British Rethinking Rules After Ill-Fated Drug Trial_NYT

All the men instantly experienced cytokine release syndrome, which involves an outpouring of toxic molecules when the immune system’s T cells are activated, causing massive organ failure, nearly killing them:

“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.”

The experiment was conducted in London by Perexel, after the German manufacturer, TeGenero, could not gain approval in Germany.  Informed consent documents have yet to be released, but two of the survivors told the Times that the only side effects they were warned about were headache and nausea.

This disastrous experiment demonstrates the nature of the undisclosed lethal risks that  volunteers may be subjected to without their knowledge or understanding. The stakeholders in clinical trials—corporate sponsors, doctors, hospitals, and ethics committees (called Institutional Review Boards in the US)—all have vested conflicts of interest. Absolutely no one represents the interest of the human subjects—some of who volunteer because they need the money, others because they have no health insurance.
 
No one admits that volunteers’ safety is left to chance. No one admits that many of the potential lethal risks are left unexamined because to fully examine the possible risks would slow down the process:

On its Web site, Parexel says, "The only services that matter are the ones that speed your product through clinical development."

“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.”  Yet, even basic information was not gathered prior to the exposure of six human beings—one of whom remain hospitalized, the others are left with damaged immune systems.

The Times reports: “It is not clear if independent immunologists reviewed the trial design, and neither Parexel nor TeGenero answered this question.”

Dr. Michael Goodyear, a Canadian oncologist and medical ethicist, outlines a number of concerns that had not been addressed, stating: “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."

Indeed, “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.”

The chilling execution of the trial (that began Monday, March 13, at 8 AM) when the men began receiving TGN1412, each 10 minutes after the last, is described by Ann Alexander, a London lawyer who is representing one of the injured men:  “Within half an hour, the first patient had a headache and chills. 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.”

The Times reports: “Parexel technicians continued to draw blood in the intensive care unit,” but  “the companies have not been willing to share the medical data or even meet with the participants and their lawyers.”

The British government, caught in the cross-fire, 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, the announcement said, "could potentially affect clinical trials regulation worldwide.”

Dr. Ezekiel J. Emanuel, chief bioethicist of the US National Institutes of Health, stood firm behind the banner of Science “Uber Alles” (above all else):

"Research is a social good — we need better treatments for leukemia and arthritis — but there are risks.” No doubt, as long as it is “others” who are subjected to those risks.  Bioethicist Ezekiel Emanuel doesn’t see “any clear ethical problems with the catastrophic trial. He told the Times,  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."

Commenting about the trial and the fact that TGN1412 was rejected by a German ethics committee before it was approved in the UK, Dr. John Abramson in an OpEd in the Los Angeles Times (below):  

“In 1998, the inspector general of the U.S. Department of Health and Human Services recommended rules to stop this practice, known as "IRB-shopping." Ironically, just two months before the London disaster, the FDA decided that such rules were not necessary.”

The FDA and NIH’s bioethicist represent a dangerous culture of Anything Goes: that cutlure must be stopped in its tracks.

Contact: Vera Hassner Sharav
veracare@ahrp.org

http://www.nytimes.com/2006/04/08/world/europe/08britain.html?ei=5094&en=30d5f7d1b424456c&hp=&ex=1144555200&partner=

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THE NEW YORK TIMES
International Herald Tribune
April 8, 2006
British Rethinking Rules After Ill-Fated Drug Trial
By ELISABETH ROSENTHAL,

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?"

http://www.latimes.com/news/printedition/opinion/la-oe-abramson7apr07,1,6341300.story?coll=la-news-comment
The Los Angeles Times  
Guarding the human guinea pigs
By John Abramson
JOHN ABRAMSON, a clinical instructor at Harvard Medical School, is the author of "Overdosed America."
April 7, 2006

MINUTES after the first of six human volunteers was injected with an experimental, genetically engineered drug in London last month, the men one by one began screaming in pain, tearing their clothes off, convulsing and losing consciousness, according to media reports.

In an interview with Britain’s Daily Mirror, Nino Abdelhady, 28, who said he was offered $3,500 to participate in the study, recalled feeling the drug "ripping through" his body "like wildfire." His head reportedly swelled to more than twice its normal size, and he didn’t regain consciousness for eight days. Other volunteers suffered organ failure, and one remains hospitalized, according to the Associated Press.

Unexpected things happen in medical research, especially when a drug is administered to humans for the first time. Eighty percent of the drugs tested on humans in the U.S. never win Food and Drug Administration approval. Still, there are several clues that the tragedy in London could have been minimized or averted — and more clues that a similar disaster could happen in the U.S. So the cautionary tale of the experimental drug called TGN1412 deserves intense scrutiny on both sides of the Atlantic.

Developed by the German company TeGenero, TGN1412 is an antibody manufactured by fusing mouse and human cells. It was designed to activate one part of the immune system specifically to attack another. TeGenero hoped it would revolutionize therapies for diseases involving the immune system, such as some types of leukemia, multiple sclerosis and rheumatoid arthritis.

The company applied in Germany for permission to administer tiny doses (one five-hundredth of the proposed therapeutic dose) to human volunteers, but was rejected. It then received permission to do the study in Britain.

Two of the volunteers told British reporters that they were warned to expect only headaches and nausea, and had no idea that monkeys given TGN1412 had developed swelling of the immune tissue in their necks.

Inexplicably, rather than giving the drug to one man at a time and waiting to rule out any untoward reaction, the six men were injected at 10-minute intervals, according to the Daily Mirror. Waiting a day or two would have been more prudent for a new biotech drug. A company spokeswoman Thursday would not comment on the dosing interval.

Abdelhady told the Daily Mirror that by the time he got the drug, the first volunteers were already sick and a man next to him, who had been given a dose minutes earlier, was complaining of head pain, "like rockets going off" — but that the experiment continued anyway.

British regulators said they found no evidence of drug contamination or improper practices, and that the tiny doses should not have caused such a reaction. The investigation is continuing.

But the fact that three weeks later British officials still don’t know what went wrong should raise alarms here as well. That’s because although the study involved a German drug in London, it was carried out by Parexel International, a U.S. research company based outside Boston. Parexel’s website boasts that it partners with drug and biotech companies "to accelerate time-to-market, control development costs, reduce risk and maximize return on investment." (The London study might have achieved all of these goals, except, of course, reducing risk.)

In the United States, "institutional review boards" are entrusted with responsibility for overseeing the safety of human volunteers in drug studies. The government established these boards to prevent a repetition of the U.S. Public Health Service’s disgraceful "Tuskegee Study of Untreated Syphilis in the Negro Male," in which poor black sharecroppers were not told they had syphilis so that the disease’s horrific effects could be studied over the next 40 years.

When the institutional review boards were created, most medical research was conducted by universities and nonprofit institutions. Now most clinical research is done by for-profit research companies such as Parexel. Similarly, oversight of the safety of human volunteers in most U.S. studies is no longer done by nonprofit IRBs, but by for-profit review companies, hired directly by the for-profit research companies. The U.S. government approves of this — but I believe this system lacks the appropriate checks and balances to protect human volunteers.

According to Bloomberg News, the largest for-profit IRB in the U.S. oversees 17,000 studies on people, yet can spend as little as four minutes a study to evaluate whether volunteers are adequately protected. And if one for-profit ethics board doesn’t approve a study, nothing stops the company from simply applying to another — like TeGenero moving its study from Germany to Britain. In 1998, the inspector general of the U.S. Department of Health and Human Services recommended rules to stop this practice, known as "IRB-shopping." Ironically, just two months before the London disaster, the FDA decided that such rules were not necessary.

Moreover, the FDA recently approved "phase 0 studies" in which human beings can be given minuscule doses of experimental drugs even before animal studies are completed. Sen. Charles Grassley (R-Iowa) recently told the journal Nature that just when more oversight is needed, "the FDA is loosening the reins on drug companies. I’m concerned for those who will be receiving these experimental drugs."

The issue isn’t simply whether the research is commercially sponsored (after all, the grotesque Tuskegee study was not for-profit), but whether there are adequate safeguards to make sure that human volunteers are not exposed to unnecessary risks, that studies are carried out as designed and that results are accurately reported.

Unfortunately, these watchdog functions are being eroded. The entrepreneurial incentive to develop new drug therapies is a great motivator. But it will not serve the greater good unless and until there is independent, noncommercial oversight of medical research.

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