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 franšaise de sÚcuritÚ sanitaire des produits
de santÚ) 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.
Setbacks for anti-obesity 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