Healthy Skepticism Library item: 3923

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: news

Rosenthal E.
British Rethinking Rules After Ill-Fated Drug Trial
New York Times 2006 Apr 8
http://www.nytimes.com/2006/04/08/world/europe/08britain.html?_r=1&th=&oref=slogin&emc=th&pagewanted=print

Keywords:
TGN1412 Parexel TeGenero

Notes:

Ralph Faggotter’s Comments:

“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. “

It seems unbelievable that the researchers continued injecting the rest of the volunteers when they could already see that the first volunteer was having a hideous reaction!

What was going through their minds?

Full text:

British Rethinking Rules After Ill-Fated Drug Trial
By ELISABETH ROSENTHAL,
International Herald Tribune
In 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 disastrously bad.

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.

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 TeGenero.

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 rheumatoid arthritis.

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 red flags.”

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 unit.

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?”