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Inquiries in Britain Uncover Loopholes in Drug Trials
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.
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.”
Posted by Min H.
