New information casts doubt on the official versions of events surrounding the death of a 49-year-old man from west France during the clinical trial of a drug earlier this year. Guillaume Molinet died on January 17th, 2016, after taking part in the trial carried out by Rennes-based French company Biotrial on behalf of Portuguese pharmaceutical company Bial. Four other volunteers involved in the testing of drug BIA 10-2474 also suffered lesions to the brain.
The health and medical authorities have insisted that the tragedy was unforeseeable and that before these four volunteers were affected there had been no sign of anything untoward in the trials, which were testing the effects of a painkiller drug. But it has now emerged that another patient, known only as 'volunteer 2305', suffered a stroke during the period that he was taking the drug.
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The volunteer concerned did not know he had a stroke at the time – it was revealed later by a scan – and fortunately appears to have suffered no serious effects from it. He told Mediapart that he feels fine and is leading a normal life. But his experience undermines the claims made by Biotrial since the death, and repeated by the company's managing director, François Peaucelle in Ouest-France newspaper as recently as May 10th, that the tragedy was “completely unforeseeable” and that there was “no element in the sequence of events of the trial that could have enabled it to be predicted”.
The health authorities have systematically backed the firm's version of events. The CHU teaching hospital at Rennes, which cared for the trial's victims and monitored all of its participants, has not contradicted it either. Yet the hospital's neurology department, presided over by Professor Gilles Edan, has had volunteer 2305's MRI scan in its hands for several months, a scan that shows the volunteer suffered a stroke. It has not made any comment on this issue, and nor have the health authorities. Meanwhile Mediapart can reveal that the hospital's neurological unit has links with the company that carried out the trial, Biotrial.
One body that has already looked into the drugs trial is France's medical safety agency the Agence Nationale de Sécurité du Médicament (ANSM). In an inspection report it carried out at Biotrial just after the tragedy, which has not been published but which has been quoted in Quest-France, it says: “No information establishing the fact that the company Biotrial knew of the existence of a particular risk for the research volunteers prior to the first undesirable serious event encountered [editor's note, the tragedy involving Guillaume Molinet] has been highlighted.”
A similar line has been adopted by the Comité Scientifique Spécialisé Temporaire (CSST), the group of experts tasked by the ANSM to analyse the causes of the accident. In its final report, which was published online by the ANSM on April 19th, the CSST states that “one of the most striking elements of the BIA 10-2474 case is the absence of toxicity … in particular of a neurological type, observed in the trial volunteers other than those in the MAD n°5 group [editor's note, the one Guillaume Molinet was part of]”.
The CSST had access to the medical files of all the volunteers. Yet apart from Molinet's group, they noticed only commonplace reactions, notably “some cases of dizziness and not very severe headaches”.
In summary, then, as far as the authorities and Biotrial are concerned nothing significant happened in the clinical trials before January 10th when Guillaume Molinet suffered severe symptoms – very violent headaches, problems with his vision, difficulties in speaking - which led him to being admitted to the CHU teaching hospital in Rennes in the evening and ultimately to his death. This portrayal of the facts reduces Biotrial's responsibility, by suggesting that the death was not predictable and had come like a bolt from the blue.
For months now Biotrial, the authorities and the hospital in Rennes have tried to maintain a cloak of silence over the real circumstances of the drugs trial and the sequences of events involved. On January 15th, health minister Marisol Touraine held a press conference with professor Gilles Edan, who is not only head of the Rennes hospital's neurology department but also a renowned world specialist on multiple sclerosis.
Marisol Touraine portrayed the tragedy as an exceptionally serious occurrence that was completely “unprecedented”, but did not even mention the name of the drug that was being tested. Professor Edan did not go any further, and nor did he mention the significant side effects that had occurred before the death. The minister of health, meanwhile, announced that the health and social affairs watchdog the Inspection Générale des Affaires Sociales (IGAS) would investigate the affair and that its report would be made public at the end of March.
Yet apart from a progress report in February, IGAS has still not published its findings. When contacted, IGAS chief Pierre Boissier and one of the IGAS rapporteurs involved in the investigation, Gilles Duhamel, thanked Mediapart for calling and hung up.
The ANSM itself has refused Mediapart's requests for a copy of its inspection report on Biotrial, or even to communicate its contents. Moreover, shortly after the trial volunteer's death the agency carried out an internal inquiry which found that an assessor at the ANSM had already raised the alarm about a possible neurological toxicity related to the drug, highlighted by studies on four animals species. The agency refused to comment in any way about this internal investigation. It takes refuge behind medical and industrial confidentiality, plus the confidentiality of judicial investigations, in order to divulge no information that differs from the version of the facts that exonerates Biotrial. The same version of facts, incidentally, also exonerates the agency itself, given that it was this body that authorised the trial despite the trial's protocols not offering enough protection for volunteers, and despite the fact that the medical value of the painkilling drug being tested was highly debatable.
'I started to have blurred vision, then headaches...'
Professor Bernard Bégaud, chairman of the CSST which is the highest French body involved in investigation pharmaceutical affairs and which showed a lack of clear-sightedness over the Mediator drugs scandal, did not reply to Mediapart's calls about the drugs trial case. But Mediapart was able to speak to two other CSST experts about whether warnings before the tragedy had been disregarded. They confirmed their view that the tragedy was the result of a sudden occurrence. The CSST's report says that the accident came about as a result of a “threshold effect” that occurred at a certain dosage of the drug. This explanation effectively rules out the possibility that warning signs were missed.
Yet despite the continuing silence from experts and the authorities, information is mounting up showing that this explanation is false, and that the incident was not as unforeseeable as some would lead us to believe. Independent of the fact that studies on animals suggested the drug could have a toxic effect on the central nervous system, some potentially alarming side effects emerged among volunteers in the earlier group who took 10mg of the drug a day, the group that included volunteer 2305 who had a stroke. There were also some worrying side effects in another group that took 20mg daily doses. Yet it was after this trial of a 20mg dose that Biotrial decided to move up to 50mg, the dosage taken by Guillaume Molinet's group of volunteers.
In the group of volunteers who took daily doses of 10mg between November 17th and 26th, 2015, two people, volunteer 2305 and volunteer 2308, suffered similar problems with their vision on two occasions, each episode lasting for ten to 30 minutes. They flagged them to the doctors at Biotrial, who formed the view that these problems did not constitute “relevant events”. What is more, they were not given MRI scans at that point.
Yet volunteer 2305 told Mediapart that he realised at the time that the sight problems were due to the drug. Both incidents occurred the same length of time after taking the medicine, and the same thing happened with volunteer 2308, and on the same days. As is common practice, the drugs trial was carried out blind, with the volunteers not knowing whether they taking the drug itself or a placebo. “When we saw the problems recur with the same time lapse for both of us, we immediately realised and said to each other: 'We have it [editor's note, the real drug]',” said volunteer 2305.
Two months later, and after the Molinet incident, all those involved in the trial were invited to have a MRI scam to reassure them that they had not suffered any brain disorder. Volunteer 2305 had the scan several days after news of the tragedy came to light. It showed a stroke affecting the cerebellum in an area quite close to those that were damaged in those volunteers who were seriously affected.
The volunteer has told Mediapart that he was monitored directly by Professor Edan, who told him that the stroke was “old”. This led volunteer 2305 to believe that he had suffered an unnoticed stroke some years earlier and which had no link to the Biotrial clinical trial.
But his MRI scans in fact tell a different story. Le Figaro newspaper had them analysed by neurobiologist Professor Alain Privat, a member of the French academy of medicine, by a neuroradiologist, the head of a scan unit, and a biophysicist. All four experts came to the same judgement: the stroke in question was not “old” in the common sense of the word, but dated back to around two months before the scan. In other words, it dated back to exactly when volunteer 2305 and one of his fellow guinea pigs had had visual problems.
The official report on volunteer 2305's MRI scan indicates that the stroke was “not recent”. In medical parlance that means that it goes back more than around ten days, but does not exclude it having taken place in the preceding months. Mediapart was unable to find information on the scan of the other volunteer in the 10mg group who also had vision problems, nor on his state of health.
Mediapart's investigation also shows that two further volunteers, who were in the group that took doses of 20mg - from December 9th to December 18th, 2015 according to IGAS – also had worrying symptoms during their trial. According to a witness account that Mediapart has obtained, a volunteer from this group went to the CHU teaching hospital in Rennes in January to have a MRI scan, and described how he had suffered very intense headaches for nearly two days. Indeed, he alerted the the Biotrial doctors and was, in his words, “put in quarantine”. The same witness says that another volunteer in the same same group also had bad headaches and was, similarly, “put in quarantine”.
Despite the quarantine procedure, the Biotrial team did not judge these headaches to be significant side effects and considered that it was possible to move on to test a dose of 50mg. This was the dosage which provoked several reactions in Guillaume Molinet and four other volunteers in that group, with violent headaches being among the first of those symptoms. One of Molinet's fellow volunteers, Stéphane Schubhan, told Mediapart: “I had dark rings under my eyes, I started to have blurred vision, then headaches. It hurt, hurt, hurt...”
Links between the hospital and Biotrial
Thus the Biotrial team was unable to detect side effects in the groups taking 10mg and 20mg doses that should have alerted competent doctors. As far as the experts at the CSST were concerned, meanwhile, the previous trial groups before the Molinet group only had routine symptoms, dizziness and “not very severe headaches” which, having regard to the accounts of the volunteers, comes across now as a somewhat perfunctory judgement.
In their report the CSST experts make no reference to the stroke suffered by volunteer 2305. Does this mean they did not have access to that volunteer's scan, which was carried out three months before their final report? If they had examined it, they would have found it hard to write that no neurological toxicity had been apparent before Guillaume Molinet developed his extremely severe symptoms. CSST declined to comment on this issue.
As for the IGAS inspectors, they had access to the ANSM's inspection report, followed the CSST's meetings and also questioned the Biotrial team as well as some of the doctors and other medical personnel at the Rennes teaching hospital. Their progress report, referred to earlier, does not suggest at any time that Biotrial ignored undesirable effects which should have come as a warning. Nor do they mention volunteer 2305's MRI scan, whose results were known when this interim note was written.
It seems staggering that no one out of the ANSM, the CSST or the IGAS picked up on the fact that a volunteer had had a stroke that went unnoticed during the trial. Did the CHU teaching hospital in Rennes alert the authorities over this? Mediapart tried to contact Professor Gilles Edan and other doctors from the hospital, and well as a doctor working for Biotrial. Professor Edan sent an email suggesting Mediapart contacted the hospital management but they have not responded. A doctor at the hospital hung up when contacted by Mediapart.
Only professor Claude Ecoffey, head of the emergency surgical unit at the hospital, responded to Mediapart's requests for a comment. It was his unit that treated Guillaume Molinet. Professor Ecoffey confirmed that in respect of the chronology of events, Biotrial had lied to IGAS. In particular Biotrial's version of events suggested that Molinet only displayed severe symptoms after around 6.30 p.m. on January 10th, 2016; whereas medical files show he displayed serious symptoms about three hours earlier. However, Professor Ecoffey did not have information on the other trial victims who were looked after by Professor Edan's neurological unit.
Did Gilles Edan alert the authorities about the “non-recent” but not particularly old stroke suffered by volunteer 2305? He has not commented on the issue, and left the volunteer thinking that it was an old episode that had no link to the Biotrial trial. The discretion shown by both Professor Edan and the hospital has enabled Biotrial to persist with its version of events. The hospital itself takes refuge behind medical confidentiality.
The CHU teaching hospital at Rennes and Professor Edan have links with Biotrial. This Rennes-based company, whose chairman is Jean-Marc Gandon, is heavily involved in innovation in the Brittany region. Professor Edan is chair of the Institut des Neurosciences Cliniques de Rennes (INCR) whose major donor, according to its website, is Biotrial.
The connection goes back some years. In 1997 Gilles Edan published an important article on the treatment of multiple sclerosis with an immunosuppressant known as mitoxantrone. The article appeared in the Journal of Neurology, Neurosurgery and Psychiatry and among the many authors Gilles Edan's name came first. Other authors included Jean-Marc Gandon, head of Biotrial, and Olivier Lyon-Caen, head of neurology at Pitié-Salpêtrière teaching hospital in Paris and currently official advisor on public health at the Elysée. Contacted by Mediapart, Lyon-Caen declined to comment.
During a press conference in 2013 organised by the INCR with the commercial law firm Fidal, asset management firm Lazard and financial consultants Family Business Group, Gilles Edan stated: “In collaboration with Biotrial, we have developed a new treatment for this condition by demonstrating the effectiveness of an immunosuppressant (mitoxantrone) in treating the aggressive forms of multiple sclerosis.” This scientific collaboration continued and is shown by articles on mitoxantrone in 2010 and 2011 in which Biotrial were thanked. This scientific collaboration is also linked with financial support from Biotrial.
Of course, there is not anything wrong in itself in the fact that Professor Edan, who is deeply involved in the fight against multiple sclerosis, has contacts with possible sponsors. But the situation shows that, in relation to Biotrial, he is not a neutral and independent intermediary.
Yet it was his unit that cared for the victims of the drugs trial and it was to him that Marisol Touraine turned for help for her press conference on the tragedy in January. His explanation of events would certainly be illuminating. The question now is why, in spite of the facts, the medical and health authorities continue to give credence to the version of events provided by Biotrial.
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- The French version of this article can be found here.
English version by Michael Streeter