Seven years ago, the former French drug regulatory agency AFSSAPS (Agence française de sécurité sanitaire des produits de santé) was in deep waters. Mediator, which had been on the market for over thirty years as a diabetes and hyperlipidemia drug and was also used as an off-label obesity treatment, was found to be associated with cardiac valve damage and pulmonary hypertension. Five million patients had been prescribed Mediator and various reports suggested that the drug had caused over 2000 deaths and thousands of hospitalizations. This late a discovery of adverse effects associated with Mediator drew criticism of France’s drug oversight. The scandal eventually led to the dissolution of AFSSAPS and the launch of ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé), with a reengineered focus on pharmacovigilance and surveillance.
Once again the French government is facing a potentially similar situation. Recent studies have demonstrated that anti-epileptic drug Depakine (valproate), when consumed by pregnant women, puts fetuses at high risk of birth defects, behavioral disorders and psychomotor impairments. In February 2016, IGAS (L’Inspection générale des affaires sociales) findings connected Depakine to major malformations in up to 10% of exposed children and autism in up to 40%. A study published by ANSM and CNAMTS (Caisse national d’assurance maladie des travailleurs salaries - National Health Insurance Fund for Employees) found that over 14,000 pregnant women in France took the drug between 2007 and 2014.
The ANSM/CNAMTS report claims that the risks associated with Depakine were known since the 1980s. The risks of developmental delays and autism in children exposed to valporate were identified in the 2000s and consequently in 2006, the drug’s use in pregnancy was explicitly discouraged. Sanofi, Depakine’s manufacturer, has stated it reported the potential side effects of Depakine on fetus’ neurological development after identifying them around 2003, with the drug information officially updated by authorities in 2006. Given the effectiveness of the drug against epilepsy and bipolar diseases, however, its use was not altogether prohibited. In 2014, an EMA advisory recommended doctors not prescribe valporate to pregnant women, women of child-bearing age and girls. An exception would be made when lacking a therapeutic alternative but only with full risk disclosure to the patient and diligent monitoring by specialists. However, victims in France claim that the risks were not communicated to them at the time of prescription and that the general practitioners who were prescribing valproate to pregnant women were not fully aware of the side effects.
In a country where Health Technology Assessments are rigorously reviewed every five years, such important information staying hidden for decades is hard to imagine. These allegations could raise questions about the credibility of both regulations and the authorities tasked with implementing them. The latest developments suggest that the Ministère des Affaires sociales et de la Santé (Ministry of Social Affairs and Health) is working on a compensation plan modelled after the plan for victims of Mediator for families adversely affected by Depakine. This compensation scheme should be voted on by Parliament by the end of 2016.
The Mediator scandal led to various reforms in the drug regulatory system in France. The post-Mediator drug regulatory regime has earned a reputation for being both strict and transparent. The ramifications for pharmaceutical companies were sizable. Periodic monitoring of drugs with marketing authorization and reporting of adverse reactions was mandated along with strengthened laws on conflict of interest disclosure and pharmacovigilance. Yet a case such as this falling through the cracks with current policies in place shows that there may still be room for improvement. For instance, while strides have been made since Mediator in improving pharmacovigilance, serious concerns remain about timeliness. Victim families are also questioning the adequacy of information flowing from the authorities to doctors and pharmacists.
In the light of recent events, the French government might be inclined towards further refining the current regulatory landscape in the country. Reforms, if any, could end up having notable implications for pharmaceutical market access as they have in the past. Ultimately, whether Depakine will trigger a reaction such as Mediator remains to be seen but is worth watching closely.