In late September 2019, the criminal trial involving Mediator° opened in France. It is due to continue for an estimated 6 months (1). In September 2019, it had been 9 years since the scale of the disaster was revealed thanks to Irène Frachon's book "Mediator°, combien de morts?", published in 2010, and 10 years since the drug was withdrawn from the market (a)(2,3).

Prescrire was already questioning the efficacy of this drug in 1986 (4). Beginning in the late 1990s, Prescrire's editorial staff has issued warnings that benfluorex is an anorectic (appetite suppressant) with increasingly foreseeable risks of pulmonary arterial hypertension and heart valve disease (b)(5-7).

Long-time subscribers will have seen the sad tale of Mediator° unfold over the years in Prescrire. As a recap and to provide some insight into the key issues of the trial, this review outlines the main articles Prescrire published about benfluorex, and Mediator° in particular, before its market withdrawal.

1986-1997: what exactly is benfluorex used for?

One of the mysteries of Mediator° is its commercial success in multiple indications, despite its insubstantial evaluation. For example, in 1986, Prescrire considered its evaluation as an "antidiabetic" unconvincing (4). In 1997, the editorial team commented that "even though it has been on the market for 20 years, it is unclear whether benfluorex benefits diabetic patients", and called for its reimbursement and marketing authorisation in diabetes and hypertriglyceridaemia to be revoked (5,6).

The drug's success (6 million boxes reimbursed in 2006) undoubtedly had more to do with advertising than with evidence-based medicine (8,9).

1990-1999: an anorectic used for weight loss

One aspect of the trial pertains to Servier's concealment of benfluorex's anorectic properties (10).

Prescrire reported that benfluorex is an anorectic back in 1990 (11). In 1997, Prescrire's editorial team expressed surprise that benfluorex was not officially classified as an anorectic in France, whereas the World Health Organization (WHO) listed it as ananorectic, and the inclusion of benfluorex, along with other anorectics, had been prohibited in extemporaneous preparations in France since 1995 (5).

Mediator° used as an appetite suppressant? A study cited in Prescrire in 1999, conducted by the former Regional Union of Health Insurance Funds (Urcam) in Bourgogne, found that 35% of prescriptions for Mediator° were off-label, and at least 15% of prescriptions were for patients also receiving treatment to help them lose weight (12).

1970-2003: foreseeable adverse effects

The association between amphetamine-like appetite suppressants and pulmonary arterial hypertension has been known since the 1970s (7). In 1997, their implication in heart valve disease led to the market withdrawal of fenfluramine (Pondéral°) and dexfenfluramine (Isoméride°), from the same pharmaceutical company as Mediator° while Prescrire called for the market withdrawal of all anorectics (7,13-15).

In 1998, Prescrire suggested that the lack of reported cases of heart valve disease in France in patients exposed to anorectics was due, at least in part, to confusion with rheumatic fever (14).

Prescrire reported in 2003 that a case of heart valve disease had been attributed to Mediator° in Spain. The same type of valve lesions were seen as with fenfluramine and dexfenfluramine, to which benfluorex is chemically related (16). Benfluorex was withdrawn from the Spanish market in 2003, at the pharmaceutical company's request (8,17).

1999-2009: the French authorities refuse to act

Those charged in the Mediator° trial include the French drug regulatory agency (called Afssaps at the time) and some of its officials (1). Prescrire's repeated calls for Mediator° to be withdrawn and its withdrawal from the Spanish market had no effect in France, where the authorities' response was to prevaricate and incessantly request new studies (18).

In 1999, a case of heart valve disease attributed to benfluorex was reported in Marseille, but due to dysfunctions within the French drug regulatory agency, the case was buried and then forgotten, against a background of pressure from the company (10). In 2005, the director of the agency wrote to Prescrire without mentioning the 1999 case and appeared to be unaware of any reports prior to 2004. He asserted that the risk of pulmonary arterial hypertension with Mediator° was very low: "about 1 case per 55 million boxes sold" (18).

In 2006, Prescrire criticised the fact that the French drug regulatory agency took a decision concerning Mediator° in the presence and with the involvement of two members of the agency who had links with Servier, including the vice-president of the pharmacovigilance committee (19). Such conflicts of interest will occupy an important place in the trial; indeed, both the concept and the reality of conflicts of interest have received a great deal of attention in the aftermath of the Mediator° disaster.

Also in 2006, the French drug regulatory agency launched a new study after learning that 17 cases of pulmonary arterial hypertension had been reported. But there were still no reports of heart valve disease. Prescrire's reaction was that "while preparations are made for the studies, benfluorex continues to be sold and patients remain exposed to an unjustified risk of adverse effects" (20).

A study published in 2006 showed that the symptoms of pulmonary arterial hypertension can develop years after taking an anorectic (21).

In 2007, after examining the data again, the French drug regulatory agency simply narrowed the indications for Mediator° (8).

2006-2019: heart valve disease demonstrated

After the "forgotten" case of heart valve disease reported in Marseille in 1999, a case observed in Toulouse in a patient exposed to Mediator° was published in 2006. The French national pharmacovigilance committee expressed reservations about Mediator°'s harm-benefit balance in 2007 (22).

More and more cases of pulmonary arterial hypertension were reported (20,22). Another case of heart valve disease was published in 2009, yet there was still no mention of the risk of pulmonary arterial hypertension or heart valve disease in the French summary of product characteristics (SPC) (23). The Besançon Pharmacovigilance Centre identified about 30 cases of heart valve disease reported in France between 1998 and 2009 (24).

Despite these reports, generic versions of Mediator° were authorised in 2008 (25).

It was not until November 2009 that the French drug regulatory agency suspended the marketing authorisations for Mediator° and its generic versions and withdrew them from the market. Their withdrawal was prompted in particular by the conclusion of a study from Brest, conducted by Irène Frachon, which showed a link between benfluorex and heart valve disease (2,10,26). In late October, a study by the national health insurance fund CNAM, designed and conducted by Alain Weill's team, had also shown a four-fold risk of valve replacement in patients exposed to Mediator° (c)(10,26).

In 2010, a study by the CNAM estimated that Mediator° had caused 500 deaths through heart valve disease in France (27). A study by two scientists from the French National Institute of Health and Medical Research (Inserm) estimated that over 1300 such deaths occurred between 1976 and 2009 (28). A total of 6743 cases of heart valve disease and 1273 cases of pulmonary arterial hypertension reported in France between 1976 and 2015 were attributed to benfluorex (29).

Denial

Knowledge of the drug class to which benfluorex belonged and analysis of the clinical results of its evaluation enabled Prescrire to urge readers to avoid this drug at a very early stage due to its foreseeable harms and lack of tangible efficacy.

For years, the French drug regulatory agency and many healthcare professionals failed to recognise the adverse effects of benfluorex for what they were, leading to underreporting and underestimation of the drug's harms. For years, benfluorex-induced heart valve disease was attributed to supposed rheumatic fever, without considering that a useless drug might be responsible.

Fortunately, while reading Prescrire, Irène Frachon made the link between Mediator° and the disorders she had observed, and then showed great tenacity in the face of the influences at work to discredit her (1,2). Thankfully, the scale of the disaster and the scandal were eventually revealed.

©Prescrire December 2019

For selected texts published in Prescrire International since 1986 :  > Key texts 

Notes :
a- Mediator, how many deaths?
b- Benfluorex also has neuropsychiatric adverse effects. This article only discusses the pulmonary arterial hypertension and heart valve disease it caused.
c- Irène Frachon is a pulmonologist at Brest Hospital; Alain Weill is a member of the studies and statistics division at the French national health insurance fund CNAM.

Selected references from Prescrire's literature search
1- "Procès Mediator°: un premier calendrier énoncé par la présidente du tribunal" Dépêche APMNews, 18 April 2019: 2 pages.
2- Prescrire Editorial Staff "Mediator° 150 mg. Sous-titre censuré" Prescrire Int 2011; 20 (112): 26.
3- Prescrire Rédaction "Benfluorex: enfin retiré du marché!" Rev Prescrire 2010; 30 (315): 13.
4- Prescrire Rédaction "Mediator°, activité ou non?" Rev Prescrire 1986; 6 (58): 42.
5- Prescrire Editorial Staff "Benfluorex antidiabetic?" Prescrire Int 1997; 6 (30): 108-109.
6- Prescrire Editorial Staff "Benfluorex: what use?" Prescrire Int 1997; 7 (34): 49-50.
7- Prescrire Editorial Staff "Severe heart valve disease on appetite suppressants" Prescrire Int 1998; 7 (33): 19-20.
8- Prescrire Rédaction "Benfluorex et retrait d'indication: une demi-mesure lamentable" Rev Prescrire 2008; 28 (291): 19.
9- Prescrire Rédaction "Publicité: trois nouvelles interdictions" Rev Prescrire 2003; 23 (237): 185.
10- Bensadon AC et al. "Enquête sur le Mediator° - Rapport définitif" IGAS 2011: 261 pages.
11- Prescrire Rédaction "Le suffixe du mois -orex" Rev Prescrire 1990; 10 (100): 402.
12- Prescrire Rédaction "Mediator° à la loupe" Rev Prescrire 1999; 19 (191): 66-67.
13- Prescrire Rédaction "Anorexigènes (suite)" Rev Prescrire 1998; 18 (182): 196.
14- Prescrire Editorial Staff "Anorectic drugs: managing the risk of valve disease and endocarditis" Prescrire Int 1998; 7 (36): 116-117.
15- Prescrire Editorial Staff "Valve disease due to appetite suppressants (cont'd)" Prescrire Int 1999; 8 (42): 115.
16- Prescrire Rédaction "Les amphétaminiques "cachés": du sevrage tabagique au diabète" Rev Prescrire 2003; 23 (243): 677-679.
17- Prescrire Rédaction "Benfluorex interdit en Espagne" Rev Prescrire 2005; 25 (264): 589.
18- Prescrire Rédaction "L'Agence française des produits de santé est-elle avant tout au service des patients ou au service des firmes pharmaceutiques?" Rev Prescrire 2005; 25 (266): 793-796.
19- Prescrire Rédaction "Conflit d'intérêts à l'Afssaps: la transparence progresse et dévoile les mauvaises habitudes" Rev Prescrire 2006; 26 (272): 382.
20- Prescrire Rédaction "Benfluorex: hypertensions artérielles pulmonaires et troubles neuropsychiatriques" Rev Prescrire 2006; 26 (273): 427.
21- Prescrire Editorial Staff "Appetite suppressants and pulmonary hypertension: a long-term risk" Prescrire Int 2006; 15 (85): 183.
22- Prescrire Editorial Staff "Benfluorex: negative data in France, but still on the market" Prescrire Int 2009; 18 (101): 124.
23- Prescrire Rédaction "Benfluorex: hypertensions artérielles pulmonaires et valvulopathies, encore" Rev Prescrire 2009; 29 (307): 349.
24- Prescrire Editorial Staff "Benfluorex: increasing reports of valve disorders" Prescrire Int 2010; 19 (105): 17.
25- Prescrire Rédaction "Benfluorex: un amphétaminique à bannir" Rev Prescrire 2009; 29 (314): 901.
26- Prescrire Editorial Staff "Benfluorex: yet more valve disorders" Prescrire Int 2010; 19 (107): 121.
27- Prescrire Editorial Staff "Benfluorex: how many deaths?" Prescrire Int 2011; 20 (113): 45.
28- Fournier A and Zureik M "Estimate of deaths due to valvular insufficiency attributable to the use of benfluorex in France" Pharmacoepidemiol Drug Saf 2012; 21 (4): 343-351.
29- Prescrire Editorial Staff "Benfluorex: adverse effects reviewed, 1976-2015" Prescrire Int 2017; 26 (179): 47.

©Prescrire December 2019

Download the text from Prescrire International

 FREE  "The Mediator° disaster: so much time wasted, so many lives destroyed" Prescrire Int 2019 ; 28 (210) : 303-305. (pdf, free)

 
For selected texts published in Prescrire International since 1986 :  > Key texts 

See also:

 Dossier Prescrire 
Autour du procès Mediator°
(complete dossier in French, with free download
of original texts from La revue Prescrire)

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