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Europe's approach to pharmacovigilance has room for improvement that European agencies are working on.
The public believes that governments and regulators will ensure the safety of the medicines they use. This means that efforts to improve available drug safety systems are always high on agendas — particularly as zerorisk medicines do not exist — but this often requires considerable investment in new electronic technologies. To achieve drug safety objectives, greater demands have also been placed on the pharmaceutical industry. Since 1995, for instance, EU regulations have required new drug applications to include details of a risk management system. Following the EU's large expansion in 2004, there was increased emphasis on drug safety in new legislation and a number of Directives touch upon key topics in this area.
In September 2010, the European Parliament approved a new set of pharmacovigilance, which were then adopted by member states' Ministers for Health in November.1 Not everyone, however, is satisfied by the new measures. In December, Health Action International Europe (HAI), Medicines in Europe Forum (MiEF) and the International Society of Drug Bulletins (ISDB) issued a joint press release criticising the new proposals as lacking ambition and having a number of faults.3 One major concern was that member states would no longer be required to support pharmacovigilance systems using public funding. There was also unease at the increased role the pharma industry would play in providing the data for pharmacovigilance systems.
The full extent of medicinal risk is rarely known at the outset of the application; clinical trials are limited in size and feature restrictions in the scope of patients studied, so full information relating to age, gender, ethnicity, restricted co-morbidities and interactions with other medications is impossible at this stage. As such, risk should be managed over a product's lifecycle and reflect the product's use in the wider population. The processes involved in such programmes include risk detection, risk assessment, risk minimisation and risk communication. Because multiple risks may be associated with a product, however, their combined impact in relation to the benefit conferred by the drug must be assessed. The EMA has published guidelines on risk management systems to help companies meet requirements in this area.4
EudraVigilance, a joint effort between the EMA and the competent authorities in member states, is a system that forms an integral part of the European approach to risk management. First developed in 2001, EudraVigilance consists of a data processing network and management system for reporting and evaluating suspected adverse drug reactions across the European Economic Area (EEA). By implementing an electronic approach to pharmacovigilance, the authorities hoped to facilitate early detection of possible safety signals associated with medicines. Data generated cover both the development and postauthorisation periods for products, but some critics of the system worry about an over-reliance on companies to report data that is used in the system.
The EudraVigilance Clinical Trial Module (EVCTM) focuses on the reporting of suspected unexpected serious adverse reactions (SUSARs) during clinical trials. SUSARs from clinical trials must be reported by the trial sponsor to the regulatory body in the country where the event occurred, and it is then that agency's responsibility to electronically report the event to the EudraVigilance system. Study sponsors in the EU must have a EUDRACT number, which functions as a unique identifier of the trial within the EU's clinical trial database. In this way, SUSARs from the same clinical programme being run at different European sites can be collectively assessed and processed. There is also a EudraVigilance Post-Authorisation Module (EVPM) designed for post-authorisation individual case study reports. Similarly with EVCTM, SUSARs must be reported to the national regulatory body, which then electronically reports the event to the EudraVigilance system.
Because drug safety issues have an international dimension, efforts have been made to enable the global exchange of relevant safety information. ICH, for example, brings together regulatory agencies from Europe, the US and Japan, along with their industry counterparts. ICH's technical working groups have produced several guidelines and documents on the secure electronic exchange of safety data for pharmacovigilance and the EudraVigilance system makes use of such safety information if it arises from outside Europe. SUSARs occurring in a trial outside the EEA must be reported electronically to the EudraVigilance system by the sponsor rather than the regulatory agency. A similar responsibility is assigned to companies regarding safety issues occurring outside the EEA for authorised products.
Despite the sophistication of the European pharmacovigilance systems introduced since 2005, many believe that improvements can still be made. In 2007, the European Commission (EC) conducted a public consultation exercise to identify weaknesses in existing systems.2 The feedback obtained highlighted the lack of clarity over roles and responsibilities for pharmacovigilance, as well as a perception of excessive bureaucracy within the regulatory agencies in different member states.
There were also suggestions that the complex reporting rules were implemented differently by regulatory bodies in the various member states, which was seen as holding back efforts to improve pharmacovigilance in the region, particularly with respect to rapid decision-making. Improvements to existing systems were also seen as representing only an evolutionary approach to pharmacovigilance and there was a sense that new thinking is required; indeed, the continued expansion of the EU and the sophistication of the products emerging from innovative R&D programmes seems to demand it.2
As an initial proposal, those behind the consultation exercise suggested a two-pronged approach, centred on implementing the existing framework and changing the legal framework. To improve systems, collaborations would be encouraged with the EC's Directorate General for Research, so that studies could be funded to examine the safety of medicines, as well as to develop new methodologies to conduct pharmacovigilance. Communication would also be initiated with individual regulatory agencies to resolve the administrative issues raised by those responding to the public consultation. On the legal front, there was a promise to strengthen transparency rules relating to pharmacovigilance data, and to introduce a clear drug safety standard. To achieve this, the EC decided to involve the EMA because of its experience in coordinating region-wide measures, with the hope that it would lead to the development of a responsive system that enabled rapid safety decisions to be applied equally across all member states.
Since the EMA's involvement began, the agency has been promoting the establishment of a European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). The idea behind the network is to better coordinate the monitoring of authorised medicines in Europe and to capture the information revealed by ongoing post-authorisation studies on safety and risk-benefit. To achieve these goals, the EMA will collaborate with European experts in pertinent fields. Those behind ENCePP have emphasized that the network aims to complement and not replace existing pharmacovigilance measures in Europe, such as EudraVigilance.3
An initial output of ENCePP was to establish a public, fully searchable electronic index of available EU research resources in the fields of pharmacoepidemiology and pharmacovigilance. At the end of 2010, ENCePP published its Work Plan 2011–2012, which outlined its intended strategy and listed deliverables and target dates.9 A steering group will meet quarterly to oversee delivery and coordination with the EMA.
While there is considerable activity on reforming the approach to pharmacovigilance across the EU, it is not clear how well this has been communicated to the public and physicians. A number of safety scandals over the years have attracted considerable media attention, and made people suspicious about the transparency of regulatory bodies and their interaction with the pharma industry. For example, the TeGenero TGN1412 incident in 2006 in the UK led to considerable public criticism of the MHRA, with some observers believing that existing information in the public domain concerning immunological mechanisms related to the drug's action should have led to a more cautious attitude.5 Presently, there is also controversy in France regarding Servier's Mediator and the failure of the country's regulatory agency to act on prior concerns raised over the cardiovascular safety of the product. On a wider scale, the pain reliever propoxyphene has been subjected to strong criticism regarding its safety; one European physician, who played a role in having the drug withdrawn from the EU market, described it as the "worst drug in history" and claimed that it was responsible for more deaths than any other drug.5
It is precisely because of such safety scandals that the joint December 2010 press release by the HAI, MiEF and ISDB called for a more ambitious approach by the European authorities to pharmacovigilance. If European authorities are to gain the public's confidence, as well as that of physicians, future pharmacovigilance measures should also indicate what the legal sanctions will be for those that fail to meet the necessary safety standards.
1. International Society of Drug bulletins, "Final proposals on pharmacovigilance: Some progress, but a missed opportunity to genuinely strengthen patient safety" (2010). www.isdbweb.org
2. EMA, "Guideline on Risk Management Systems for Medicinal Products for Human Use" (2005). www.ema.europa.eu
3. ENCePP, "Strengthening medicines safety monitoring" (2007). www.encepp.eu
4. C. Horvath and M. Milton, Toxicol. Pathol., 37(3) 372–383 (2009).l
5. Medscape, "Physicians Say Good Riddance to 'Worst Drug in History'" (2011). www.medscape.com