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Drug to blame for clinical-trial disaster?

April 5, 2006 By Michael Hopkin This article courtesy of Nature News.

Interim report on London case shows no evidence of contamination.

The drug-trial disaster that put six British patients in intensive care does not seem to have been due to contamination or a failure to follow protocol, says the agency investigating the incident. If the preliminary finding is confirmed, it would indicate that the drug itself caused the negative effects.

The interim report by the UK Medicines and Healthcare Products Regulatory Agency (MHRA), which approves clinical trials, says they found no evidence to suggest that procedure was not followed correctly.

The finding raises the possibility that antibody therapies such as the one being tested, called TGN1412, may not be safe for humans and that preliminary animal tests may not spot potential dangers.

TGN1412 targets immune cells called T cells (see ' Tragic drug trial spotlights potent molecule'). The drug was successfully tested in non-human primates, but provoked an unexpected adverse reaction of the human immune system that caused participants in the first trial to suffer multiple organ failure.

All but one of the six participants have now been discharged from hospital after the incident in London on 13 March; MHRA chief executive Kent Woods says the remaining patient is making "good progress".

Smaller dose

"We believe there was a powerful pharmacological action of this drug in man that was not detected or detectable in animals," Woods told a press conference on 5 April. The men were given a dose 500 times smaller than those used in animal trials, leading to questions over whether animal tests are sufficient precaution when testing drugs of this type.

The MHRA has now convened an expert group, led by University of Sheffield pharmacologist Gordon Duff, to advise on how to proceed safely with 'phase I' clinical trials - the first stage at which humans are exposed to a candidate drug.

Until this panel reports back in a few months' time, the MHRA has decided not approve any more phase I trials for any kind of novel biological agent without expert outside consultation.

Exceptional case

More than 20 antibodies have been approved for human therapy or are in late-stage trials, says a statement released today by Britain's Academy of Medical Sciences. But TGN1412 is different from those already approved: it is a 'superagonist' antibody that seeks to activate a larger range of immune cells.

It remains to be seen whether superagonist therapies can recover from this setback. "This does raise questions about the development of monoclonal antibodies and drugs targeting the immune system," says David Webb, a clinical pharmacologist at the University of Edinburgh, UK.

"It is important to recognize that the events in this trial were exceptional and, we understand, relate to a specific pathway and mechanism of action of this particular product candidate," says Aisling Burnand, chief executive of the BioIndustry Association, a London-based trade organization.

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