As part of its legislative package for pharma, the EU Commission is proposing changes to the pharmacovigilance system. Hilary Ayshford summarises the views put forward at the recent TOPRA conference
A study carried out in 2005 identified shortcomings in the EU's pharmacovigilance system, relating particularly to overlapping reporting requirements, which result in duplication of work on the part of the Market Authorisation Holder (MAH) and the competent authorities. The aim of the Commission's legal proposal is therefore to clarify the roles and responsibilities of the various parties involved in pharmacovigilance activities, said Lenita Lindstroem-Rossi of the Pharmaceuticals Unit of DG Enterprise and Industry, European Commission.
Amendments will be required to Directive 2001/83/EC (nationally authorised products and common provisions) and Regulation (EC) No 726/2004 (specific provisions on centrally authorised products and tasks of the European Medicines Agency).
There are four main objectives:
1. To establish clear tasks and responsibilities for all parties
2. To improve decision-making procedures and efficient use of resources
3. To lay down proactive and proportionate risk management avoiding unnecessary administrative burden and providing for stronger links between safety assessments and regulatory action
4. To strengthen transparency, patient involve-ment and oversight of non-interventional studies
The role of the European Medicines Agency (EMEA) as a co-ordinator in the Community pharmacovigilance system would be strengthened. EMEA would also have a key role in detecting signals on safety issues and following up on them.
A new scientific committee would be set up at the EMEA. The Pharmacovigilance Risk Assessment Advisory Committee (PhV committee) would be responsible for providing scientific advice on pharmacovigilance. Its structure would reflect the complexity of the pharmacovigilance area and the need to appoint the best possible experts.
It would consist of 10 members and 10 alternates appointed by the Management Board of EMEA based on proposals by the national competent authorities. In addition five members and five alternates would be appointed by the Commission, on the basis of a public call for expression of interest. But all Member States would be able to attend all the meetings of the PhV committee, Lindstroem-Rossi stressed.
The new committee would give scientific advice to the Committee for Medicinal Products for Human Use (CHMP) or to the Co-ordination Group for Mutual Recognition and Decentralised Procedures Human (Co-ordination group), depending on whether or not the medicinal product was approved using the centralised procedure.
Member States will play a key role in conducting pharmacovigilance for products placed on their markets, as well as in signal detection and follow-up with the MAH, healthcare professionals and patients for example, in forwarding adverse reaction reports to the Eudravigilance database. Member States will also be responsible for ensuring that penalties are sufficient to deter non-compliance.
The current system requires the MAH to submit a detailed description of its pharmacovigilance system and to apply for a variation to the MA every time even a relatively small change is made to the PhV system. This is a burden on both the MAH and the authorities, said Lindstroem-Rossi.
The Commission is therefore proposing that the MAH would submit only a summary of the PhV system, with a detailed description contained in the PhV system master file. This master file would be kept available on a specific site, would be kept up to date continuously and could be requested at any time by the authorities.
A detailed risk management system should also be part of the MA. This would be legally binding and would contain a detailed description of identifying the possible risks of the product and the measures the MAH envisages taking should those risks emerge. The risk management system would be proportionate: the higher the risk the product has, the greater the requirements for a more detailed risk management system. The MAH would need to monitor all the safety information continuously, including clinical trials or use of the product outside the SPC, and update the MA accordingly.
Proposed changes to decision-making procedures aim to clarify what triggers the procedures and the roles and responsibilities of the various parties. Where medicinal products are authorised in several Member States, there are a number of different reporting systems and these are not implemented in a co-ordinated manner, putting a huge burden on the authorities that need to assess the information.
The Commission is proposing an EU reference date for harmonised frequency of reporting, which would provide for a single assessment for products authorised in more than one Member State, and for products containing the same active substance.
But it is one thing to identify the safety issues and another to lay down how those alerts lead to concrete action, said Lindstroem-Rossi. The Commission is proposing that the decision-making procedures would be triggered by:
Periodic safety update reports (PSURs)
Risk minimisation measures
Updates to risk management system
Monitoring data in the centralised Eudravigilance database
Oversight of post-authorisation safety studies (PASS)
Community (urgency) procedure
Member States would initiate the Community (urgency) procedure in specific circumstances, e.g. when they are considering prohibiting the supply of a medicinal product or suspending or revoking an MA.
The legal proposal provides for proactive monitoring and signal detection. There is also now a clear legal base for an MA to be issued subject to conditions - for example, on condition of conducting a PASS. These products will be put on a list of intensively monitored products. This list will be updated continuously by EMEA.
All adverse drug reaction reports would go directly to the Eudravigilance database, irrespective of which procedure they fall under. This database is kept by EMEA and all Member States will have access to the information at the same time. Furthermore, the definition of adverse drug reactions would be widened: rather than being limited to side-effects in normal conditions of use, it would also include medication errors and overdose.
The Commission's proposals also provide a clear legal basis for patient reporting in all Member States: patients would be able to submit reports that will go to the national competent authority to be forwarded to the Eudravigilance database.
Finally, the Commission is proposing that the Eudravigilance database should become a single point of reference for the receiving and sharing of reports. It is also suggesting a network of European and national safety web portals. "This is very important as we are proposing to move more towards work-sharing arrangements," said Lindstroem-Rossi. "There must be adequate communication channels in place so that the competent authorities have access to the same information in order to take adequate action." Periodic safety update reports (PSURs)
A national view
Although the preparatory work done by the Commission prior to the launch of these proposals is highly appreciated, the impact assessment is not exhaustive, delegates to the TOPRA conference were told. Doris Stenver, chief medical officer, consumer safety division, pharmacovigilance working party delegate at the Danish Medicines Agency, expressed serious reservations about several aspects of the proposals and in particular about the PhV committee.
Although she was pleased to hear that the committee would be made up of experts from the Member States, "where are we going to find these experts?" she asked.
"Denmark is one of the examples of EU differentiation. The Commission's proposals are not going to work in Denmark," she stated. "We fear that the PhV committee will create a credibility gap and a responsibility gap and will thereby create problems for the national agencies, and furthermore that it will compromise knowledge-sharing and development of competencies at national level."
On a more positive note, Stenver welcomed other elements of the proposals - in particular the pharmacovigilance master file that makes more effective use of resources both on the regulatory and on the industry side. She also supported the strengthening of the risk management procedures, the clarification of the rules for PASS, the strengthening and change of way of use of the PSUR and the simplification of the reporting of adverse drug reactions.
Stenver is also in favour of the adoption of patient reporting of ADRs as standard across the EU. This was introduced in Denmark in 2003, and in 2007 almost 20% of the total number of adverse drug reports came from patients and their relatives.
"We agree that there is a need for a new strategic and legislative approach and we see several elements in the proposal that will have a positive impact overall on patient safety," she concluded. "But it is important that the system is improved so that Member States still have the opportunity to retain credibility and responsibility in relation to their citizens."
An industry view
The pharmaceutical industry welcomed the proposals but found positive and negative elements. Val Simmons, QPPV Executive, Global Patient Safety, Eli Lilly, agreed with Stenver that the concept of a PhV master file is particularly good. Single point reporting to Eudravigilance is also a very positive move and something we have fought long and hard to get into the legislation, she told delegates.
However, her principal concern is that although it states in the Regulation that "Member States should not impose on marketing authorisation holders any additional reporting requirements," there is no corresponding statement in the Directive. "We would like to see what is currently in the Regulation reflected in the Directive to the effect that the Eudravigilance database should function as the single point of receipt for the information and that there should be no additional reporting requirements," she stressed.
"No one is saying we should do away with national databases, but at least it will be possible to centralise reports within Eudravigilance and that will still allow for national evaluation. But most importantly it does facilitate a single, robust database on which to base signal detection and evaluation."
With regard to improving transparency, Simmons suggested that as PSURs, PASS and RMPs are long and complex documents written for the benefit of the competent authorities rather than the general public, the publication of these on the safety web portals to be set up by EMEA and the Member States should be confined to summaries rather than the full documents. This would also preserve the confidentiality of proprietary information.
Simmons also expressed concerns over the new definition of a "Suspected ADR". Rather than defining it as "an adverse reaction in respect of which a causal relationship between the event and the medicinal product cannot be excluded", it would be better described as "an adverse event in respect of which a causal relationship between the event and the medicinal product is at least a reasonable possibility. "
Much of the proposed new legislation is very pragmatic and makes sense in the current environment, but the challenges will lie in the implementation, Simmons concluded. "Whether the changes will lead to greater rationalisation and simplification in practice remains to be seen," she said. "The devil will definitely be in the detail."