Earlier trials had shown that drug group was highly toxic
Another twist to the tragic story of the Tegenero CD28 agonist Phase 1 trial in which six healthy volunteers were strciken with severe adverse reactions that will leave them recovering for months. In this Times piece, Professor Angus Dagleish questions the decision to allow the trial, given prior experience with another monoclonal antibody that, like the Tegenero drug, increased T cells via co-stimulatory pathway modulation and also led to serious side effects. He also questions the decision to proceed with administration to six volunteers simultaneously. Expect to see more of the Monday-morning quaterbacking in the weeks and months ahead, as formal investigations and, probably, legal battles play out. Generally speaking, administration of an investigational drug to six volunteers simultaneously is not unusual, since the initial dosing is always begun well below the anticipated toxicity level based on preclinical data. What is quite unusual is the failure of preclinical studies to predict severe toxicity at the starting dose. Why this failure now? I can’t speculate wisely without additional information. Assuming the predictive failure was the result of a failure to identify a pharmacological effect (i.e. related to the drug’s mechanism of action), as opposed to a pharmaceutical effect (i.e. related to the pharmaceutical properties of the drug per se), it represents the inability to quantify either the degree or implications of cell-mediated immunity over-drive via co-stimulatory pathway agonism. In that case, all molecules that work through this mechansim would be expected to suffer from the same imprecision of preclinical testing, necessitating extreme caution in their application, as advised by Professor Dagleish.
From a broader lessons standpoint, this tragedy serves as a jolting reminder of the need for much better predictive science prior to human testing, a need the Critical Path Institute and FDA are addressing via their proposed predictive safety consortium initiative that facilitates sharing of information among major pharmaceutical labs.
BOB FIDDAMAN said,
April 6, 2006 at 4:46 am
MHRA - In whose Interests?
The recent TeGenero drug trial debacle was an accident waiting to happen. As long as the Pharmaceutical Industry continues to suppress clinical trial data the MHRA (Medicines and Healthcare products Regulatory Agency) will walk blindly and feed the British public false information.
News this week that GlaxoSmithKline knowingly withheld clinical trial data from the MHRA regarding the top selling anti-depressant drug Seroxat will add further fuel to the fire and hopefully push for an independent review into how the MHRA could be duped into believing that a drug they have reviewed on numerous occasions was safe.
The MHRA are made up of medical experts, some of whom are former employees and shareholders of the pharmaceutical companies they grant licenses to. Surely this is wrong and at the very least there is the suspicion of a conflict of interest?
For too long now the MHRA have been hoodwinked by the Pharmaceutical Industry. Lawsuits for damages in respect of harm caused to patients are popping up all over the place, but avoid media and public scrutiny because they are usually settled out of court on the proviso that evidence is not made public.
A public enquiry is needed to examine how the MHRA is run and why former Pharmaceutical Industry directors are allowed onto the board. Would a convicted drink driver be allowed to adjudicate on a road safety panel?
The MHRA need to pull the plug NOW on their close associations with the Pharmaceutical Industry. The British public expects and naively assumes impartiality and not a regulatory authority whose main interest seems to be one of ‘delivering jobs for the boys.’
Mr Robert Fiddaman (Group Moderator of the Online Seroxat Support Group)
Birmingham, UK