October 13

BBC News: Key Data ‘Missing” in Catastrophic TGN1412 Drug Trial

BBC reports (below) that an article in the journal, The Lancet, by experts from the Netherlands have determined that: "UK regulators did not receive
findings that might have warned them of damage TGN1412 could do." 

The authors, Kenter and Cohen, [1] propose a detailed system of additional safeguards for clinical trials-safeguards to prevent such catastrophic
consequences. They reason: "The mechanism of the antibody TGN1412 suggested that deleterious effects in man could not be ruled out conclusively from findings of animal experiments.

There are two potential areas of concern. First, TGN1412 administration could lead to T-cell activation and massive cytokine release. Second, the antibody could result in a strong expansion of regulatory T cells and non-specific immunosuppression. Therefore, either possibility-activation or  immunosuppression-could not be ruled out with the  available data and, since these effects would have serious outcomes, the risk category should have been increased accordingly."

They note that although "Neither activation nor immunosuppression was reported in non-human primate studies…cytokine release was already recorded at a low dose in this species." Therefore, they reason, the dose given to the six volunteers in the trial–0.1 mg/kg–was much too high: "a proper starting dose would most probably be much less than a 500th of the concentration causing eff ects in the monkey-even assuming the sensitivity of man and monkey to TGN1412 was equal."

Furthermore, they note the known longlasting effects of TGN1412: "Most monoclonal antibodies have long plasma half-lives, and animal data in the
investigator’s brochure show that TGN1412 has a half life of about 8 days. Thus, full removal from the body would take about a month. This factor is an
additional risk because any untoward effects would be equally longlasting."

The TGN1412 experiment underscores the fact that no one in the peer review process actually fully examines all relevant bits of information that might
reveal hidden hazards. In 2001, a Johns Hopkins experiment killed Ellen Roche, a healthy volunteer who was exposed to hexamethonium. In that case, the investigator failed to examine the scientific literature which contained warnings.

The fact remains that the medical research community has failed to adopt and to enforce agreed upon standards regarding how extensively one should search for safety information prior to conducting a human experiment. Whether this is due to negligence, incompetence or competing interests, none of the stakeholders can be trusted to follow the necessary steps to ensure the safety of the human subjects. 

Unless and until independent monitors (inspectors) are authorized to conduct unannounced inspections–as is done in animal research–safety will take a
back seat because the financial stakes are so high. As long as no one is held accountable, Unless rules are enforced and stiff penalties imposed on
violators, no one is held accountable.

See: M J H Kenter, A F Cohen. Viewpoint.  Establishing risk of human experimentation with drugs: lessons from TGN1412, the Lancet, Vol 368 October 14, 2006

Contact: Vera Hassner Sharav
veracare@ahrp.org <mailto:veracare@ahrp.org>  
 Key data ‘missing’ in drug trial 
 Key information was absent from a research file prior to a London drug trial that left six men seriously ill, investigators have concluded.

 Drug research experts from the Netherlands say UK regulators did not receive findings that might have warned them of damage TGN1412 could do.

 The worst affected of the six men, Ryan Wilson, had fingers and toes amputated, and his future health is uncertain.

 In The Lancet, the authors propose a system of extra checks for trial drugs.

 Omissions:   An expert group set up by the UK’s Health Secretary is looking at how to safeguard against such adverse events when experimental drugs are tested.

 A preliminary report by the group recommends the initial drug dose should be given to just one person – which was not the case in the London
  The assessors did not receive all relevant findings  The Dutch researchers  
   And it recommends drugs which affect the immune system, like the monoclonal antibody TGN1412, may be best given to people who are already ill.

 The Lancet paper authors tested their own proposed list of safety checks using the case of TGN1412.

 The checks include factors such as how much is known about how the experimental drug works in the lab, in animals and in humans and how predictable these effects are.

 In the case of TGN1412, the scientists from the German company TeGenero reported that the site in the body where the drug binds was identical in humans beings and monkeys.

      Ryan Wilson was the worst affected of the six volunteers Drug victim interview <http://news.bbc.co.uk/2/hi/help/3681938.stm>      However, no detailed data on such a comparison was included.

 When the Dutch researchers explored this they found clear differences between humans and monkeys.

 The research file on TGN1412 also lacked information about how the drug affects certain human immune cells compared to monkey immune cells.

 Dr Adam Cohen, from the Centre for Human Drug Research in Leiden, the Netherlands, said: "Essential information was absent.  The assessors did
not receive all relevant findings."

 Dr Cohen and his team say drug developers need to ensure they provide all essential information, and trial assessors need to use internationally consistent ways to evaluate which human experiments should go ahead.

 A spokesman for the UK’s drug trial assessor, the Medicines and Healthcare products Regulatory Agency, said: "We conducted a rigorous assessment of the application by experienced assessors who concluded it was reasonable to proceed with the trial."

 He said the MHRA had implemented recommendations since made by the UK’s independent expert group on the way such trials are reviewed in the

 "Clinical trials in general have an excellent safety record but it is important that we learn the lessons from the TGN 1412 incident," he added.

        C BBC MMVI
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