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Pharmaceutical Technology Europe
In France, public confidence in health authorities and pharmaceutical industry has been shaken by a safety scandal over the drug Mediator (benfluorex hydrochloride).
In France, public confidence in health authorities and pharmaceutical industry has been shaken by a safety scandal over the drug Mediator (benfluorex hydrochloride), which was marketed by Servier and acts as a hypolipidemic and hypoglycemic drug. Medicines containing this agent were first approved in Europe in the mid to late 1970s. Besides appearing on the French market as Mediator, the product was also available in Portugal, Spain and Italy, and benfluorex-containing products were also authorised, but not marketed, in Cyprus and Luxembourg.
Although Mediator was licensed in France for the treatment of diabetes, it became widely used offlabel in the country as a weight loss treatment. In November 2009, several reports appeared that linked the drug to valvular heart disease and pulmonary arterial hypertension.1 Upon review of this information, the French medicines regulator AFSSAPS (Agence française de sécurité sanitaire des produits de santé) suspended the product's marketauthorisation.
Following Mediator's market withdrawal, an initial study suggested that it was linked to 500 deaths in France between 1976 and November 2009;2 however, further research has suggested that the figure could be much higher, leading to an outcry from the French public and media. Much of the criticism has been directed at AFSSAPS, which is accused of failing to act earlier on available information and to draw conclusions from issues with structurally similar drugs.
Although there is continuing controversy regarding Mediator itself, the situation has wider implications for the field of anti-obesity drug development as a whole, which has already experienced setbacks such as the withdrawal of rimonabant. Companies developing products in this area will probably face higher regulatory hurdles and a skeptical public.
Obesity has long been recognised as a major cause of morbidity and mortality. This led to the idea that pharmacotherapy tackling obesity could be beneficial as an adjunctive support to diet, exercise and lifestyle modification. However, early agents in the field ran into safety problems, some of which were chemically related to benfluorex.
In 1997, a study was published that linked the appetite suppressants fenfluramine and dexfenfluramine to cardiac valve disease. At first, the risk was attributed to the two drugs when used in combination, but cases of valve disease were later reported in patients who had been treated exclusively with either fenfluramine or dexafenfluramine.3
In September 1997, the FDA asked manufacturers to voluntarily withdraw both treatments from the US market based on the results of echocardiograms of patients who had been on the medications.4 Findings supplied by physicians showed that approximately 30% of the evaluated patients had abnormal echocardiograms, despite having no symptoms. This rate was much higher than expected, forcing the FDA to take immediate action as well as to defend itself for not acting earlier. According to the FDA, before these physician reports there had been no information to suggest an association of heart valve disease with fenfluramine and dexfenfluramine. The FDA also pointed out that heart disease had also not been observed in a oneyear European study that had been used in the regulatory application for dexfenfluramine. Seeing the situation that the FDA was faced with, the EMA decided to take stronger measures by withdrawing the licences for fenfluramine and dexfenfluramine, as well as a number of other anti-obesity agents where clinical benefit was in doubt.3
In France, the safety issues regarding dexfenfluramine have led to a flurry of lawsuits against Servier, who had marketed the drug as Isomeride. In 2000, Anna Paulos, a patient suffering from pulmonary arterial hypertension, claimed that Isomeride was responsible for her condition and won 349000 in damages from Servier.5 The family of another patient, who died in 1995, also fought a long-running court battle with Servier, which concluded in January 2011 when a court of appeal ordered the company to pay 145500 as compensation.5 The success of these lawsuits and the media coverage they generated has led to other cases against Servier, backed by the high profile patient group L'Association des Victimes du Mediator et de l'Isoméride, which campaigns for those who took the drug.
When the recent safety issues regarding Mediator are considered in light of previous safety concerns over fenfluramine and dexfenfluramine, it is no surprise that there has been anger in France, since benfluorex is a fenfluramine derivative. In fact, recognising the link between the two drugs, the patient organisation campaigning for victims of Isomeride is now inviting those who took Mediator to come forward.
In 2003, the first case of valvular heart disease due to benfluorex was reported in a Spanish medical journal, with the authors describing how a 50year old woman who had been taking benfluorex for a year developed cardiovascular symptoms.6 They noted that the patient had been examined two years prior to treatment, at which time her cardiovascular profile had been normal. Post-treatment, microscopic examination of the valves revealed that the damage seen was identical to that described in patients who had taken fenfluramine and dexfenfluramine. The authors suggested that fenfluramine, dexfenfluramine and benfluorex shared a common mechanism in damaging heart valves.
Despite this case report, and a number of other papers strongly suggesting that patients treated with benfluorex incurred a risk of valvular heart disease, it was not until November 2009 that the French authorities took the drug off the market. Recent reports in the French press show that as long ago as 1998, three eminent French physicians wrote to the AFSSAPS advising them to reevaluate the use of Mediator in diabetes and obesity. The French newspaper, Le Figaro, has been at the forefront of covering the scandal and has obtained a copy of this letter and other enquiries sent to the agency concerning the safety of benfluorex-containing medicines.7
In 1998, at the request of the Italian health authority, a Europeanlevel investigation was initiated over the safety implications of the structural similarity between benfluorex and fenfluramine. According to Le Figaro, both Italy and France were rapporteurs for the enquiry, but while the results of the investigation prompted Italy and Spain to take Mediator off their markets, no action was taken in France. Not surprisingly, these media reports have led to accusations that the AFSSAPS and the French government are too close to the pharmaceutical industry.2
Ever since a World Health Organization report in 2000 ranked the French healthcare system as the best in the world, there has been considerable national pride over the service. The country also has one of the highest levels of pharmaceutical consumption, so the scandal surrounding Mediator and the failings of the country's regulatory system have caused great public anger that will shake confidence in the pharmaceutical industry and its products.
Servier's reputation, in particular, has been damaged. Servier has often publicised the fact that it is one of the most successful French pharmaceutical companies, but there has long been speculation in the French press regarding the extensive political connections of its founder, Jacques Servier. In 2009, he was awarded the prestigious Grandcroix de la Légion d'honneur by French president Nicolas Sarkozy, to whose party some claim he has made contributions to.8 So far, Servier has rejected the links between its drug and valvular heart disease, and is fighting legal claims from patients who used the product. There will be considerable public interest in the outcome of these cases, in addition to how the company is treated as a result of the ongoing government action over the scandal.
Recognising the level of public feeling, French Health Minister Xavier Bertrand announced in January 2011 that there would be a thorough reform of the country's pharmacovigilance system, which is due to be completed by the end of the year.9 He also stated that the decisionmaking process would be reassessed so that the burden of proof would lie with companies regarding safety issues. To date, one of the explanations from the AFSSAPS as to why Mediator was allowed to stay on the French market for so long is that the safety issues recorded through pharmacovigilance measures were not enough to prompt market withdrawal. However, there has been no explanation as to why concerns raised elsewhere in Europe did not feed through to the French system. The French Health Minister has proposed that following the withdrawal of a drug, all countries should be systematically informed.
The scandal regarding Mediator continues to grow, generating almost daily coverage in the French media, and illustrates the importance of establishing a robust and transparent pharmacovigilance system that can respond to safety findings elsewhere in the world. If regulators are implicated in safety scandals, they will be called to account, as was the case with the head of AFSSAPS, Jean Marimbert, who was forced to resign. Similarly, unless the public believe that decisions over the licensing of medicines are taken in a scientific and impartial way, the pharma industry will be subject to increasing suspicion regarding its activities. In a major market such as France, the industry can ill afford to lose public confidence.
1. EMA, "Questions and answers on the withdrawal of medicines containing benfluorex" (2010). www.ema.europa.eu
2. Inpharm, "Servier's Mediator provokes French drug safety controversy" (2010). www.inpharm.com
3. D.J. Heal, J. Gosden and S.L. Smith, Br. J Clin. Pharmacol., 68(6), 861–874 (2009).
4. FDA, "Questions and Answers about Withdrawal of Fenfluramine (Pondimin) and Dexfenfluramine (Redux)" (1997). www.fda.gov
5. Libération, "Un mal rare pour quelques kilos de trop" (2000). www.liberation.fr
6. J.R. Ribera et al., Rev. Esp. Cardiol., 56(2), 215–6 (2003).
7. Le Figaro, "Mediator: l'Assurance maladie mettait en garde dès 1998" (2011).www.lefigaro.fr
8. Le Post, "Mediator: Jacques Servier a-t-il financé Nicolas Sarkozy et l'UMP?" (2010). www.lepost.fr
9. Le Monde, "Mediator: Xavier Bertrand annonce une réforme de la pharmaco-vigilance" (2011). www.lemonde.fr