When drug trials go horribly wrong

[Guest guest]

When drug trials go horribly wrong

SUNDAY, APRIL 9, 2006

http://www.iht.com/articles/2006/04/07/news/drug.php#

LONDON In February, when Rob O. saw the text message pop up on his

cellphone from Parexel International - " healthy males needed for a drug

trial " for £2,000 - it seemed like a harmless opportunity to make

much-needed cash.

Parexel, based in Waltham, Massachusetts, contracts with drugmakers 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 into his heart and

arteries; on dialysis; his immune system, liver, kidneys and lungs all

failing - the victim of a drug trial gone disastrously bad.

One of six healthy young men to receive TGN1412, a novel type of

immune stimulant that had never been used in humans, Rob O., who agreed to

speak for this article on condition his family name not be used, took part

in a study that has sent shock waves through the research world and has

caused regulators to rethink procedures for testing certain new drugs.

Although tests of TGN1412 in monkeys showed no major trouble, all six

human subjects nearly died. One is still hospitalized, and the others -

though discharged - have impaired immune systems, and their future health is

uncertain.

Within minutes of receiving the milky white drug in a Parexel research

unit, on March 13, the volunteers were racked by chills, pain and nausea,

Rob O. recalled in a telephone interview. 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 like ibuprofen, for

arthritis.

The chilling answer: " 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, TGN1412 belongs to a completely novel class

of synthetic antibodies - the company trademarked the name superMABS - which

researchers thought might revolutionize the treatment of leukemia and

rheumatoid arthritis.

Now, TGN1412 seems poised to go down in medical history as a

pharmaceutical lemon, its near-tragic trial raising serious questions about

whether patient safety is adequately protected in the lucrative race to get

products to the market. TeGenero obtained licensing for TGN1412 from

European regulators to treat a rare form of leukemia in 2005, a year before

it had even been injected into the subjects.

The British Medicines and Healthcare Products Regulatory Agency, which

approved the trial at Northwick Park in London, announced Wednesday that the

way the trial was run had not contributed to patient injuries, according to

its investigation. The men experienced " cytokine release syndrome, " which

involves an outpouring of toxic molecules when T-cells are activated, the

report said. It could not have been predicted from prior animal studies

using the drug, the health research group, TeGenero and Parexel all agree.

But importantly, 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 - compounds with novel types of action or which manipulate the

immune system.

In statements this week, Parexel and TeGenero highlighted that the

companies had complied with regulatory requirements and conducted the trial

according to protocol, but declined to answer further questions about

specifics of the science involved.

" The companies have worked according to strict standards applicable

for such type of studies, " said Kaufmann, a TeGenero spokeswoman.

Indeed, many experts say that clinical trials on this compound were

extraordinarily dangerous, since the drug overrides the body's normal immune

regulatory mechanisms, making the trial the first time anyone had toyed with

what some have called a " Pandora's box. "

" There was strong reason to be very cautious, " said Dr.

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. "

Goodyear, an oncologist and medical ethicist at Dalhousie

University in Halifax, Nova Scotia, said the conduct of the trial " raises a

number of big red flags. "

Rob O., subject No. 7, received his injection long after the first

volunteer was already experiencing symptoms possibly serious enough to halt

the trial. Standard practice for such trials is to space out testing, one

patient at a time.

The research application submitted by TeGenero to British regulators

mentioned that a cytokine burst " could occur " after TGN1412 infusion. But

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 promises corporate customers that it will

" speed your product through clinical development. " Did the company

consciously decide to test a potentially risky drug in Britain, where

approval was quick and liability for injuries less than in the United

States?

Rob O. said the novelty of TGN1412 never came up in upbeat pre-trial

briefings, adding: " I had no idea it altered the immune system. I trusted I

was in safe hands. "

Phase I trials - also called first in man studies - are risky and

ethically complicated. They are designed to see if a compound is safe, not

to provide benefit. For cancer drugs, volunteers are patients who have

exhausted other possibilities. But for the Parexel TGN1412 study, the only

incentive was money.

" Research is a social good - we need better treatments for leukemia

and arthritis - but there are risks, " said Dr. Ezekiel Emanuel, chief of

bioethics at the U.S. 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 regulators 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. "

Fees and other incentives have multiplied in recent years; £2,000, or

about $3,500, would not be unusual for a weeklong inpatient study, experts

said.

Aggressive recruiting has " taken off because of all the money to be

made in drug development, " said Dr. Aideen , a medical ethicist at the

University of Toronto, noting that companies like Parexel have taken over

phase I trials from academic centers.

She said one company performed studies in Florida, a lure for research

subjects. " It's cold in Canada and if a mother enrolls a child, the whole

family gets a warm vacation, " she said.

Parexel's recruiting Web site features soft focus pictures of pool

tables, videogames and - of course - checks.

The TGN1412 trial - which involved commitment to a three-day inpatient

stay - included students, immigrants and unemployed men who needed money.

" These were all guys who needed a few bob and they thought this was

relatively risk-free, " said Martyn Day, a senior partner in the London law

firm Leigh Day and Company, which is representing four of the men.

At Parexel's orientation meeting there was little time to read the

study's 11-page consent form before signing, Rob O. said. Headaches and

bruising were listed as potential side effects, as well as the possibility

of a severe allergy. But that risk was downplayed.

Parexel applied to test TGN1412 in both England and Germany in late

December, receiving permission in England first, on Jan. 27. Many countries

are streamlining their review process to attract biomedical research - a

strategy that may have backfired in this case, Goodyear said.

On March 13 at 8 a.m., the men got TGN1412, each 10 minutes after the

last.

Within half an hour, patient No. 1 had a headache and chills, said Ann

, a London lawyer who is representing him; doctors continued

injecting new patients. About the time Rob O.'s infusion started, at 9:10

a.m., the first patient had actually passed out in the adjacent room,

according to .

Rob O. too began to ache and shiver, like being " submerged in Arctic

ice. " For the rest of the day, six previously healthy men moaned in

uncontrollable pain, vomited and struggled for breath, participants said.

Though a dose of steroids temporarily blunted the symptoms, their lab values

deteriorated and they were transferred to Northwick Park's intensive care

unit. A couple 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 an

" unforeseen and unexpected " tragedy, noting that doses were 500 times

smaller than what had proved safe in animals.

The experimental application filed with the 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 reaction, and that animal studies showed some concerning, if

confusing, signs of immune overdrive: Lymph nodes were swollen and levels of

destructive immune molecules underwent a moderate rise.

Those worries were set aside when monkeys infused with TGN1412 showed

no overt health problems. Immunologists suggest the monkeys might not have

reacted because their CD28 receptor, to which the drug binds, may be much

less sensitive than in humans.

Although Parexel technicians continued to draw blood in the intensive

care unit, the companies have been unwilling to meet with the trial subjects

or provide more data, Day said.

Rob O. cannot work nor even take the Underground. His liver and kidney

tests are still abnormal. The National Health Service covers his doctor's

fees, but he pays the £50 cab fare.

By British law, compensation for drug trial injuries are set by a

national insurance plan. He may be eligible for £30,000 to £40,000, Day

said, unless he can demonstrate permanent damages. TeGenero, which is

legally liable, took out only £2 million insurance to cover the trial.

" 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? "