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[SANET-MG] high risk drugs
The article below is on the testing of high risk drugs following the
drug test disaster in UK. A cursory glance at the adverse event reports
on the monoclonal antibody drugs approved by FDA shows that adverse
events even leading to death are normally associated with such drugs
(the risk in treating cancer are probably worth taking) but healthy
experimental volunteers should have been warned of the risks.
The report does not cope with the production of such dangerous drugs in
food crops. France, for example, has been carrying on open field
experiments with maize modified with the dangerous drugs. In a sane
world the tests should not be protected by trade secrecy protection. The
French courts like USA and Canadian courts seems irrational in allowing
such open tests to go on without the knowledge of those being polluted
by the tests. Such insanity must be stopped..
Published online: 7 December 2006; | doi:10.1038/news061204-13
New test could weed out dangerous drug trials
High-risk drugs such as antibodies need better safety checks, say experts.
Help or harm? Future tests might better tell when a drug trial will go
Immunologists studying what went wrong in the fateful Northwick Park
drug trial in London in March 2006 have developed a test that they say
may have spotted the near-deadly effects of the 'superantibody' drug
The announcement came at the unveiling of a report by the expert
scientific group convened to provide guidelines to the Medicines and
Healthcare Products Regulatory Agency (MHRA), which governs UK clinical
trials. The group has provided a list of 22 recommendations to minimize
the risk from phase-one clinical trials, during which a new drug is
tested on humans for the first time.
Six volunteers became critically ill during the phase-one test of
TGN1412, developed by now-defunct drug firm TeGenero. Although
preclinical research on monkeys had shown no sign of danger, the drug
provoked devastating immune reactions in the human subjects.
Immunologist Stephen Inglis a researcher at the National Institute for
Biological Standards and Control in London and a member of the expert
group, has now developed a lab test using human immune cells that shows
the same overactivation and proliferation seen in the volunteers.
Although still being refined and developed, he hopes that similar tests
could become a routine part of preclinical testing of new drugs that
target the immune system.
If our test had been available, I would say it should have been used.
Stephen Inglis, Expert Scientific Group on phase-one clinical trials.
Stuck and dried
The victims of the TGN1412 disaster suffered a 'cytokine storm',
featuring massive release of inflammatory molecules called cytokines,
and overproliferation of immune cells known as CD4 cells. In Inglis's
studies, this effect could only be reproduced when the TGN1412
antibodies were dried onto the surface of an experimental vessel before
being presented with human immune cells, rather than floating in
solution as in usual preclinical toxicity tests. Antibodies that are
dried and stuck to a surface are often more active.
It is not entirely clear why the drug produced such devastating effects
in humans but not in macaques, which possess an almost identical
receptor protein for the antibody. But using antibody-immobilization
tests such as the one developed by Inglis could help to identify
potential dangers not flagged up by animal tests.
"If I were developing a drug of this kind in the future, I would take
these tests seriously," Inglis said at the unveiling of the expert
group's report. "I would hope they become standard in future." He and
his colleagues are preparing to publish details of the test in a
Gordon Duff, chair of the group, said that every effort should be made
to consult outside experts and search preclinical results to highlight
particular dangers of "high-risk" drug candidates. These include drugs
that act on the immune system, as well as compounds with new biological
activities and those with species-specific effects for which animal
tests might not be reliable. This could be done in advance to create a
large database, as well as on a case-by-case basis for proposed drug trials.
The group also called for the creation of a Europe-wide database of
preclinical data, including details of 'failed' animal studies in which
drug candidates were found to be toxic. "We need information from
abandoned trials," said group member Janet Darbyshire, of the Medical
Research Council's Clinical Trials Unit in London. Usually, the MHRA
only sees data from preclinical trials that have produced successful
results, which are submitted as part of clinical trial applications, she
Among the group's other recommendations to the MHRA were that dedicated
centres for phase-one drug tests should be set up within existing
hospitals, that doses should be staggered between patients and patients
monitored carefully, and that initial doses for phase-one trials should
be less than the drug's "minimum anticipated biological effect level".
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