March 12, 2007
Nigel Hawkes, Health Editor
The drug trial that left six young men seriously injured was poorly designed and possible risks had not been taken fully into account, a report by the Royal Statistical Society has concluded. The trial, at Northwick Park in northwest London, went disastrously wrong when a drug codenamed TGN 1412, being tested on human beings for the first time, produced horrifying effects, triggering a violent reaction from the six volunteers’ immune systems that caused extensive organ damage.
The society set up an expert committee to review the trial. It concludes that it had major defects, some of which could have been anticipated. Giving six volunteers doses of the drugs without a sufficient interval between them to assess ill-effects was the most serious error.
Had there been a proper interval, the effects would have become apparent after the first volunteer, and the others could have been spared.
The society also criticises the use of animal data to provide assurances that the much smaller doses given to the volunteers would be safe.
In future, it says, tests should be done on human cells in test-tubes to try to work out safe doses for such biological agents. In preparing the report, the society sought to establish how many “first-in-man” trials using biological agents had been done, and whether any others had had unexpected outcomes.
The Medicines and Healthcare products Regulatory Agency initially refused a request under the Freedom of Information Act to reveal this data, on ground of cost, but agreed to do so after an appeal.
The reason why the agency had been reluctant was that it had two databases, one listing study designs and the other adverse events. The two could not be linked so the data had to be correlated manually. The society said that the lack of a link was not satisfactory.
Its panel also reviewed the role taken by the Brent Ethics Committee, the local committee that approved the trial. It concludes that the committee did its best, raising several pertinent issues and seeking advice from an immunologist.
It was given advice from an unnamed immunologist on headed notepaper of the company, TeGenero, that developed the drug, saying that the “risk of inducing a clinically apparent cytokine release syndrome is considered to be low, although it cannot be completely excluded”. Yet that is exactly what happened.
Despite that warning, the ethics committee did not query the plan to give the drug to the volunteers in quick succession, nor raise the issue of how a violent reaction would be monitored and treated.
It appears to have been several hours before doctors at Northwick Park realised that is what they were dealing with. Quicker treatment with drugs might have helped.
Professor Stephen Senn, chairman of the working group, said: “First-in-man studies need to be designed and described much better than currently is the case. Particular attention must be paid to starting doses, dose intervals, dose steps and plans for allocating subjects to these.”