday that ''the
way the trial was run'' had not contributed to patient injuries,
according to its preliminary investigation. The men experienced
cytokine release syndrome, which involves an outpouring of toxic
molecules when the immune system's T cells are activated, the report
said; it could not have been predicted from previous animal studies
using the drug, the association, TeGenero and Parexel agree.
But British regulators took the highly unusual additional step of
appointing an expert panel to explore whether more stringent
safeguards should be required for testing new biological drugs like
TGN1412 that manipulate the immune system.
Many experts say that because TGN1412's unique property is to turn on
potent, immune system T cells, overriding normal regulatory
mechanisms, the clinical trials were extraordinarily risky. ''There
was strong reason to be very cautious,'' said Dr. Michael Ehrenstein,
of University College London, who studies the molecules that TGN1412
affects. ''Many people would say this was a very high-risk strategy.
I'd have to agree with that.''
Michael Goodyear, a Canadian oncologist and medical ethicist, said
that even if the trial was not illegal or unethical, the research
protocol and conduct on the day of the trial raise ''a number of big
The concerns Dr. Goodyear and lawyers for the subjects raised include
these: Rob O. began receiving the drug intravenously long after the
first volunteer was already experiencing symptoms possibly serious
enough to halt the trial. Standard practice for such trials is to use
just one patient or to separate tests by many days.
The information submitted by TeGenero to British regulators mentioned
that a cytokine burst ''could occur'' after TGN1412 infusion. But in
their application, researchers deemed the reaction ''not expected'' on
the basis of trials with a single animal species, and did not mention
this risk to the recruits, Rob O. said.
On its Web site, Parexel says, ''The only services that matter are the
ones that speed your product through clinical development.'' The
subjects point out that approvals for drug trials in Britain are
quicker than in the United States and the liability for injuries is less.
Rob O. said the novelty of TGN1412 never came up in upbeat pretrial
briefings, adding, ''I had no idea it altered the immune system.''
The first human trials are risky and ethically complicated. They are
designed to determine whether a compound is safe, not to provide a
benefit to the subject. Such human trials must be approved by national
regulators as well as medical ethics boards, though standards vary
somewhat among countries and even among different panels.
''Research is a social good -- we need better treatments for leukemia
and arthritis -- but there are risks,'' said Dr. Ezekiel J. Emanuel,
chief of bioethics at the United States National Institutes of Health.
''Being a construction worker is very risky, and we pay people to do
that. So why not this?''
Noting that the TGN1412 trial had been approved by two separate
British regulatory bodies and that the medicine had been tested in
animals, he said, ''This is a terrible, tragic event but so far I
don't see any clear ethical problems.''
The trial subjects, who were to spend three days as hospital
inpatients, were mostly immigrants, some of them students or unemployed.
''These were not people who were well off,'' said Martyn Day, of the
London law firm Leigh Day & Company, which is representing four of the
men. ''They thought this was relatively risk free.''
At the orientation meeting there was little time to read the 11-page
consent form, Rob O. said, although they had a chance to take it home.
Headaches and bruising were listed as potential side effects, as well
as a severe allergy. But eating nuts or using new cosmetics could
create similar reactions, the form said.
In fact, so-called monoclonal antibodies frequently produce severe
generalized symptoms like aches and chills, though their use is
justified by the enormous potential benefit. ''At my hospital, we
almost killed people the first few times we used Herceptin,'' said Dr.
Goodyear, referring to the popular breast cancer drug, adding that he
now pretreats patients with medicines to counter possible reactions.
Parexel applied to test TGN1412 in both England and Germany in
December, receiving permission in England first, on Jan. 27. Many
countries are streamlining review processes to attract biomedical
research, a strategy that may have backfired here, Dr. Goodyear said.
It is not clear if independent immunologists reviewed the trial
design, and neither Parexel nor TeGenero answered this question.
The trial began Monday, March 13, at 8 a.m., when the men began
receiving TGN1412, each 10 minutes after the last. Within half an
hour, the first patient had a headache and chills, said Ann Alexander,
a London lawyer who is representing him. Nevertheless, doctors
continued injecting new patients. About the time Rob O.'s infusion
started, at 9:10 a.m., the first patient had passed out in an adjacent
room, according to Ms. Alexander.
Before long, Rob O. said, he began to ache and shiver, feeling as if
he had been ''submerged in arctic ice.'' For the rest of the day, six
previously healthy men moaned in uncontrollable pain, vomited and
struggled for breath, Rob O. and other participants said. Though a
dose of steroids temporarily blunted the symptoms, their vital signs
steadily deteriorated, and they were transferred to the intensive care
Two of them were placed on ventilators. Uniformed men wheeled in blood
filtering machines, Rob O. recalled, to cleanse the blood of acid.
Doctors told him that his immune cells were attacking his organs.
The patients' families were summoned to the hospital at 3 a.m.
In statements, Parexel and TeGenero called the reactions ''unforeseen
and unexpected,'' noting that doses hundreds of times more powerful
had proved safe in animals.
The experimental application filed with British authorities --
released this week in response to a Freedom of Information Act request
-- showed that the companies at least realized the possibility of a
devastating immune-system reaction, and that animal studies showed
some signs of immune overdrive.
Those worries were set aside when monkeys infused with TGN1412 had no
problems. Although Parexel technicians continued to draw blood in the
intensive care unit, the companies have not been willing to share the
medical data or even meet with the participants and their lawyers, Mr.
Day, the lawyer, said.
With his immune system now essentially disabled, Rob O. says he cannot
work, or even take the subway, for fear of infection. His liver and
kidney tests are still abnormal. Britain's National Health Service
covers his doctor's bills, but he has to pay the $87 cab fare.
Under British law, Rob O. may be eligible only for $50,000 to $70,000
in compensation, said Mr. Day, unless he can demonstrate permanent
harm. Anyway, tiny TeGenero took out only a $3.5 million insurance
policy to cover the trial.
Lawyers for the subjects are hoping to arrange for financial
compensation and full disclosure of medical information on the drug
without having to go to court.
''I can't believe that nobody will pay and nobody will be punished,''
Rob O. said. ''If I've lost 20 years of life because my liver packs in
at 60 rather than 80, who will cover that?''