Improved EU Pharmacovigilance May Not Prevent Another Mediator

The affair surrounding Servier's withdrawn Mediator drug highlights serious loopholes in the new EU pharmacovigilance system.

While France reverberates from the scandal surrounding Servier's diabetes drug, Mediator (benfluorex), it is becoming clear that safeguards put in place by the European Union to minimize the risk of similar threats to patient health may not be as effective as originally intended.

Although the EU's new pharmacovigilance legislation, published in final form on Dec. 31, 2010, and the accompanying Eudravigilance database for reporting adverse incidents, represent a step in the right direction, the Mediator case has highlighted a number of loopholes and deficiencies.

Mediator was withdrawn from the French market in 2009 following reports of links to 500 deaths. The case, billed as France's biggest health scandal in several decades, led earlier this month to the resignation of the national regulator chief (Also see "France's Agency Chief Quits Over Servier Drug Safety Furor" - Pink Sheet, 13 Jan, 2011.).

Central to the EU's increased pharmacovigilance drive is the establishment of a risk-watchdog called Pharmacovigilance Risk Assessment Committee (PRAC). This body, created as part of the London-based European Medicines Agency (EMA), is tasked with ensuring that any drug-related risk identified in one European member state leads to appropriate action in all of the others.

Mediator was withdrawn in Spain in 2003 and Italy in 2004, albeit not, ostensibly, for safety reasons.

Coordinated Drug Withdrawal Process Across EU

The new rules emphasize that a single decision regarding a drug's risk be implemented across all member states. It will no longer be possible to withdraw a product for safety reasons in one European country, while maintaining it on the market in others.

Under the previous system, the EMA's Committee for Human Medicinal Products (CHMP) made a recommendation, which member states could choose to implement - or not.

The PRAC will liaise with the CHMP in the case of centrally-authorized products, and with the Coordination Committee of the Heads of Medicines Agencies (CMD(h)) in the case of nationally-authorized products, or those that have been the subject of Mutual Recognition or Decentralized Procedures (MRP and DCP). If the Member States represented in the CMD(h) cannot reach agreement in implementing the PRAC recommendation, they will put the matter to a vote and the result will then be put before the European Commission, which will then decide on a course of action.

How Serious is Serious? The Loopholes

However, the pharmacovigilance legislation will not be effective in two specific instances - a fact that has taken on increased salience since the Mediator affair broke. Firstly, in order for pan-EU action to be taken, the incident that a member state reports to PRAC must be classified as "serious.".But the definition of "serious" may vary by country. Some may prefer to deal with drug-risk issues internally rather than pushing them onto the European stage - as it's possible to imagine France would have preferred to do in respect of Mediator, manufactured by a French, family-owned firm whose chief was decorated by the president in 2009 ('Servier Chief Steps Down from G5 Presidency,' The In Vivo Blog, Jan. 25, 2011).

There is no sanction envisaged in the legislation for countries that do not share information that others may classify as serious.

The second problem is that the legislation contains no punitive element to prevent a marketing authorization holder from either hiding or manipulating information relating to a drug's risk profile. So in any eventual case similar to Mediator, in which Servier has been accused of suspect marketing tactics, the legislation appears ineffective.

Furthermore, if a company voluntarily withdraws a drug from the market for non-safety-related issues (any safety-related issues must be flagged to regulators), as Servier did with Mediator in Spain in 2003 and Italy in 2004, the legislation contains no mechanism to communicate this to other EU countries. Thus, a company could withdraw a product about which it has some concerns in one country, announce that it is doing so for marketing reasons, and the potentially dangerous drug will still be provided to patients in other EU nations.

The Eudravigilance Database: Unreliable

The Eudravigilance database designed to underpin the new legislation isn't without its problems either.

The idea is that each EU member state reports drug-related adverse incidents in the database, which would then be accessible to all relevant authorities in other member states. However, because Europe's members don't have to implement the provisions within the legislation until mid-2012, the database is very likely to remain unreliable until then.

And even then, say sources close to the project, technological hiccups - programming challenges, including related linguistic barriers -- are likely to mean that the database will not be fully functional for months, or even years after this deadline has passed.

On the positive side, the new pharmacovigilance legislation obliges competent authorities and marketing authorization holders to accept and take note of direct reports from patients, a process that is already fully- functional in the UK. If numerous patients report similar issues to a particular national authority, this could force escalation to the PRAC and thus prevent further problems arising across the region.

In the end, though, the legislation will only be effective if punishing sanctions can be imposed on those that trangress (sanctions beyond the aggressive media onslaught facing Servier). Without such sanctions in place (for example, financial penalties), the risk is that companies consider, should they wish, exploiting the system's weaknesses.

-Faraz Kermani ([email protected])