Watchdog 'was given warning on danger of drug trial'

The British Government's drugs safety authority was warned in advance about a drug trial which was to leave six men, including a New Zealander, in intensive care.

The warning of a risk of a catastrophic reaction came from TeGenero, the German manufacturer of TGN1412, in its application to the Medicines and Healthcare Products Regulatory Authority.

TeGenero told the MHRA that there had been previous incidence in which similar drugs had provoked serious adverse reaction in human volunteers.

Yet the MHRA allowed the trial to go ahead and six men who received the drug suffered a massive immune response known as a "cytokine storm".

The MHRA was satisfied that TeGenero's decision to administer to volunteers a 500-fold dilution of the drug, compared to that given in earlier trials to animals, provided sufficient protection.

An interim report of the inquiry issued last Wednesday said no human error had been found in the manufacture, preparation or dose of the drug.

The only remaining possibility was "a previously unknown biological effect on humans that did not arise in any of the animal testing phases", the report said.

But documents submitted to the MHRA by TeGenero show that the "biological effect" was not "previously unknown".

There had been an earlier incident of a cytokine storm in humans tested with a similar drug.

The Investigators Brochure, which summarises evidence for the study, says: "Although not to be expected after TGN1412 administration, a cytokine release syndrome or other immunological complications may occur after infusion of TGN1412."

The reason for the warning was that TGN1412 is a monoclonal antibody that targets only specific types of cell.

But unlike most monoclonal antibodies it does not disable or destroy the cells but instead seeks out cells in the body's own immune system and turbocharges them.

Tests on animals including cynomologus monkeys revealed no ill effects.

The Investigators Brochure, referring to two earlier studies, says: "These data [from the monkey tests] sharply contrast with the induction of high concentrations of pro-inflammatory cytokines... in non-human primates (Hsu et al, 1999) and in a clinically apparent cytokine release syndrome in humans (Abramowicz et al 1989) upon administration of CD3 antibodies."

The Abramowicz study involved a similar drug - called OKT-3 - which was being tested to prevent rejection of transplanted organs.

It was given to patients whose immune systems had been suppressed, not healthy volunteers as in the TG1412 trial, yet still triggered a cytokine storm.

Professor Kent Woods, chief executive of the MHRA, denied that risks had been ignored.

He said: "The possibility of a cytokine storm was specifically considered and tested for in a particular species of monkey which showed no toxic reaction.

"With a 500-fold dilution the protocol for the study was as precautionary as you could get."

- INDEPENDENT