Healthy Skepticism Library item: 5790

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Publication type: news

Rosenthal E.
Inquiries in Britain Uncover Loopholes in Drug Trials
New York Times 2006 Aug 3
http://www.nytimes.com/2006/08/03/world/europe/03britain.html?_r=1&oref=slogin

Full text:

Inquiries in Britain Uncover Loopholes in Drug Trials

http://www.nytimes.com/2006/08/03/world/europe/03britain.html?_r=1&oref=slogin

Article By
By ELISABETH ROSENTHAL
Published: August 3, 2006

The trial of a new drug in a London hospital that nearly killed six men
three months ago and left them in intensive care for weeks has prompted
numerous reports and recommendations that will change the way drugs are
tested.

Navneet Modi was one of six subjects who nearly died in the trial.

But the six men, who were all young and healthy just months ago, now
suffer from serious medical problems, and they have been unable to get
any of the drug companies involved in the trial to cover their medical
expenses, or provide compensation – other than a one-time payment of
under $20,000 apiece.

In recent weeks, lab tests and medical reports have shown that the men
are suffering from severely damaged immune systems that will probably
leave them vulnerable to disease for life. All have spent weeks in
intensive care with organs failing, and they still suffer myriad symptoms.

One of the men, Navneet Modi, 25, who recently received a master’s
degree in business, said that his damaged memory and blackouts made it
impossible for him to work, and that he also suffered from fatigue and
diarrhea.

“Everyone’s turned their back, and I’m angry, really angry,” Mr. Modi
said. He noted that the British National Health Service has covered his
medical costs so far, but that the company that performed the trial
would not reimburse the cost of travel to the hospital.

New tests and investigations into the incident have highlighted
loopholes in a drug-testing system that in some instances seems better
devised to bring drugs to market than to protect human safety,
especially when it comes to medicines made possible by advanced
biotechnology, specialists said. Already, regulators in the United
States and Europe say they are taking a go-slow approach as they develop
new procedures.

The trial three months ago, conducted at London’s Northwick Park
Hospital, “highlighted an urgent need to review the safety of
first-in-man trials of novel agents,” concluded an interim British
Health Department panel’s report, which was released in late July. The
report also urged an examination of “how risks in medicine development
are currently assessed and minimized” by drug makers.

The drug in the Northwick Park trial, TGN1412, was a potent immune
system stimulant that overrides the body’s normal regulatory mechanisms.
But it was tested according to much the same standards that govern more
ordinary pharmaceuticals. British regulators approved the trial in just
17 days, and the testing company did not have an adequate response plan
should disastrous adverse reactions occur, British investigators have
concluded.

Since the trial, the British Health Department, the United States Food
and Drug Administration and the Association of the British
Pharmaceutical Industry have been reviewing the data and issuing
recommendations for testing new medicines, particularly those aimed at
essential biological pathways.

“The lesson learned is that now when we see a molecule like this – one
with a novel mechanism – we need a very different approach,” said Dr.
John K. Jenkins, of the F.D.A. “Now that we’ve seen this episode, we
will be very cautious going forward.”

TeGenero, the small German biotechnology firm that developed the drug as
a revolutionary treatment for cancer and arthritis, filed for
bankruptcy-court protection on July 4. A lawyer for four of the six
trial subjects, including Mr. Modi, said TeGenero’s insurance coverage –
which was $3.7 million – was not adequate to cover a calamitous outcome.

The lawyer, Martyn Day, of Leigh Day & Company in London, said the
insurance policy included a clause that no payments would be made to
subjects who sued. The American-based testing firm that conducted the
trial, Parexel International, of Waltham, Mass., has said that it
carried out the trial according to “appropriate policies and
procedures,” and that it is not culpable.

Parexel, which declined to comment for this article, does contract drug
testing, with centers in the United States, Europe and Africa. It
continues to operate research units at Northwick Park, and has removed
all mention of the trial from its Web site.

Recent investigations into the trial said all parties did their jobs
according to formal regulatory and legal requirements. But, in
retrospect, almost all scientists agree that these requirements were
inadequate for TGN1412.

Mr. Day said that under British law, TeGenero was primarily responsible.
The company has maintained that the reactions were unforeseeable.

But he said that he would argue that Parexel should have made sure that
TeGenero had adequate insurance. He also questioned the design and
conduct of what it should have seen as a delicate trial.

The six research subjects were given infusions of the new and unknown
drugs only 10 minutes apart. Virtually all reviews of the trial have
concluded that such new drugs should be given to one patient at a time,
with long intervals in between, so that monitors can screen for serious
side effects.

Mr. Day said that the men should have immediately been given high doses
of steroids to treat the serious reaction to the new drug. He said such
a reaction was noted as a possibility in the study’s official protocol.

He also said that he was shocked to discover that British regulators had
approved the first trial of the new drug after 17 days, and had not
called in specialists to guide them. In contrast, he said, “It would
take three to four months, minimum, to get a paper about this drug
published in a peer-reviewed journal.”

Within hours of being injected with the new drug, the six men were all
experiencing a syndrome called cytokine storm, where an outpouring of
immune molecules attack organs of the body. All required weeks of
intensive care, suffering failure of their kidneys, lungs and
circulatory systems.

Lab work on their blood has been recently made public, and immunologists
have been thunderstruck by the fury of the reaction.

“These numbers are over the top, far different than anything that would
occur in nature,” said Marc Gavin, an immunologist who studies immune
regulation at the University of Washington in Seattle. “The drug went
right to the very heart of immune activation.”

In recent tests on four of the subjects, all showed previously
unheard-of severe depletion of a type of immune cell called “regulatory
T-cells,” according to reports from Prof. Richard Powell, an
immunologist, provided by Mr. Day.

The cells modulate the body’s reaction to foreign molecules, like those
that produce allergies or even infections, and if they are lacking or
dysfunctional, it can create overwhelming immune reactions against minor
allergens or even the body itself.

At the milder end of the spectrum are diseases like lupus and colitis.
Professor Powell wrote that Mr. Modi was “highly likely” to develop one
of these disorders, at least, based on symptoms and lab tests.

For the past three months, regulators all over the world have been
trying to piece together what went wrong, because the drug has not
outwardly provoked such a response during animal testing. In the United
States, the F.D.A. is trying to develope “better biomarkers for human
toxicity” that can be used to screen new products for safety before they
are introduced into humans for the first time, Dr. Jenkins said.

Mr. Modi had just finished business school in London when he signed up
with Parexel to earn a bit of extra money, about $3,000. He had planned
to return to India this summer to join his family’s electronics business
in Calcutta.

At 8:30 a.m. on March 13, he became the third human to be infused with
TGN1412 at Northwick Park. Within 90 minutes, the pain in his head and
back was unbearable, he recalled.

Soon, all six trial subjects were moaning or screaming and begging for
pain pills. The doctor and half-dozen nurses from Parexel running the
trial urged everyone to remain calm and administered paracetamol, a mild
pain reliever.

Mr. Day said that after Mr. Modi had lapsed into semiconsciousness, the
team administered a low dose of steroids.

In testimony before the British expert review panel, the intensive-care
doctors said that while they were aware that the patients seemed to be
having an “inflammatory” reaction, the Parexel team did not inform them
of the possibility of cytokine storm for hours.

Mr. Modi expressed anger at Parexel, saying that the night he was
transferred to the intensive-care unit, the company “turned their back
and drew up the drawbridge.”