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Pharmaceutical Technology Europe
The scandal surrounding Servier's diabetes drug, Mediator, continues to unravel in France and could have implications for the whole pharmaceutical industry as the country scrutinises its regulatory systems.
However 2012 ends up, it will be a dramatic year for Servier. The French company has a number of ongoing collaborations that could lead to a new generation of products, but any positive news from these developments is likely to be overshadowed by the ongoing safety scandal of its diabetes treatment Mediator (benfluorex hydrochloride), which was withdrawn from the market in 2009. A major court case is set for mid-year and the controversy continues to implicate an ever-growing list of prominent people in France. The scandal receives regular coverage in the French media, some of which has drawn an angry response from Servier's legal team (1). It is also worrying for the pharmaceutical industry as a whole because the developments are prompting changes in the way that drugs are approved in France (2).
Servier has always prided itself as being different to other pharmaceutical companies (3). Although it is among the top 10 companies in Europe and ranks among the top 30 worldwide, it remains an independent company. In 2004, Servier's ownership structure was changed to a foundation to prevent takeovers. According to the company's founder, Jacques Servier, this is the best way to enable continuity for the company's mission.
Its publicly available information highlights the difference between itself and other companies and this has been emphasised by its founder in his rare interviews (4, 5). For example, Servier states that it reinvests a higher proportion of its turnover back into its research. Whereas the top ten pharmaceutical companies reinvest 14% of turnover, and French industry as a whole reinvests 9%, Servier reinvests 25% (3). Servier refers to this as the "invent or die" principle, citing the fact that it has synthesised 50 000 chemical entities as evidence of its innovation credentials.
Another aspect of the company's independent approach has been its internationalisation strategy. It is now present in 140 countries and 90% of its medicines are used internationally. This success stems from adopting a global strategy early on. For example, the company established itself in eastern Europe before the fall of the Berlin wall, which meant that it was well positioned in the aftermath. In 1998, a major economic crisis hit Russia and prompted a number of US companies to withdraw from the market, but Servier chose to stay and has since benefited from the market resurgence.
At present, the company is banking on a number of collaborations bearing fruit in the near future to continue its strong growth. In January 2012, Servier announced a deal with the Swedish company BioInvent International under which Servier will use BioInvent's technology to select an antibody candidate for the development of an unspecified oncology target (5). At the end of 2011, Servier also entered into an agreement with MacroGenics, a US biotech company, for the development and commercialisation of MGA271, a first-in-class monoclonal antibody candidate that is being studied in Phase I for the treatment of solid tumours. The deal is potentially worth $470 million (5, 6). Servier also has an ongoing alliance with Belgian biotech firm Galapagos to develop a novel osteoarthritis drug, which led to a milestone payment of €4 million from Servier in December 2011 (7).
Unfortunately for Servier, most mention of its name at present is connected with Mediator. The drug was originally on the market as a diabetes treatment, but became widely used off label for weight loss (8). In 2009, it was revealed that the drug might be linked to 500 deaths in France, and media and public outcry led to its removal from the market (2). Astonishingly, Jacques Servier was quoted in the French media as saying that there had been no more than three deaths due to Mediator, which prompted an angry reaction from the Health Minister Xavier Bertrand (9).
The French regulator, the Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS), was criticised for not acting on earlier information that structurally similar drugs could cause valvular heart disease and pulmonary arterial hypertension (8). Regulators in other European markets and the US had taken strong action over related agents and there is still anger as to why similar action was so slow to take place in France. The Mediator scandal has also had a dramatic effect on the regulatory mechanisms of the French healthcare system. In January 2011, the head of the French regulatory agency was forced to resign and the agency has since also been renamed the National Agency for the Safety of Medicines and Health Products (ANSM) (10).
Although acknowledging that safety regulators had missed a series of warning signs in previous years, the French government has pointed the finger at Servier. However, it has been difficult for the government to totally shift the blame after an interministerial commission revealed that voting members of the approval committee had been allowed to simultaneously serve as consultants or employees of the companies they were supposed to be regulating (11).
Such revelations have led to an overhaul of the French system, and in December 2011, a law to reform how drugs are approved and regulated was adopted by the parliament (2). Under the new system, potential new drugs must be compared with existing approved therapies rather than just with placebos, if they are to be reimbursed under the public health insurance system. Furthermore, greater transparency is being insisted on, with pharmaceutical companies being forced to declare their links with outside organisations and individuals or face criminal sanctions for failure to comply (2). The new law is still in development, but has been criticised over certain aspects, such as an additional clause that states that a drug will be reviewed every five years regardless of problems. The French pharmaceutical industry body, les enterprises du medicament (LEEM), has also expressed concerns at clauses in the new law intended to restrict visits by sales representatives and ban company-funded medical education (12).
Patient groups have launched a number of legal cases against Servier and in December 2011, the Cour de Cassation, France's highest criminal and civil court of appeal, rejected a request from Servier, for all lawsuits being brought against the company to be consolidated into a single trial (13). This is a major setback for Servier as the cases are likely to drag on for several years. One of the first cases will be a trial before the correctional court of Nanterre, where Jacques Servier himself and several executives of the company will face charges of "deception", which they were charged with in September 2011 (13). Beyond this, the company's executives face more serious charges for "involuntary homicide and injuries" (13).
Public demand for someone senior to be held accountable is high and the authorities will be keen to be seen as dispensing justice. Jacques Servier risks a maximum prison sentence of four years and the company is likely to face huge claims for damages. The worst-case scenario could see the company lose its operating license.
Servier's R&D successes this year will be pushed into the background as further details about Mediator emerge. The ongoing case also has wider ramifications because it may set a precedent for future cases involving drug safety issues. It is unusual for a company's top executives to be named and shamed, and the Servier case shows that in serious cases involving public health, senior people may find themselves on trial. Equally, regulators will be under greater scrutiny and are likely to become increasingly conservative because any oversight may come back to haunt them.
The pharmaceutical industry as a whole will also be concerned that the fallout from the Mediator case will cloud the public's views over what can be considered acceptable regarding the risk–benefit profile of products. The industry's interactions with regulators and healthcare professionals will also come under greater scrutiny. Servier has often publicly highlighted how it differs from other pharmaceutical companies in the way it operates its business, but the irony is that critics of the pharmaceutical industry will consider Servier's actions as typical of the sector. The Mediator case has already led to changes in the way that France approaches the regulation and promotion of medicines. Whatever emerges over the next year also has the potential to influence markets in other countries, which will be keen to safeguard against any flaws proven in the French system.
1. E. Lanez, "Mediator : l'effarante boîte à mensonges" (Le Point.fr, 2011) www.lepoint.fr, accessed Jan. 9, 2012.
2. B. Casassus, "With New Law, France Revamps Drug Approval" (Science, 2011). http://news.sciencemag.org, accessed Jan. 9, 2012.
3. Servier, "Research is as vital as being an industry " (Servier website, 2011). www.servier.com, accessed 9 Jan., 2012.
4. J. Upton, "Servier: patience and passion," Pharmaceutical Executive Europe (November 2008).
5. Focus Reports, "Interview—Jacques Servier" (2011). www.pharma.focusreports.net, accessed 9 Jan., 2012.
6. K. Grogan, "Servier signs cancer deal with Sweden's BioInvent" (Pharma Times, 2012). www.pharmatimes.com, accessed Jan. 9, 2012.
7. European Biotechnology Science & Industry News "Galapagos gets €4 million in alliance with Servier" (2011). www.eurobiotechnews.eu, accessed 9 Jan., 2012.
8. N. Jessop, Pharm. Technol. Eur. 23 (3), 14–18 (2011).
9. Le Point.fr, "Mediator, un jugement pour 2012?" (2011). www.lepoint.fr, accessed Jan. 9, 2012.
10. S. Sayare, "Scandal Over Mediator, a French Weight-Loss Drug, Prompts Calls for Wide Changes" (New York Times, 2011). www.nytimes.com, accessed Jan. 9, 2012
11. Assemblée Nationale (2011). www.assemblee-nationale.fr/13/rap-info/i3552.asp, accessed Jan. 11, 2012
12. InPharm, "2011 Year In Review" (2012). www.inpharm.com, accessed Jan. 9, 2012.
13. Le Nouvel Observateur, "Mediator: la cour rejette le regroupement des procédures" (2011). http://tempsreel.nouvelobs.com, accessed Jan. 11, 2012.