Duff reports on clinical trial safety

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TeGeneroAfter six members of a Phase I trial of TeGenero’s TGN1412 nearly died, an expert scientific group, headed by Professor Gordon Duff, was convened to investigate the incident and recommend new procedures to increase the safety of future ‘first-in-man’ trials.

The drugs, which passed standard pre-clinical trials, were supposed to subtly “retune” the immune system. Instead they sent the immune system into overload and the members of the trial suffered multiple-organ failure. The effects were so severe that fingers and toes had to be amputated.

The report called for increased communication between the drug developer and the regulatory body before application for Phase I trials. Pre-clinical trial safety information should be submitted to a database to speed-up the process. This should allow the regulators to identify potential concerns and discuss these with appropriate independent specialist experts.

New higher-risk drugs should be administered to volunteers in ‘first-in-man’ trials sequentially with an appropriate period of observation between dosing individual subjects.

Investigators should also seriously consider whether patients that are already ill could be used rather than healthy volunteers.

The report also recommended exploring the possibility of developing specialist centres for Phase I clinical trials of higher risk agents.

TGN1412 induced a rapid and large release of biologically potent proteins; known as cytokines, that transmit signals between immune cells and tissue cells. This rapid release of cytokines is known as a “cytokine storm”.

No adverse effects were observed in monkeys even though they were given a dose 500 times greater than the human volunteers.

Speaking at the press conference yesterday, Dr Stephen Inglis, director of the national Institute for Biological Standards and Control (NISBC) said: “Conventional methods for presenting the antibody of the sort that were used in the pre-clinical testing before the trial didn’t work – they didn’t stimulate the immune system at all!”

“Our scientists developed a new testing approach that has been able to mimic what seems to have happened in the patients, involving a complex manipulation that effectively presents the antibody to the human immune system in a way that really stimulated them very dramatically.”

The data obtained from these in vitro assays suggests that the dose of TGN1412 given to the volunteers was close to the minimum stimulatory-response.

Professor Duff told the meeting: “The biotechnology medicines that have been produced in the last decade or so have transformed lives in a remarkable way and that technology has enormous potential for creating many more valuable medicines.”

“What we have to be sure is that the first in-human exposure is safe and that’s what our 22 recommendations very clearly are trying to achieve.”

source - Drug Researcher