Healthy Skepticism Library item: 3880

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Publication type: news

US drug test should have alerted trial doctors
The Times 2006 Mar 20
http://www.theaustralian.news.com.au/common/story_page/0,5744,18525400%255E23289,00.html

Keywords:
TGN1412

Notes:

Ralph Faggotter’s Comments:

One of the potential problems of hi-tech biotechnology is demonstrated by this story.

In former times when simpler molecules were being trialed, the chances are that the same types of common physiological pathways would be targeted by the pharmaceutical in both rodents and humans, so the outcomme of rodent experiments was more likely to be replicated in human subjects.

However, complex genetically engineered molecules like mono-clonal antibodies may well target physiological systems and pathways which are unique to one species- especially when it comes to targeting the poorly understood immune system.

Consequently, the reliability with which the outcome of rodent ( and other experimental animal subjects) testing could be translated to humans has been sharply eroded.

Full text: US drug test should have alerted trial doctors

March 20, 2006

LONDON: Experts knew that drugs similar to the one that nearly killed six men at a London hospital last week could have dangerous side effects.

Trials last year in the US of a similar “monoclonal antibody” caused severe toxic reactions in patients. But the British study went ahead after the regulatory authority failed to consult outside specialists who would have warned against proceeding.

Angus Dalgleish, a world expert on immunology, said at the weekend he was amazed the trial had been allowed to proceed.

“The previous studies which caused similar severe side effects were in patients already suffering from cancer, but (the researchers) should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways,” Professor Dalgleish said.

Last week six healthy young male volunteers, who were to be paid pound stg. 2000 ($4800) for the trial, suffered catastrophic side effects within minutes of receiving an experimental drug called TGN1412, which was being tested as a potential treatment for leukemia, rheumatoid arthritis and multiple sclerosis.

Two of those given the drug are still in a coma at Northwick Park Hospital, northwest London.

The other four have regained consciousness and spoken to relatives.

But doctors said the four men could face months of slow recovery. The monoclonal antibody they were given can linger in the system for months, unlike most conventional drugs that are flushed out in days.

The two others were critically ill in intensive care, and relatives of one of them, Ryan Wilson, said they had been told he could be in a medically induced coma for up to a year.

Ganesh Suntharalingam, clinical director of intensive care at Northwick Park Hospital, said an advisory panel was meeting regularly and developing a more detailed understanding of what had happened to the volunteers.

Professor Dalgleish said the Medicines and Healthcare Products Regulatory Agency (MHRA), which approves such drug trials, should have consulted a specialist before approving the study.

“I can’t understand it. They are normally super-cautious. I would have told the people doing this trial not to do it because the dangers were so great,” he said.

The data that should have raised the alarm were presented at a meeting of the American Society of Clinical Oncology in May last year.

Professor Dalgleish — a professor of cancer at St George’s Hospital medical school, south London — said an engineered antibody using the same pathway as TGN1412 had produced severe side effects in about half of a group of patients who were dying of cancer.

British experts told The Times last week it had been a mistake to give the drugs to six volunteers at the same time, but MHRA has defended the trial.

A spokesman said the MHRA had reviewed the dossier of data that the drug’s developer, TeGenero, had produced and confirmed that all was in order.

Given the same data, the agency would approve the trial again, he said. “We have (since) given the trial protocol to a new set of assessors and they came to the same conclusions. There was nothing wrong with it.”

In Germany, where the drug was developed, prosecutors said they were examining whether to start an investigation into the biotech company TeGenero.

And the body responsible for licensing trials, the Paul-Ehrlich-Institut, hinted changes would be needed in the way trials were run.

Their spokeswoman told German radio: “We are all going to think about whether to start off with a single person for studies where there is a risk of this kind.”

The Sunday Times, The Times