- Email: [email protected]
Mediator: who's to blame?
Correspondence
PW was employed by the UK medicines regulatory authority from 1990 to 2002 and was a member of the Committee for Proprietary Medicinal Products (1998–2000) and chair of its Pharmacovigilance Working Party (1998–2001). He currently holds a contract with the Medicines and Healthcare products Regulatory Agency to provide pharmacovigilance services. SE has been a co-opted independent member of the Pharmacovigilance Working Party at the European Medicines Agency since 2006. He was employed at the UK Medicines Control Agency between 1995 and 1999 and between 2000 and 2002.
Del Prato et al (n=438)3 Moulin et al (n=325)4 Comparator Treatment duration (months) Mean (SE) body-mass index (kg/m²)
29·5 (0·2)
12 29·5 (0·1)
Versus placebo or comparator
–0·86 (0·17) (p<0·0001)
–1·01 (0·13) (p<0·0001)
Change from baseline to last value
–0·60 (0·08)
–0·82 (0·09)
–0·54 (0·06)
0·33 (0·08) (p=0·19)*
Versus placebo or comparator
–3·48 (1·47) (p=0·018)
–0·64 (0·25) (p=0·010)
–4·9 (0·27)† (p<0·0001)
Change from baseline to last value in benfluorex group
–1·9 (0·2)
–1·3 (0·2)
–1·60 (0·2)
*p for non-inferiority. †–1·6 (0·2) for benfluorex vs 3·3 (0·2) for pioglitazone.
London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
Table: Effects of benfluorex on HbA1c and bodyweight in double-blind controlled trials in patients with type 2 diabetes
Mullard A. Mediator scandal rocks French medical community. Lancet 2011; 377: 890–02.
www.thelancet.com Vol 377 June 11, 2011
4·5
29·9 (0·3)
Bodyweight (kg)
[email protected]
The World Report “Mediator scandal rocks French medical community”1 severely criticises Servier and its antidiabetic drug Mediator (benfluorex). We would like to address three inaccurate and misleading statements that the article reproduces. First, the “estimation” that 500–2000 deaths can be attributed to benfluorex owing to valvulopathy is pure extrapolation using unjustified, hard-line hypotheses and unproven facts. Moreover, it was derived from questionable retrospective analyses in databases that were never intended for that use—weaknesses that the authors of these analyses highlight.2 These figures seem to be disconnected from all available trial data and formal pharmacovigilance surveys. Second, the World Report amalgamates benfluorex and amphetamines. In benfluorex, the α-methylphenylethylamine core is sufficiently modified to alter its biopharmaceutical, pharmacological, and medical properties. Thus neither the pharmacological profile nor the ten most frequently reported adverse events of benfluorex can be classified as “amphetamine-like”. Third, the World Report reiterates the accusation that Servier marketed benfluorex at odds with its medical properties, implying scientific dishonesty. We all know that drug development involves evolving knowledge and shifts in the initial
Placebo on top of sulfonylurea Pioglitazone on top of sulfonylurea
6
Mean (SE) change in HbA1c (%) adjusted for baseline
*Patrick Waller, Stephen Evans
1
Placebo monotherapy
Moulin et al (n=847)5
vision of therapeutic potential. Servier has always interacted rigorously, openly, and appropriately with regulatory authorities so that the marketing authorisation of benfluorex remained in line with the scientific data gathered. Its efficacy has been assessed in more than 70 clinical studies, including three recent trials3–5 in patients with type 2 diabetes (table). Treatment with benfluorex3,4 was associated with 0·9–1·0% reductions in HbA1c versus placebo, comparable to those seen with currently approved antidiabetic regimens. The last clinical trial,5 which included echocardiography before and after 1 year’s treatment, showed emergent grade 1 valvular regurgitations in a subgroup of patients—an observation that contributed to the decision to withdraw benfluorex from the market. LV, BG, YT, and EC are employees of Servier.
Lucy Vincent, *Béatrice Guardiola, Yannis Tsouderos, Emmanuel Canet [email protected] Institut de Recherches Internationales Servier (IRIS), 6 Place de Pleiades, 92415 Courbevoie, France 1
2
3
Mullard A. Mediator scandal rocks French medical community. Lancet 2011; 377: 890–02. Geoffroy-Perez B, Imbernon E, Gilg Soit Ilg A, Goldberg M. Comparison of the French DRG based information system (PMSI) with the National Mesothelioma Surveillance Program database. Rev Epidemiol Sante Publique 2006; 54: 475–83. Del Prato S, Erkelens DW, Leutenegger M. Six-month efficacy of benfluorex vs. placebo or metformin in diet-failed type 2 diabetic patients. Acta Diabetol 2003; 40: 20–27.
4
5
Moulin P, André M, Alawi H, et al. Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients. Diabetes Care 2006; 29: 515–20. Moulin P, de Champvallins M, Bruckert E, et al. P161 comparaison à 1 an de benfluorex et pioglitazone dans le diabète de type 2: étude regulate. Diabetes Metab 2010; 36: A76–77.
Asher Mullard1 focuses his analysis of the French “Mediator scandal” on the drug company Servier and AFSSAPS, the French Medicines Agency, and might have missed several points. The report of the Inspection Générale des Affaires Sociales (IGAS), requested by the Health Minister, is not exactly an “independent account”. The co-Director General of AFSSAPS is an IGAS member. In 2006, she was the technical adviser for medicinal products in the cabinet of the Health Minister who renewed the reimbursement of Mediator (benfluorex) through the mandatory national health insurance scheme. This minister, who is now again in charge, promoted her to interim Director General of AFSSAPS. Additionally, none of the IGAS inspectors is known for expertise on drugs. Mullard could also have mentioned that AFSSAPS long ignored the yearly calls from the independent drug bulletin La Revue Prescrire for benfluorex’s withdrawal.2 AFSSAPS also allowed the marketing of two generics of Mediator in 2009, yet, by contrast, issued a national warning to pharmacists and doctors after a mix-up in the labelling of two homoeopathic remedies.3 2003
PW was employed by the UK medicines regulatory authority from 1990 to 2002 and was a member of the Committee for Proprietary Medicinal Products (1998–2000) and chair of its Pharmacovigilance Working Party (1998–2001). He currently holds a contract with the Medicines and Healthcare products Regulatory Agency to provide pharmacovigilance services. SE has been a co-opted independent member of the Pharmacovigilance Working Party at the European Medicines Agency since 2006. He was employed at the UK Medicines Control Agency between 1995 and 1999 and between 2000 and 2002.
Del Prato et al (n=438)3 Moulin et al (n=325)4 Comparator Treatment duration (months) Mean (SE) body-mass index (kg/m²)
29·5 (0·2)
12 29·5 (0·1)
Versus placebo or comparator
–0·86 (0·17) (p<0·0001)
–1·01 (0·13) (p<0·0001)
Change from baseline to last value
–0·60 (0·08)
–0·82 (0·09)
–0·54 (0·06)
0·33 (0·08) (p=0·19)*
Versus placebo or comparator
–3·48 (1·47) (p=0·018)
–0·64 (0·25) (p=0·010)
–4·9 (0·27)† (p<0·0001)
Change from baseline to last value in benfluorex group
–1·9 (0·2)
–1·3 (0·2)
–1·60 (0·2)
*p for non-inferiority. †–1·6 (0·2) for benfluorex vs 3·3 (0·2) for pioglitazone.
London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
Table: Effects of benfluorex on HbA1c and bodyweight in double-blind controlled trials in patients with type 2 diabetes
Mullard A. Mediator scandal rocks French medical community. Lancet 2011; 377: 890–02.
www.thelancet.com Vol 377 June 11, 2011
4·5
29·9 (0·3)
Bodyweight (kg)
[email protected]
The World Report “Mediator scandal rocks French medical community”1 severely criticises Servier and its antidiabetic drug Mediator (benfluorex). We would like to address three inaccurate and misleading statements that the article reproduces. First, the “estimation” that 500–2000 deaths can be attributed to benfluorex owing to valvulopathy is pure extrapolation using unjustified, hard-line hypotheses and unproven facts. Moreover, it was derived from questionable retrospective analyses in databases that were never intended for that use—weaknesses that the authors of these analyses highlight.2 These figures seem to be disconnected from all available trial data and formal pharmacovigilance surveys. Second, the World Report amalgamates benfluorex and amphetamines. In benfluorex, the α-methylphenylethylamine core is sufficiently modified to alter its biopharmaceutical, pharmacological, and medical properties. Thus neither the pharmacological profile nor the ten most frequently reported adverse events of benfluorex can be classified as “amphetamine-like”. Third, the World Report reiterates the accusation that Servier marketed benfluorex at odds with its medical properties, implying scientific dishonesty. We all know that drug development involves evolving knowledge and shifts in the initial
Placebo on top of sulfonylurea Pioglitazone on top of sulfonylurea
6
Mean (SE) change in HbA1c (%) adjusted for baseline
*Patrick Waller, Stephen Evans
1
Placebo monotherapy
Moulin et al (n=847)5
vision of therapeutic potential. Servier has always interacted rigorously, openly, and appropriately with regulatory authorities so that the marketing authorisation of benfluorex remained in line with the scientific data gathered. Its efficacy has been assessed in more than 70 clinical studies, including three recent trials3–5 in patients with type 2 diabetes (table). Treatment with benfluorex3,4 was associated with 0·9–1·0% reductions in HbA1c versus placebo, comparable to those seen with currently approved antidiabetic regimens. The last clinical trial,5 which included echocardiography before and after 1 year’s treatment, showed emergent grade 1 valvular regurgitations in a subgroup of patients—an observation that contributed to the decision to withdraw benfluorex from the market. LV, BG, YT, and EC are employees of Servier.
Lucy Vincent, *Béatrice Guardiola, Yannis Tsouderos, Emmanuel Canet [email protected] Institut de Recherches Internationales Servier (IRIS), 6 Place de Pleiades, 92415 Courbevoie, France 1
2
3
Mullard A. Mediator scandal rocks French medical community. Lancet 2011; 377: 890–02. Geoffroy-Perez B, Imbernon E, Gilg Soit Ilg A, Goldberg M. Comparison of the French DRG based information system (PMSI) with the National Mesothelioma Surveillance Program database. Rev Epidemiol Sante Publique 2006; 54: 475–83. Del Prato S, Erkelens DW, Leutenegger M. Six-month efficacy of benfluorex vs. placebo or metformin in diet-failed type 2 diabetic patients. Acta Diabetol 2003; 40: 20–27.
4
5
Moulin P, André M, Alawi H, et al. Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients. Diabetes Care 2006; 29: 515–20. Moulin P, de Champvallins M, Bruckert E, et al. P161 comparaison à 1 an de benfluorex et pioglitazone dans le diabète de type 2: étude regulate. Diabetes Metab 2010; 36: A76–77.
Asher Mullard1 focuses his analysis of the French “Mediator scandal” on the drug company Servier and AFSSAPS, the French Medicines Agency, and might have missed several points. The report of the Inspection Générale des Affaires Sociales (IGAS), requested by the Health Minister, is not exactly an “independent account”. The co-Director General of AFSSAPS is an IGAS member. In 2006, she was the technical adviser for medicinal products in the cabinet of the Health Minister who renewed the reimbursement of Mediator (benfluorex) through the mandatory national health insurance scheme. This minister, who is now again in charge, promoted her to interim Director General of AFSSAPS. Additionally, none of the IGAS inspectors is known for expertise on drugs. Mullard could also have mentioned that AFSSAPS long ignored the yearly calls from the independent drug bulletin La Revue Prescrire for benfluorex’s withdrawal.2 AFSSAPS also allowed the marketing of two generics of Mediator in 2009, yet, by contrast, issued a national warning to pharmacists and doctors after a mix-up in the labelling of two homoeopathic remedies.3 2003