Drug effect blamed in UK trial

Pharmaceutical watchdog reaffirms that an unexpected biological effect of TGN1412 probably caused reactions in six men

By | May 25, 2006

An unexpected biological effect of the monoclonal antibody TGN1412 was the most likely cause of the severe reactions in six men participating in a clinical trial in March, Britain's drug watchdog reiterated Thursday (May 25). The final report from the Medicines and Healthcare products Regulatory Agency (MHRA) confirms the main findings from an interim report published in April. "We are satisfied that the adverse incidents which occurred were not as a result of any errors made in the manufacture of TGN1412, its formulation, dilution or administration to trial participants," the MHRA's chief executive, Kent Woods, said in a statement. The report does, however, note that the contract research company running the trial, Parexel, failed to meet good clinical practice guidelines in several areas -- for example, not putting in place a formal arrangement for 24-hour medical cover for patients. However, none of these lapses likely caused the serious adverse events seen in the trial. Parexel did not immediately respond to a request for comment. In response to the report, TeGenero, the company that sponsored the drug, said in a statement that it remains "devastated that such unpredicted side effects could have been caused by one of our products." On March 13, six healthy volunteers for the phase I trial of TGN1412 experienced life-threatening side effects grouped under the title "Cytokine Release Syndrome." All had received the drug; two volunteers given placebo did not experience similar side effects. The MHRA suspended the trial, and began investigating the cause of the severe reactions. In the wake of the report, the government has also released details of an investigation that will be carried out by an expert working group into the clinical trials of monoclonal antibodies. "This is a complex scientific issue which raises important questions about the potential risks associated with this type of drug," Health Minister Andy Burnham said in a statement. "The Expert Group will provide advice for the future authorization of trials involving these types of products." The group will be led by Gordon Duff from Sheffield University, and will include Carol Black, President of the Royal College of Physicians; Janet Darbyshire, director of the MRC Clinical Trials Unit; and Mark Walport, Director of the Welcome Trust, among others. They had their first meeting yesterday (May 24), a spokeswoman for the Department of Health told The Scientist. An interim report is expected within three months of that first meeting, she added. The government has asked the group specifically to look into what may be necessary in the transition from pre-clinical to Phase 1 studies for biological molecules, new agents with species-specific action, and new immune system drugs. Geoff Hale, professor of therapeutic immunology at the University of Oxford, told The Scientist that there is definite room for improvement to the process of approving and managing Phase I clinical trials. For one, he suggested focusing on "the timing of administering drugs to patients." As many commentators have pointed out, staggering dosing in the TGN1412 trial might have lessened the scale of the tragedy, he said. Hale, CEO of BioAnaLab, a contract research company that analyses biologic drugs, also noted that it is possible to test for the type of cytokine storm reaction the TGN1412 patients suffered with a blood assay. "It's something that we and others do in analogous situations," he said. "You take blood from the patient and simply add the antibody in question and look for the cytokine reaction." The test is validated and used by several groups, he said, "but for some reason it is not part of the routine requirements for testing antibodies." Stephen Pincock spincock@the-scientist.com Links within this article Final report on TGN1412 www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&useSecondary=true&ssDocName=CON2023822&ssTargetNodeId=389 A. McCook, "UK drug trial effects were 'unpredicted'," The Scientist, April 6, 2006. www.the-scientist.com/news/display/23275/ Parexel www.drugtrial.co.uk/default.ihtml?step=4&pid=4 "Statement re TGN1412," TeGenero, May 25, 2006. www.tegenero.com/news/statement_re_tgn1412/index.php Carol Black "Wellcome Trust appoints new director," Wellcome Trust, January 30, 2003. http://www.wellcome.ac.uk/doc_WTD002908.html BioAnaLab www.bioanalab.com


May 28, 2006

Such a conclusion is shameful in the extreme. As a clinical pharmacologist with over 30 years experience working with discovery comounds albeit at later trial phases, I am apalled at this abdication of accountability to the molecules "misbehaviour". Wherever did our clinical acumen and clinical commitment to patient welfare go? Out the window? What are we worth as clinical researchers, if we cannot prevent such disaster? It is PRECISELY SUCH EVENTS THAT WE ARE EXPECTED TO ANTICIPATE, TO HAVE NIGHTMARES ABOUT, TO DREAD, SO THAT THE PATIENT OR VOLUNTEER DOES NOT PAY THE PRICE FOR OUR COMPLACENCE, OR BLIND CONFIDENCE IN THE GOOD BEHAVIOUR OF A NEWLY ENGINEERED MOLECULAR ENTITY WHOSE EFFECTS IN MAN MAY BE COMPLETELY UNPREDICTABLE.\n\nFor shame.\n\n

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