We have previously posted, most recently here, here, and here, about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG, which is now bankrupt.
The International Herald Tribune summarized some new information about how the trial was conducted, focussed on the Parexel's conduct.
In recent weeks, experts said, new medical tests and investigations into the incident have highlighted loopholes in a drug testing system that in some instances is better designed to bring drugs to market than to protect humans, particularly when it comes to some of the newest medicines.
[An interim report on the trial by Professor Gordon Duff] called for reviews 'to examine how risks in medicine development are currently assessed and minimized' by drug makers.
Indeed, although the innovative drug being tested, TGN1412, was a potent immune system stimulant that overrode the body's normal regulatory mechanisms, it was tested according to much the same standards that govern far more ordinary pharmaceuticals.
British regulators approved the TGN1412 trial in just 17 days and the testing company did not have an adequate response plan for adverse reactions, regulators have said.
The American-based testing company that conducted the trial, Parexel International, of Waltham, Massachusetts, has said repeatedly that it carried out the trial according to "appropriate policies and procedures."
Parexel, a world leader in contract drug testing, with centers in the United States, Europe and Africa, said it could not provide further information.
The British drug regulators who reviewed the trial performed those duties according to accepted standards and to the best of their ability and so have no liability, lawyers said.
All parties did their jobs according to formal regulatory and legal requirements, narrowly defined.
But, in retrospect, almost all scientists agree that those requirements were inadequate for TGN1412 and that common sense would dictate different testing practices.
Day [the lawyer for four of the TGN 1412 trial subjects] said he would argue that Parexel, which contracts with drug makers to test new medicines, should have made sure that its client had adequate insurance. He also questioned the design and conduct of what it should have seen as a delicate trial, he said.
They gave the six research subjects infusions of new and unknown drugs only 10 minutes apart, so that there was no time to screen for serious side effects.
In addition, Day said, the men should have immediately been given high doses of steroids for the disastrous reaction that TGN1412 precipitated. He said that such a reaction was noted as a possibility in the study's official protocol.
The six [TGN 1412 subjects] were not moved from the Parexel Research wing to Northwick Park's intensive care unit for up to 16 hours, despite severe symptoms.
In testimony before the British expert review panel, the intensive care doctors said that while they were aware that the patients seemed to be having an inflammatory reaction, the Parexel team did not inform them of the possibility of a cytokine 'storm' until hours after the patients reached the intensive care unit.
Clearly, this article raises concerns about whether Parexel could have done a better job protecting its research subjects. Minimizing the risks to human research subjects should be the highest priority for those who do clinical research.
Parexel International, meanwhile, is also involved in a countroversy about another trial in the UK. The BBC just reported
Leading scientists have raised serious concerns about a major government study into the effectiveness of drugs used by thousands of people with MS.This article raises concerns whether results from a trial to be run by Parexel International could be selectively suppressed were such results to threaten the interests of any of the commercial sponsors of the trial. Selective suppression of undesired research results would violate the integrity of the clinical research data base, and insult the altruism of the people who volunteered as research subjects thinking by doing so they would be contributing to science and the advancement of health.
The study was originally being conducted by an established team at Sheffield University.
But it has been switched to Parexel - a company with commercial links to three of the four pharmaceutical companies involved in the study.
The original contract to evaluate the progress of the thousands of MS patients on the scheme was given to the Sheffield team.
However, sources have told the BBC that the contract was re-tendered last year following a dispute over the university's right to publish independently on their findings. [Editor's note - it is unclear whether this has anything to do with the controversy about Sheffield's firing of Dr Aubrey Blumsohn after he went public about his difficulties getting access to data from his own research study, see most recent post here.]
Sir Iain Chalmers, editor of the James Lind Library, which reviews scientific research, is uneasy about the decision.
He said: 'I think it's a totally unreasonable expectation, that information which may be important to patients and prescribers should potentially be suppressed because a company does not find it in its interests to see it made public.'
One of the pharmaceutical companies involved in the scheme has denied that any of the research will be suppressed, even though each company in the risk sharing scheme has the right to decide if any research involving their own drugs should be published.
Pete Smith, managing director of Biogen Idec in the UK and Ireland, said: 'It may look like a veto but it really isn't a veto. 'We are very confident that our drug is going to demonstrate its value here in the UK and to those patients who are in need of care and we are quite frankly looking forward to those results being published at the completion of this study.'
The scheme was being overseen by a project management group that included the MS Trust charity, four pharmaceutical companies, the Department of Health and several others including scientists and academics.
However, the BBC understands that the group as a whole was not consulted about the decision to appoint Parexel, which was taken instead by the drugs companies, the Department of Health and the MS Trust.
It is more disturbing that while this was all going on, a recent announcement by Parexel International emphasized its "commitment to providing solutions that expedite time-to-market and peak market penetration."
Did this need for speed account for the (in retrospect) badly taken decisions about the design of the TGN 1412 trial? Will haste lead to waste, or worst, in the new multiple sclerosis trial?
More broadly, what are the real goals of contract research organizations? Should they be entrusted to protect their study subjects, and to ensure that their voluntarism is honored by he complete and honest dissemination of the results they helped to generate?
A FINAL IRONY: the announcement noted above was of the newest member of the Parexel board of directors. She is Ellen M. Zane, " President and Chief Executive Officer of Tufts-New England Medical Center (Tufts-NEMC) and Floating Hospital for Children, located in Boston, Massachusetts." She also "serves on the Board of Overseers at the Tufts University School of Medicine." Since Tufts University School of Medicine and Tufts-New England Medical Center are major sites for clinical research, the potential for conflict of interest here is obvious.