One of France’s biggest-ever pharmaceutical scandals is the subject of a trial that opened in Paris on Monday and which is expected to last until the end of April. It centres on an amphetamine-derived drug called Mediator, which was produced by Servier, France’s second-largest pharmaceutical company, as a treatment for overweight type-2 diabetes patients, but which was also widely prescribed as an appetite suppressant for people who wanted to lose weight.
Despite its severe and even fatal side effects, around five million people are believed to have been prescribed the pill in France – where its cost was granted a 65% refund by the healthcare system, a boon for its maker – between 1976 until its forced withdrawal in 2009.
Between 500 and 2,000 people, according to separate estimates, are believed to have died as a direct result of taking Mediator, which causes pulmonary hypertension and valvular heart disease. Around 500 people have had open-heart surgery for damage caused by the pill.
Servier is accused by prosecutors of “knowingly hiding” the grave dangers of the drug, and the French drug safety watchdog is accused of failing to take action to remove it from sale because of the financial links between some of its leading officials and Servier. The plaintiffs in the case number more than 2,600.
Servier and nine of its subsidiaries, along with the Agence nationale de securite du medicament (National Agency for the Safety of Medicines) and 12 individuals, are standing trial on charges ranging from “aggravated deception” and “influence peddling” to “involuntary homicides and harming”. The individual defendants include Servier managers and former directors of the drug safety watchdog, several of whom were either former Servier employees or joined the firm after leaving the agency, while others were occasionally remunerated by Servier.
Also among the accused is former senator Marie-Thérèse Hermange and a former director of France’s health and medical research institute INSERM, Claude Griscelli, who had close links with Servier. Hermange is alleged to have modified, to Servier’s advantage, a senate report on Mediator after secret lobbying by Griscelli, who is to be tried on charges of influence peddling. Hermange is charged with complicity in influence peddling.
Five people who were placed under investigation (a legal status that precedes charges) in the judicial probe into the scandal have since died, including Jacques Servier, the controversial founder of the pharmaceutical company. The billionaire passed away in April 2014 at the age of 92.
The Mediator scandal was first revealed by Irène Frachon, a pulmonologist with the CHU (teaching) hospital in the town of Brest, north-west France. She began investigating the pill in 2007 after finding that it had been taken by a number of her patients suffering from heart and pulmonary disease. During her research she discovered that benfluorex, the chemical marketed under the name Mediator, was closely related to the chemical composition of another appetite suppressant sold by Servier under the name of Isoméride, which was banned in France in 1997 because of its side effects of pulmonary arterial hypertension and valvular heart disease.
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After she began an epidemiological study, Frachon, whose dogged investigations met obstacles and intimidation from the medical establishment, collected concrete evidence of the same side effects on people who had taken Mediator, and her findings led to the drug's withdrawal from sale in November 2009. In 2010, Frachon published a book, Mediator 150 mg, combien de morts ? (“Mediator 150mg, How many deaths?”) in which she recounted her investigations and the scandalous opposition to her campaign by health safety authorities. In 2016, a feature film was released about her long struggle, called La Fille de Brest (English title 150 milligrams).
As she explains in this interview with Mediapart, Frachon, 56, who still works at the hospital in Brest, has since been ostracised by a number of her colleagues for disturbing the cosy relationship between healthcare professionals and pharmaceutical firms. For the past year she has taken no holiday leave in order to be able to attend the lengthy trial in Paris.
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Mediapart: Why has it taken ten years since the withdrawal from sale of Mediator for this trial to begin?
Irène Frachon: I was always convinced that there would be a criminal trial. In 2008, Servier sent me a document to explain that Mediator and Isoméride, the other amphetamine-based drug that they manufactured, banned in France in 1997 like other appetite suppressants because of their dangers, had no part in things.
I thought I’d taken the wrong direction – it was impossible that this was a lie, that Servier had kept another Isoméride on the market. So I thought that Mediator was vaguely a derivative, whereas it had the same toxicity linked to a molecule in common with the formidably dangerous Isoméride. When I discovered that, thanks notably to the archives of the [monthly French medical] review Prescrire, I knew that those documents would one day end up on the desk of an investigating magistrate.
What is dramatic is that victims, like Annie Oger, one of the first to be identified, died before obtaining the satisfaction of a criminal court ruling. On the other hand, the slowness in the organisation of a trial, which is a consequence of the multiple delaying tactics of Servier, had at least one merit – major scientific publications, published up until 2018, consolidated the case.
We have now arrived with a complete body of medical knowledge and a more precise idea of the number of victims and the type of harm suffered. In all, they are nearly 3,700 to have been recognised [as victims] by [the French national office for the compensation of medical accidents] ONIAM, of who more than 500 had to have open heart surgery. The list is incredible. The Mediator affair was a huge jigsaw puzzle. For a long time Servier scattered the pieces. Now they are gathered together.
Mediapart: In which way did the Servier group’s influence prevent the French National Agency for the Safety of Medicines, the ANSM, from ensuring health security in the name of the state?
I.F.: Double agents, sort of, with one foot in the Agency and the other at Servier, like Jean-Roger Claude, were present on the key commission of the AFSAPPS [renamed the ANSM in 2012], more specifically the all-powerful commission [the AMM] for the authorisation of marketing [a drug or medicine], and who could monitor things for Servier, even put pressure on experts who were critical of Servier products.
This AMM commission decided everything and exercised an unrivalled power to the point of ensuring that the pharmacovigilance commission’s observations were put into effect. Members of the pharmacovigilance at the Agency told me how they could be tackled, humiliated even, when they raised alerts, which were necessarily complex, fragile and inconvenient.
Jean-Roger Claude even tried to intimidate [the Brest regional pharmacovigilance centre director] Christian Riché, telling him, “You got your hands dirty with [Irène Frachon] and you’ll pay for it in your professional and private life”. In the end, Servier was a sort of unofficial national institution, more powerful than the medicines agency that was supposed to control it.
Mediapart: Servier stands trial for involuntary homicides and injuries, and also deception. A total of some 4,000 people, associations and insurance bodies argue they have been misled. Will the trial be that of the patient victims?
I.F.: We don’t know exactly how many will effectively be present. Some have abandoned the criminal procedure, because most patients have come to an agreement with Servier. When they received decent compensation propositions from the company we advised them to take the money. That doesn’t remove the legal case against Servier and that money was often more than necessary, vital.
I know of victims who spent years before receiving compensation, and who died a few months later. It was too late. For the past year, everything has been settled fast. Servier’s aim is to arrive at the trial as clean as possible, to pretend that its unique preoccupation has been to compensate the victims, whereas for years it attempted to pay out as late and as little as possible. That reflects a lot of cynicism.
Mediapart: Patients came up against other obstacles during their long path for compensation, or to become civil parties to the case. How is it that doctors balked at providing the proof of prescriptions for Mediator?
I.F.: Doctors have a tendency to worry about the medico-legal consequences of their actions, which is admissible. Here, they ran the risk of being placed in question as prescribers of Mediator, out of bounds of the AMM [advice]. They prescribed it as an appetite suppressant whereas it was presented by Servier as an antidiabetic agent.
I understand this worry, but some victims wrote to me to recount shocking situations of refusal from their family doctor, who told them straight in the eyes, “I never prescribed Mediator for you” – after years of prescriptions! [Former health minister] Xavier Bertrand and I insisted upon the importance of not pointing the barrel at doctors, who were misled by Servier about the innocuity of the product. That would have blocked the system of compensations for the victims. The [office for compensation of medical accidents] ONIAM finally accepted that it was possible not to implicate the doctors. That facilitated the drawing up of certificates testifying to prescriptions which were indispensable when [original] prescriptions were lost or thrown away.
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Mediapart: Did Servier sell other dangerous drugs or medicines?
I.F.: In my eyes, Servier is a company that is culturally “pharmaco delinquent”, for there are other ‘Mediators’ in its historic product range. For example, a molecule called Almitrine and marketed by Servier under two names, Duxil and Vectarion, were supposed to improve oxygenation of the blood. In reality, it was ineffective, highly toxic for the nerves of lower limbs and also caused weight loss.
It took more than 30 years before this molecule was definitively withdrawn from all markets, in 2013, when there were more than 2,000 declared cases of neuropathy. It was the same with Protelos [marketed for osteoporosis], Pneumorel – a syrop [for treating coughs] that was dangerous for the heart – and, above all, the anti-depressant Survector, a product responsible for psychological dependency, and voluntarily misused by heroin addicts.
They were withdrawn from sale because of their toxicity. With Mediator, a disguised amphetamine derivative, and Survector, a psychotropic substance with addictive potential, we are really on the borderlines of drugs that are normally those of narcotics dealers. I have received numerous accounts of the shocking means of pressure systematically put in place by Servier in an attempt to deny or minimise the dangers of these products.
Less serious for public health, but disastrous from an economic angle, were the lengthy periods of sales of useless products refunded by the social security system, like Daflon for heavy legs or Locabiotal, a throat spray. The list is long, and it raises questions about the protection that the company may have profited from, thus literally siphoning the healthcare system without any demonstrable benefit for health.
Perhaps the very particular character of Jacques Servier, made up of a megalomania tinted by paranoia, explains this in part. In the examining magistrates’ report of their decision to send the case for trial, some [quotes from statements given by] staff mention the term “sect”. As for Jacques Servier, a veritable guru, he talked about the “house”.
Mediapart: In the film La Fille de Brest [English title "150 milligrams", which tells the story of Irène Frachon’s campaign] your character explains “I’m not an alter-globalisation activist, I collaborate with the pharmaceutical industry and I believe in scientific research”. Do you today support cooperation between doctors and the pharma industry?
I.F.: I believe what is said in the film. The collaboration between doctors and pharmaceutical firms, notably to include French patients in clinical trials which allow for the validation of innovating treatments, is necessary. In these cases, laboratories fund centres of clinical investigation in hospitals, establishing agreements. Before the case of Mediator, I fixed rules for myself. I accepted invitations to symposiums financed by the pharmaceutical industry, which I believed were primordial. On the other hand I refused to be paid directly by the laboratories. For me, that’s the minimum.
The problem is that lots accept, notably consultant doctors who give advice to firms on promotion and marketing and who receive remunerations for that. Many of them retort that they would have difficulty in paying for the higher education studies of their children without this “supplement”, sometimes very significant, to their salaries.
Mediapart: How have you managed your own links with the pharmaceutical laboratories since the Mediator affair?
I.F.: Shortly after the affair broke, I cut off all links with the industry. I had to, I needed to be coherent with what I denounced, these terrible conflicts [of interest] which served as the basis of the Mediator drama. But that had the effect of totally marginalising myself, because my network of healthcare professionals involved pharmaceutical industry financing.
I can no longer coordinate the Brest centre for pulmonary arterial hypertension [PAH], for example. I was excommunicated by some colleagues for having denounced the dangers of conflicts of interest. I’m 56-years-old, [so] I don’t care, I don’t need these links.
I work three days per week at the Brest hospital, and two days per week at that in Carhaix [the commune of Carhaix-Plouguer, north-west Brittany], right in a medical desert. But I understand that for young doctors it is difficult to deprive oneself of any links with the pharmaceutical industry, above all in France's teaching hospitals.
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- The original French text of this interview can be found here.
English version by Graham Tearse
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