Tightening Up European Pharmacovigilance

The beginning of the new year has brought the beginning of a new intensity to pharmaco-vigilance in the European Union. Partly for political reasons, and partly for technical reasons, the European Agency for the Evaluation of Medicinal Products has stepped up its activities in this area. The pressure is likely to increase as time goes by.

One of the political reasons for tougher controls is a desire at the highest levels of the European Commission to avoid being caught unaware. Embarrassment came close during 2001, when the President of the European Commission himself, Romano Prodi, felt obliged to issue a statement distancing the European regulatory system from the withdrawal of a medicine after side effects came to light. The product had not been authorized through the EU system, he pointed out, trying to deflect criticism over EU laxity. The national regulatory systems in the EU member states were responsible, the Commission insisted. But it could clearly see the risks of the European Union itself being dragged into yet another safety scandal. The EU had already endured the prolonged European bovine spongiform encephalopathy (mad cow) crisis, the 2001 foot-and-mouth outbreak (which was largely contained in the UK but threatened the whole of Europe), and the continuing arguments with the EU over the safety of genetically modified organisms.

To try to limit the scope for repetitions, there have been energetic efforts to clarify pharmacovigilance responsibilities at the national and EU level. After all, the European Commission knows well enough that if it tries too often to lay off the blame on member states, it will be accused of not doing its own job of making sure the EU rules are followed. And people in the European Commission still have vivid memories of the humiliations of the late 1990s, when criticism of its ineptitude led to the mass resignation of all 20 of the Commissioners who headed it up, and of the thenCommission President, Jacques Santer.

Another of the political reasons is that the Commission is aiming to prepare the way for abolishing the regular five-year renewal of marketing authorizations in Europe. It plans to introduce reforms to many aspects of the EU drug regulatory exercise over the coming years. And one of them is to eliminate the waste of time and effort in unnecessary administration. But to be able to win the battle against conservative forces that champion renewals as safeguards of patients, the Commission will have to provide plenty of reassurance. Tougher pharmacovigilance is one of the strongest weapons in that armoryand is being deployed with great vigor.

At the technical level, too, it is evident to the Commission and the EMEA that numerous minor improvements can be made to raise the quality and efficacy of pharmacovigilance, and thus enhance patient safety. So the new year has started with a new position paper in force on compliance with EU pharmaco-vigilance rules, and an action-packed program of work for the EMEA experts in this field, the Committee for Proprietary Medicinal Products (CPMP) Pharmacovigilance Working Party (PhVWP).

The program
The pharmacovigilance working party program for 2002 has already firmly scheduled two-day meetings for most months of the year, and provides also for two additional three-day and two further one-day meetings. Some 50 cases are expected to arise from requests from the CPMP to contribute to a product assessment, and a similar number as a result of member states requests. There are expected to be 35 drafting/expert groups this year.

There is a forbidding list of CPMP guidance documents to be developed. A new guideline, aimed at competent authorities, is to be created on good pharmacovigilance practice (to be known as GVP). Other pharmacovigilance-related guidelines on the stocks, according to the draft work program, include an update of the note for guidance on the conduct of pharmacovigilance for centrally authorized productsboth to further strengthen pharmacovigilance and with a view to new therapies. An update is to be prepared for the crisis management plan regarding centrally authorized products for human use, to further improve provisions and procedures.

Further guidance is to be developed under the title principles of study system for safety monitoring, in the light of national experience. A concept paper will be developed on reporting adverse drug reactions from clinical trials to take account of the EU directive on good clinical practice. And under the new heading of Eudra-Vigilance, a paper is to be developed on predefined queries for signal generation, in collaboration with the joint subgroup of the Eudra-Vigilance telematics implementation grouplinking pharmacovigilance ever closer to electronic communications.

Other guidelines will include

• a review of the current instructions on processing renewals in the centralized procedure.
• finalization of a standard operating procedure on urgent safety restrictions for medicinal products authorized through the mutual recognition procedure.
• finalization of a list of points-to-consider on xenogeneic cell therapy, following consultation with experts in the second quarter of the year (based on the concept paper adopted by the CPMP in November 2000).
• further work on the need for postmarketing data for the use of medicinal products during pregnancy (following the note for guidance adopted by the CPMP in June 2001).
• further work on the link between data and labeling in risk assessment of human reproductive and development toxicities (again following up on a June 2001 CPMP concept paper).
• a contribution to the note for guidance on the nonclinical documentation of medicinal products with well-established use being drafted by the CPMPs safety working party.

In light of the work in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the working party will make a contribution to maintenance of pharmacovigilance-relevant ICH recommendations, and will take part in ICH meetings. In particular, the working party will contribute to new ICH activities following the ICH meeting in Brussels in February 2002. In the framework of ongoing EU regulatory activities, it will contribute to the revision by a multidisciplinary working group of the guideline on the summary of product characteristics in the European Commissions December 1999 Notice to Applicants. With non-EU authorities, each meeting of the working group will include a regular videoconference and exchanges of urgent information with the U.S. Food and Drug Administration. There will be frequent liaison with regulators from the dozen countries now bidding to join the European Union. And with industry, there will be regular interaction with marketing authorization holders on product-related safety issues in form of data requests and oral clarifications as necessary, and interaction with industry associations at European level with regard to guidelines as necessary.

Reviews will also take place of the existing Standard Operating Procedure for the Review of CPMP Scientific Advice by the CPMP Pharmacovigilance Working Party, the Principles of Urgent Exchange of Important Information between the FDA and the PhVWP. And the PhVWP Work Program will be systematically updated at six-month intervals.

The working group has acquired additional status, too, in that its chairperson, vice-chairperson, and one representative per member state are reimbursed by the EMEA, as CPMP members and additional experts participating in the plenary meetings may also be (around 30 additional expert-days are expected to be reimbursed by the EMEA). This apparently insignificant detail reinforces the independence of the EMEA operation, making it less subject to the indirect psychological control of the member states, and thus adding another small push to the EU efforts to build a genuinely European regulatory system.

Regulatory compliance obligations
The new position paper on compliance with pharmacovigilance regulatory obligations (CPMP/PhVWP/1618/01) came into effect in January 2002. In its present shape, it sets out principles that the regulatory authorities in the member states are obliged to followand to require that marketing authorization holders also follow.

The rapid and effective identification and assessment of drug safety issues is dependent on early access to complete information, it states. And, it insists that this is fundamental to being able to protect public health and to take appropriate action swiftly when problems are identified. National authorities, it goes on, have an obligation to implement medicines legislation, and noncompliance with pharmacovigilance regulatory obligations could have a potentially serious public health impact.

The EUs pharmacovigilance regulatory obligations include not only the relevant sections of EU primary legislation (in the directives and regulations on pharmaceuticals) but also the range of guidelines. But what they boil down to for companies is the need for an appropriate system of pharmacovigilance to ensure responsibility for their products on the market and to ensure that appropriate action can be taken when necessary. This includes continuous availability of at least one appropriately qualified person responsible for pharmacovigilance within the European Economic Area (that is, the EU plus Norway, Iceland, and Liechtenstein). It establishes a system for the collection, preparation, and submission of expedited adverse drug reactions (ADRs) and periodic safety update reports to competent authorities.

The competent national authorities are required to monitor companies for compliance with pharmacovigilance regulatory obligations, and are obliged to exchange information in cases of noncompliance and take appropriate regulatory action. Any failure to immediately notify competent authorities of any change in the balance of risks and benefits of products may result in enforcement action, the guideline says. It should be noted that enforcement action is within the competency of individual member states, it states, leaving the onus for action firmly at the door of national authorities.

Competent authorities have to ensure that a system of pharmacovigilance is in place in each company whose products they authorize, through scrutiny of standard operating procedures and pharmacovigilance inspections. When marketing authorization applications are being assessed, national authorities should consider requesting documentation demonstrating that a system of pharmacovigilance is in place, the note says.

The guideline suggests a mixture of carrot and stick. The aim is to induce companies to undertake effective pharmacovigilance activityand also to make sure they are penalized for failure to do so. To ensure that companies comply with pharmacovigilance regulatory obligations and to facilitate compliance, competent authorities may conduct pharmacovigilance inspections, but, the guideline says, there should be collaboration between them to minimize duplication and maximize coverage. Inspections will be random and systematic, as well as targeted to companies suspected of being noncompliant, and the results will be routinely provided to the inspected company, which will be given the opportunity to comment on the findings. The results will be used to help companies improve compliance, it saysbut they may also be used as a basis for enforcement action.

When noncompliance is detected, the necessary action will be judged on a case-by-case basis. What action is taken will depend on the potential negative public health impact of non-compliance, but any instance of non-compliance may be referred for enforcement action. Regulatory options outlined by the guideline include

• education and facilitation (companies may be informed of non-compliance and advised on how this can be remedied).
• inspection (noncompliant companies may be inspected to determine the extent of noncompliance and then reinspected to ensure that compliance is achieved).
• a formal warning from the competent authority.
• naming (making public a list of companies found to be seriously or persistently noncompliant).
• a formal caution in cases where it is admitted that a criminal offence has occurred.
• prosecution in cases of serious or persistent noncompliance (which may extend to company directors, managers, or the qualified person responsible for pharmacovigilance).The guidelineas the 2002 work program of the pharmacovigilance working group makes clearis going to be subject to continuing discussion on implementation issues. Already under way is a process of developing further guidance documents, in cooperation with an EMEA ad hoc meeting of GCP inspection services. So things are not going to get any more lax in Europe.

SIDEBAR: Regulatory Obligations for Pharmacovigilance
Each companys pharmacovigilance system should be capable of expedited reporting, periodic safety update reporting, responding to requests for information from competent authorities, handling of urgent safety restrictions and safety variations, continuous monitoring of the safety profile of authorized medicinal products and notifying competent authorities and health professionals of changes to the benefit/risk of products, meeting CPMP commitments for centralized marketing authorizations, and internal audit of the pharmacovigilance system. Pharmacovigilance data should be collated, and be accessible, at least at one point within the EEA.