UK drug trial effects were 'unpredicted'

Neither the manufacturing process nor problems in dosing or study protocol were to blame for the violent reactions that felled six healthy volunteers last month who took a new monoclonal antibody designed to treat autoimmune disease and leukemia, according to an interim report from the UK Medicines and Healthcare Products Regulatory Agency (MHRA) released Wednesday (April 5). Instead, the report suggests that an ?unpredicted biological action of the drug? caused the reactions in humans.?If these findings were to be confirmed, it would indicate that this product showed a pharmacological effect in man which was not seen in pre-clinical tests in animals at much higher doses,? MHRA?s chief executive professor Kent Woods said in a statement.The report said that an independent group of experts plans to look further into the evidence from the investigation, and consider whether there should be sweeping changes in how clinical trials are carried out, specifically those involving monoclonal antibodies.TeGenero, the company that sponsored the drug, called TGN1412, said yesterday that pre-clinical animal tests did not show any deaths related to the drug, and only one animal had to be euthanized after an unrelated bacterial infection. The company did not return a request for comment.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 set in place a program of investigations that probed whether problems in dosage, formulation, contamination, or other aspects of protocol or manufacturing had taken place. The report found no evidence of any such occurrence. Five of the six volunteers have since been released from the hospital.Adil Shamoo, bioethicist at the University of Maryland and chief editor of the journal Accountability in Research, told The Scientist that the MHRA report was a good first step, but the organization has an interest in reporting ?no deficiencies found,? given that it approved the trial in the first place. ?They are going to justify what they have already done themselves -- they approved it,? he said.Shamoo added that report also fails to discuss why TeGenero and the company that ran the trial, Parexel International, chose to administer a potentially serious drug to six people simultaneously, rather than one at a time to watch for adverse events.Simon Best, chairman of the BioIndustry Association (BIA), the UK biotechnology trade association, said he was concerned that the MHRA decision to investigate trials of monoclonal antibodies in general may be ?broader than it needs to be.? The problem with the TGN1412 trial was not the monoclonal antibody, Best argued, but its target, CD28, a regulator of the immune system. Even if the drug had been a classic pharmaceutical, the result would likely have been the same, he told The Scientist.This incident, and the latest report, may help fuel a ?growing recognition that biologics are different from? classic pharmaceuticals, said Thomas Murray, president of the Hastings Center for bioethics research in New York. The MHRA appears to recognize that it?s time to ?think about the right way to evaluate? biologics, to avoid similar ?horrendous? side effects in the future, he said.Alison McCook amccook@the-scientist.comLinks within this articleI.Mellman, ?Where next for cancer immunotherapy?,? The Scientist, January 1, 2006. http://www.the-scientist.com/article/display/18859/Medicines and Healthcare Products Regulatory Agency http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=5TeGenero http://www.tegenero.com/Adil Shamoo http://www.umaryland.edu/bmb/faculty/shamoo.htmlAccountability in Research http://www.tandf.co.uk/journals/journal.asp?issn=0898-9621&linktype=5BioIndustry Association http://www.bioindustry.org/D. Fitzgerald, ?Antibody drug development: On target,? The Scientist, November 17, 2003. http://www.the-scientist.com/article/display/14260/Hastings Center http://www.thehastingscenter.org/contact/contact.asp

UK drug trial effects were 'unpredicted'

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