BioWorld International Correspondent

LONDON - The UK regulator uncovered some discrepancies with Good Clinical Practice in its investigation into the Phase I safety trial of TeGenero AG's TGN1412, but stuck to the original conclusion that the life-threatening cytokine storm suffered by six health volunteers was due to "an unexpected biological effect."

"We are satisfied the adverse incidents that occurred were not as a result of any errors made in the manufacturer of TGN1412, its formulation, dilution or administration to trial participants," said Kent Woods, chief executive of the Medicines and Healthcare Products Regulatory Agency (MHRA).

The final report on what caused the fiasco at Northwick Park Hospital in London on March 13 is based on further inspections by the MHRA and the German authorities, following publication of the interim conclusions April 5.

The report was condemned as "totally inadequate" by the lawyer representing the two most seriously affected men, Ann Alexander, of the law firm Irwin Mitchell. She called for an independent inquiry into how the trial was conducted and described the self-regulating MHRA as "an insular organization with an archaic approach."

At the time the interim report was published, the UK government announced it was setting up an expert group to investigate the wider implications and consider what changes to clinical trials procedures might be required. The MHRA said that at this point the findings of the expert group would attract international interest and "could potentially affect clinical trials regulation worldwide."

Inspections have been carried out at TeGenero's facility in Wurzburg, Germany, along with those of TGN1412's manufacturer, Boehringer Ingelheim, the unnamed laboratory that carried out the pivotal animal toxicology studies of the monoclonal antibody, and Paraxel, the contract research organization that conducted the trial.

The MHRA said there were no irregularities in the preclinical work carried out by TeGenero, the toxicology studies on monkeys were in accordance with Good Laboratory Practice, all tests on the administered product showed it complied fully with the release specification and there were no differences between the initial batch used in toxicology testing and the full-scale production batch administered in the trial.

A number of discrepancies were uncovered at Paraxel's Clinical Pharmacology Research Unit Clinic, including failure to complete the full medical record of one of the trial subjects, employment of a physician who was not adequately trained or suitably experienced for the role, failure to check TeGenero's insurance policy, and permitting the two volunteers who received the placebo to leave before unblinding the trial to check they had not received the active drug.

However, the inspectors concluded that "there were no findings which we believed to be likely to have contributed to the serious adverse reactions suffered by the trial subjects."

And the MHRA's overall conclusion is that "the adverse events did not involve errors in the manufacture of TGN1412, or in its formulation, dilution or administration to trial participants."

With the expert study in progress, this is in many respects the worst outcome for the overall industry. The agency went on to note TGN1412 is a new class of monoclonal antibody, designed to stimulate, rather than dampen the immune system. "In this case, the resulting activity seen in humans was not predicted from apparently adequate preclinical testing. This is a complex scientific issue which raises important scientific and medical questions about the potential risks associated with this type of drug."

The job given to the expert group, to be headed by Gordon Duff, professor of Molecular Medicine at Sheffield University, is to "consider what may be necessary in the transition from preclinical to first-in-man Phase I studies, and in the design of these trials, with specific reference to biological molecules with novel mechanisms of action; new agents with a highly species-specific action; and new drugs directed toward immune system targets."

The lawyer Alexander questioned the MHRA's finding that the reaction of the volunteers was unpredictable, and asked if the animals involved were an appropriate comparison with human subjects, and what the effects TGN1412 had on the test animals.

She also questioned why all eight volunteers were injected with gaps of only 10 minutes and charged that the volunteers were not treated for up to five hours after the first symptoms were reported.