BMJ 2016;352:i466 doi: 10.1136/bmj.i466 (Published 25 January 2016)

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NEWS French drug trial protocol fails to answer key questions Nigel Hawkes London

Details of the drug trial in France in which one man died and others were left with severe health problems have emerged, but there is still no clear evidence of what went wrong.

After Le Figaro published the trial protocol,1 the French national agency for the safety of medicines and health products formally released it. The report revealed the chemical structure of the drug BIA 10-2474, developed by the Portuguese company Bial, and the trial procedure—single administrations of the drug at increasingly higher doses, followed by multiple administrations given on successive days.

Of the six people who were given multiple doses, five developed side effects of varying severity and one died.2 He was named as Guillaume Molinet, a 49 year old man from Brittany. The protocol does not make it clear if there was any interval between the participants beginning multiple doses. From information given by the French health minister, Marisol Touraine, however, it appears that all six began multiple doses on the same day. The man who died was admitted to hospital three days later.

Catherine Hill, a biostatistician who has served on the French agency’s scientific board, told Nature that giving all six participants multiple doses at the same time was “a big mistake.” A delay should have been incorporated. “You have to do things reasonably, and I think it’s an unreasonable protocol,” she said. The protocol leaves the size of the multiple dose to be decided on the basis of experience from the single dose portion of the trial, stating that it will not exceed a third of the maximum tolerated dose, or a third of the maximum dose reached if the maximum tolerated dose is not established.

Moving from single to multiple doses is a critical stage in a trial, points out Stephen Senn, a statistician who heads the Competence Centre for Methodology and Statistics at Luxembourg Institute of Health. The concentrations reached during multiple dosing depend on the pharmacokinetics of the drug—those with a longer half life build up higher concentrations. This needs to be carefully considered when moving from single to multiple doses. The protocol also shows that the substance was tested in four animal species—mice, rats, dogs, and monkeys—with few adverse events. The claim by Touraine that it had been tested in chimpanzees seems to have been a mistake.

The Royal Statistical Society said that there are “clear statistical reservations” about the trial and urged the French investigatory teams to include statisticians. In addition, it said that the investigator brochure, which usually describes preclinical studies in detail, needs to be published, the dose levels disclosed, and the multiple administration regimen published. The society said that the trial did not appear to follow the recommendations made by its own working party, which was chaired by Senn, after the 2006 study at Northwick Park Hospital in northwest London in which six healthy volunteers were injured.3 1 2 3

Clinical Study Protocol BIA 102474-101 http://www.youscribe.com/Product/Download/ 2691486?embed=true&key=903363fcb42cf7897f2efeb2620d253064a9dbb1&format=1. Hawkes N. Details of French trial must be released urgently, say UK experts. BMJ 2016;352:i319. Mayor S. Inquiry into adverse events in trial blames drug, not study design. BMJ 2006;332:870.

Cite this as: BMJ 2016;352:i466 © BMJ Publishing Group Ltd 2016

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French drug trial protocol fails to answer key questions.

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