BMJ 2016;352:i784 doi: 10.1136/bmj.i784 (Published 8 February 2016)
Page 1 of 2
News
NEWS French drug trial had three major failings, says initial report Nigel Hawkes London
Three major shortcomings have been identified in the drug trial that led to the death of a volunteer last month, the French health minister, Marisol Touraine, has said. Administration of the drug being tested continued even after the first volunteer had fallen ill, Touraine said at a press conference on 4 February. This man, believed to be a 49 year old singer and artist from Brittany called Guillaume Molinet, had been given a dose of the drug on 7 January and admitted to hospital on the evening of 10 January. But on the morning of 11 January Biotrial, the French company carrying out the trial, administered the same dose to five more participants. The second error was not to inform these volunteers of what had happened the previous evening, to give them the chance to withdraw their consent.
The third had been not reporting the incident to the French national medicines safety agency (ANSM) until four days after the first volunteer had been admitted to hospital.
Touraine’s comments were based on a preliminary report from the French social affairs inspectorate (Inspection Générale des Affaires Sociales),1 which is carrying out an investigation that is expected to reach final conclusions at the end of March. It is one of three inquiries ordered into the disaster that led to adverse effects in six volunteers three days after the trial started on 7 January.2 The social affairs inspectorate said that the conditions under which the trial was authorised “did not violate current regulations,” while also remarking on a lack of precision in the trial protocol. The preliminary report also suggested that the qualification criteria for inclusion in the trial may not have been sufficiently clear in excluding people who used psychoactive drugs.
Touraine was asked at a press conference whether the volunteer who died—referred to in the report as “subject 2508”—was a cannabis user. Because the experimental drug targeted the cannabis receptors in the brain, this was a relevant question. “It is possible,” the minister replied without elaborating. The report said that participants were asked about their use of cannabis when recruited to the trial but that the criteria for exclusion “lacked coherence and precision.” Subject 2508 said that he did not use drugs, and urine testing at the time of recruitment proved negative, but the report said that deeper investigation of this point was needed.
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The chain of events on Sunday 10 January is critical. At this stage the six volunteers were on their fifth day of a regime of 50 mg a day of the experimental drug, more than twice as high as any dose given to previous participants. Biotrial said in a statement that subject 2508 had been admitted to hospital on that day with mild symptoms, that reports during the night had been reassuring, and that he was expected to leave hospital the next morning. There was nothing to justify terminating the trial.
The social affairs inspectorate’s report gave a more detailed and slightly different account. It said that he had apparently trivial symptoms at 9 am on Sunday morning and that they did not involve the central nervous system. Later in the morning he reported a second symptom that could, in retrospect, have been related to the central nervous system, but it too was regarded as trivial and transitory. The first serious symptoms had appeared at about 6 30 pm when he awoke from a nap. It was the other volunteers who alerted staff, who called a doctor who in turn found “alarming signs,” and the decision was taken to transfer him to hospital. This contradicts the claim that the other volunteers were unaware of the problems. However, they were not apparently given the chance to withdraw their consent in light of this and were themselves given a sixth 50 mg dose of the drug the next morning. All five were subsequently admitted to hospital. Their condition remains unclear. Touraine said that they continue to improve and have been discharged, despite claims made after they were admitted to hospital that some had brain damage. All the other 90 volunteers have been contacted, and 75 have undergone magnetic resonance images. None showed the abnormalities present in the volunteers who were admitted to hospital.
Overall, the report did not find that the trial protocol failed to meet current regulations or that the French medicines safety agency was wrong to approve it, “despite the weaknesses identified.” Among those weaknesses was a lack of precision in how the escalation of doses should be calculated. The report did not question why 50 mg was chosen as the dose for multiple administration, nor whether pharmacokinetic data from the single dose phase of the trial had been taken into account in calculating it. The report did clarify that there was no proper interval between doses in the multiple dose group. The report identified at least one “major gap in good practice and regulations.” An email to the principal investigator, dated 12 January, asked him to delegate responsibility for a particular Subscribe: http://www.bmj.com/subscribe
BMJ 2016;352:i784 doi: 10.1136/bmj.i784 (Published 8 February 2016)
Page 2 of 2
NEWS
task to a subordinate, backdating the approval to 4 January, apparently to make it look as if this act of delegation had taken place before the final stage of the trial began. The importance of this apparent attempt to deceive, the report said, is the doubt it may throw on the conduct of the trial as a whole, because the doctor to whom the task was delegated had just started work for Biotrial and was merely an observer in the trial planning.
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D’Autume C, Duhamel G. Inquet sur des incidents graves survenus dans le cadre de la realisation d’un essai clinique. Inspection Générale des Affaires Sociales. http://socialsante.gouv.fr/IMG/pdf/fevrier_2016_-_note_etape_-_accident_essai_clinique.pdf. Hawkes N. Details of French trial must be released urgently, say UK experts. BMJ 2016;352:i319.
Cite this as: BMJ 2016;352:i784 © BMJ Publishing Group Ltd 2016
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
News
NEWS French drug trial had three major failings, says initial report Nigel Hawkes London
Three major shortcomings have been identified in the drug trial that led to the death of a volunteer last month, the French health minister, Marisol Touraine, has said. Administration of the drug being tested continued even after the first volunteer had fallen ill, Touraine said at a press conference on 4 February. This man, believed to be a 49 year old singer and artist from Brittany called Guillaume Molinet, had been given a dose of the drug on 7 January and admitted to hospital on the evening of 10 January. But on the morning of 11 January Biotrial, the French company carrying out the trial, administered the same dose to five more participants. The second error was not to inform these volunteers of what had happened the previous evening, to give them the chance to withdraw their consent.
The third had been not reporting the incident to the French national medicines safety agency (ANSM) until four days after the first volunteer had been admitted to hospital.
Touraine’s comments were based on a preliminary report from the French social affairs inspectorate (Inspection Générale des Affaires Sociales),1 which is carrying out an investigation that is expected to reach final conclusions at the end of March. It is one of three inquiries ordered into the disaster that led to adverse effects in six volunteers three days after the trial started on 7 January.2 The social affairs inspectorate said that the conditions under which the trial was authorised “did not violate current regulations,” while also remarking on a lack of precision in the trial protocol. The preliminary report also suggested that the qualification criteria for inclusion in the trial may not have been sufficiently clear in excluding people who used psychoactive drugs.
Touraine was asked at a press conference whether the volunteer who died—referred to in the report as “subject 2508”—was a cannabis user. Because the experimental drug targeted the cannabis receptors in the brain, this was a relevant question. “It is possible,” the minister replied without elaborating. The report said that participants were asked about their use of cannabis when recruited to the trial but that the criteria for exclusion “lacked coherence and precision.” Subject 2508 said that he did not use drugs, and urine testing at the time of recruitment proved negative, but the report said that deeper investigation of this point was needed.
For personal use only: See rights and reprints http://www.bmj.com/permissions
The chain of events on Sunday 10 January is critical. At this stage the six volunteers were on their fifth day of a regime of 50 mg a day of the experimental drug, more than twice as high as any dose given to previous participants. Biotrial said in a statement that subject 2508 had been admitted to hospital on that day with mild symptoms, that reports during the night had been reassuring, and that he was expected to leave hospital the next morning. There was nothing to justify terminating the trial.
The social affairs inspectorate’s report gave a more detailed and slightly different account. It said that he had apparently trivial symptoms at 9 am on Sunday morning and that they did not involve the central nervous system. Later in the morning he reported a second symptom that could, in retrospect, have been related to the central nervous system, but it too was regarded as trivial and transitory. The first serious symptoms had appeared at about 6 30 pm when he awoke from a nap. It was the other volunteers who alerted staff, who called a doctor who in turn found “alarming signs,” and the decision was taken to transfer him to hospital. This contradicts the claim that the other volunteers were unaware of the problems. However, they were not apparently given the chance to withdraw their consent in light of this and were themselves given a sixth 50 mg dose of the drug the next morning. All five were subsequently admitted to hospital. Their condition remains unclear. Touraine said that they continue to improve and have been discharged, despite claims made after they were admitted to hospital that some had brain damage. All the other 90 volunteers have been contacted, and 75 have undergone magnetic resonance images. None showed the abnormalities present in the volunteers who were admitted to hospital.
Overall, the report did not find that the trial protocol failed to meet current regulations or that the French medicines safety agency was wrong to approve it, “despite the weaknesses identified.” Among those weaknesses was a lack of precision in how the escalation of doses should be calculated. The report did not question why 50 mg was chosen as the dose for multiple administration, nor whether pharmacokinetic data from the single dose phase of the trial had been taken into account in calculating it. The report did clarify that there was no proper interval between doses in the multiple dose group. The report identified at least one “major gap in good practice and regulations.” An email to the principal investigator, dated 12 January, asked him to delegate responsibility for a particular Subscribe: http://www.bmj.com/subscribe
BMJ 2016;352:i784 doi: 10.1136/bmj.i784 (Published 8 February 2016)
Page 2 of 2
NEWS
task to a subordinate, backdating the approval to 4 January, apparently to make it look as if this act of delegation had taken place before the final stage of the trial began. The importance of this apparent attempt to deceive, the report said, is the doubt it may throw on the conduct of the trial as a whole, because the doctor to whom the task was delegated had just started work for Biotrial and was merely an observer in the trial planning.
For personal use only: See rights and reprints http://www.bmj.com/permissions
1 2
D’Autume C, Duhamel G. Inquet sur des incidents graves survenus dans le cadre de la realisation d’un essai clinique. Inspection Générale des Affaires Sociales. http://socialsante.gouv.fr/IMG/pdf/fevrier_2016_-_note_etape_-_accident_essai_clinique.pdf. Hawkes N. Details of French trial must be released urgently, say UK experts. BMJ 2016;352:i319.
Cite this as: BMJ 2016;352:i784 © BMJ Publishing Group Ltd 2016
Subscribe: http://www.bmj.com/subscribe
