Botched Drug Test Stirs Ethical Concerns

Highlights need to improve safety measures for clinical trials, researchers say

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By Steven Reinberg
HealthDay Reporter

MONDAY, Aug. 14, 2006 (HealthDay News) -- In March, a well-publicized test in England of an experimental drug designed to fight autoimmune diseases left all six healthy male participants with multiple organ failure.

That catastrophe has prompted medical experts to call for reviews and reforms of the drug-approval process. Their concerns are published in the Sept. 7 issue of the New England Journal of Medicine.

The phase 1 trial, which was designed to test the safety of the new drug, took place in Great Britain. The drug is called TGN1412, and it's a new so-called superagonist monoclonal antibody that directly stimulates immune system T-cells.

T-cells dampen the function of other parts of the immune system in a healthy individual by preventing the body from attacking itself. When this safeguard fails, it can lead to autoimmune diseases that the drug's maker -- TeGenero AG, a German biotech company -- was trying to thwart. Those diseases include rheumatoid arthritis, multiple sclerosis and certain types of leukemia, according to published reports.

Within 90 minutes of receiving a single intravenous dose of the drug, all six volunteers experienced headache, muscle aches, nausea, diarrhea, skin rash and low blood pressure caused by a rapid induction of inflammatory-producing substances called cytokines.

After 12 to 16 hours, all six men were critically ill, with toxic liquid in the lungs, lung injury, kidney failure and blood disorders. After 24 hours, there was severe depletion of both red and white blood cells.

All six patients were transferred to an intensive care unit where they received intensive cardiopulmonary treatment, including dialysis; high-dose Medrol, a corticosteroid used to reduce inflammation; and an anti-interleukin-2 receptor antibody.

Two of the patients developed cardiovascular shock and acute respiratory distress syndrome, which required eight to 16 days of organ support. Fortunately, all six men survived, although one has early signs of lymphatic cancer, according to news reports.

The most seriously injured volunteer was 21-year-old Ryan Wilson, who had to have parts of his fingers and toes amputated because he developed gangrene.

The volunteers were paid about $3,500 each for taking part in the trial. Four of the men have received compensation payments of about $25,000 from TeGenero, which filed for bankruptcy in July. The other volunteers are waiting for the results of medical tests before making specific compensation claims.

Lead report author Dr. Ganesh Suntharalingam is director of intensive care at Northwick Park and St. Marks Hospital, in London, and one of the doctors who treated the patients. He said, "There may be a category of drugs that are high risk for causing an unprecedented immunological reaction. These drugs need to be identified in advance and then do the phase 1 studies in a different way."

Suntharalingam was not involved in the trial itself.

Patients were given the drug at 10-minute intervals, Suntharalingam said. Perhaps there needs to be more time between doses, he said. In addition, these patients were lucky that the trial took place at a fully equipped medical center, he added. "They were able to get to intensive care very quickly when they needed to."

Suntharalingam said he and his colleagues wanted to get the information out to push a discussion of how to identify potentially dangerous drugs and "stop this from happening in the future."

TeGenero filed for bankruptcy July 4, because it was not able to attract investors after the incident. The trial was conducted by Parexel International Corp., of Waltham, Mass.

One expert thinks the design and application of the trial was flawed.

"They dosed these people one after another without a sufficient period of time to see the effect," said Adil E. Shamoo, of the Department of Biochemistry & Molecular Biology at the University of Maryland, Baltimore, and co-founder of the watchdog group Citizens for Responsible Care and Research.

Phase 1 trials are the most ethically challenging experiments, Shamoo said. "Doing these experiments in healthy subjects is done for money. So, you are taking a high risk for money, and that is ethically problematic," he said. "That's why there has to be extra protection for human subjects -- human subjects are not animals."

Shamoo believes there needs to be more animal experiments before experimental drugs are tried on patients. "Especially now that we know these immunologically challenging studies have a high risk," he said.

The fact that TeGenero declared bankruptcy may leave the six men in a position where they'll have to cover their own medical costs, Shamoo said. "We have called for no-fault insurance to protect subjects in trials," he said. "This way, the subjects don't get left holding an empty bag."

The New England Journal of Medicine said it released its package on the controversial trial early to allow the information in it to become available during the current comment period established by the British government and its Medicines and Healthcare Products Regulatory Agency. Until a group of leading international experts formed to consider the issues involved releases its report, further applications involving first-in-humans trials of any monoclonal antibody or other novel molecules targeting the immune system will not be authorized in the U.K., according to news reports.

But another expert doesn't want the results of this trial to cloud the use of this type of new drug, which she said could benefit many people.

"This antibody was very unusual in the way it worked," said Dr. Arlene Sharpe, of Brigham & Women's Hospital, in Boston, and the author of an accompanying perspective piece in the journal.

In studies in mice, the drug was able to prevent disease or make certain autoimmune diseases better with no adverse side effects, Sharpe said. However, the tests in primates were never published, but showed no serious side effects.

"In people, instead of doing this, it seems this antibody activated cytokines that produced immune responses," Sharpe said. "It seems that such large amounts of cytokines were produced that this is what damaged patients."

Sharpe noted there are several drugs in use that act on the same pathways in the body. "There is a lot of promise with these drugs if one can understand the pathways, and how to use them well," she said.

More information

The U.S. Food and Drug Administration can tell you more about clinical trials.

SOURCES: Ganesh Suntharalingam, M.D., director of intensive care, Northwick Park and St. Marks Hospital, London, England; Arlene Sharpe, M.D., Ph.D., Brigham & Womens Hospital, Boston; Adil E. Shamoo, Ph.D., Department of Biochemistry & Molecular Biology, University of Maryland, Baltimore, and co-founder, Citizens for Responsible Care and Research; Sept. 7, 2006, New England Journal of Medicine

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