EU Looks Closer at Pharmacovigilance

New rules for pharmacovigilance are on the way in Europe. European Union health ministers took their first look at the proposals* in June, and changes can be expected to be decided before the end of this year. The initiative comes from European industry commissioner Günter Verheugen, who made clear last December when he announced a "pharma package" of proposed new rules that he was determined to tighten up EU monitoring of adverse effects.

Peter O'Donnell

Although ministers took no decisions when they met as the EU health council on June 9, they did have an opportunity to review the progress made by the expert working party of national officials that is examining the draft. An extensive report lists where consensus is emerging—and where it is not.

The objective as defined by the Commission is to "strengthen and rationalize" the EU pharmacovigilance system to ensure full and equal coverage for "all relevant products" across the EU, "with a view to preventing unnecessary patient exposure to risks." The proposals envisage clearer roles for everyone involved, greater transparency on medicines safety and on the way companies' pharmacovigilance systems function, better quality data-collection, and closer involvement of patients.

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Among the proposals

The proposals suggest tougher obligations on companies to provide information on their products. "The marketing authorization holder shall forthwith supply to the national competent authority any new information which might entail the amendment of the particulars or documents" covered by the authorization, and "In particular, he shall forthwith inform the national competent authority of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product for human use is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product for human use concerned."

This information is to include both positive and negative results of trials or other studies in all indications and populations, whether or not included in the marketing authorization, as well as data on the use of the medicinal product not in accordance with the summary of the product characteristics.

In addition, the marketing authorization holder "shall ensure that the product information is kept up to date with the current scientific knowledge," and "in order that the risk-benefit balance may be continuously assessed, the national competent authority may at any time ask the holder of the marketing authorization to forward data demonstrating that the risk-benefit balance remains favourable."

The EU's Working Party on Pharmaceuticals and Medical Devices—the technical experts from the 27 member states—has so far examined the proposals six times, and all countries are still holding back from a general endorsement of the proposals. This does not mean they fundamentally oppose it.

As is clear from the report—drawn up by the Czech Republic, which has been in the EU's rotating presidency seat for the first six months of this year—there is general agreement among national officials that "these important proposals must be pursued with high priority." But officials from some countries are not convinced that the proposals meet the designated objectives, and many national delegations to the working party have reservations on individual provisions.

For instance, while there is broad agreement that a new scientific committee responsible for pharmacovigilance should be set up in the EMEA, there are divergent views over who should sit on it. The proposals foresee a committee with 10 members appointed by the EMEA Management Board and five members appointed by the Commission, but nearly all the member states insist on every country having a seat. A compromise is under discussion under which every member state would have the right, but not the obligation, to actively participate in the work of the committee.

Loose ends to tie

There are differences over the role of the pharmacovigilance committee, too. The debate is partly over whether its recommendations should serve merely as advice for the Committee for Medicinal Products for Human Use (CHMP) and the coordination group (CMD), as the Commission has proposed, or should be binding, or binding except where the CHMP and CMD "have well-founded reasons for not accepting the recommendation." Both the composition and the role of the committee in relation to the other scientific committees of EMEA (including CAT) also need further discussion, according to the report of discussions in the working party.

There have been lengthy discussions of the proposed definitions, in particular the definition of "adverse reaction." Some national delegations support the proposed new definition of adverse reaction, "Adverse reaction: A response to a medicinal product which is noxious and unintended." While some other delegations would prefer to maintain the current definition, "Adverse reaction: A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function." And others would accept the current definition "potentially with minor changes."

Some delegations have suggested two separate definitions, one covering adverse reactions within the use in compliance with the summary of the product characteristics (SPC) and the other covering off-label use.

The potential need for a definition of "medication error" has also been discussed, and first suggestions for a definition have been provided. This discussion has in turn produced further complications, since "misuse" and "medication error" are terms that are not yet defined in EU legislation. So the proposed definitions, as well as the missing definitions, require further reflection.

The proposal for a list of medicinal products for human use under intensive monitoring has generated dissension over its impact and the practical aspects. There are questions over who in the EMEA should manage it and how, and the concept of including a special statement into the package leaflet (PIL) to indicate the medicine's status has raised eyebrows.

There are many national officials who fear that such a statement to the public would give rise to unsubstantiated concerns for patients, with possible negative effects on compliance. It would also mean what are seen as unjustified administrative burdens for marketing authorization holders—if their product was removed from the list, they might have to seek a variation of the marketing authorization to accommodate the modification of the PIL. Similar concerns have been expressed over the proposed inclusion of the summary of essential safety information in the SPC and PIL.

Further examination will also be needed of the proposals on supervision of postauthorization safety studies. These constraints will apply to noninterventional postauthorization safety studies that are initiated, managed or financed by the marketing authorization holder, voluntarily or following a requirement, and which involve the collection of data from patients or health care professionals. "The studies shall not be performed where the act of conducting the study promotes the use of a medicinal product," according to the draft text.

Before such a study is conducted, the marketing authorization holder will have to submit a draft protocol to the national competent authority if only one member state is involved, and to the Pharmacovigilance Risk Assessment Advisory Committee for studies to be conducted more widely. If the committee has any reservations, it will, within 60 days, issue either a recommendation on the draft protocol or letter of objection (based on detailed grounds, for instance if it considers that the study is a clinical trial falling under the scope of Directive 2001/20/EC, or the study promotes the use of a product).

During the conduct of the study, the marketing authorization holder will have to continuously monitor the data generated and its implications for the risk–benefit balance of the product, and communicate to the authorities any new information that might influence the risk–benefit balance.

Final study reports are to be submitted to the national competent authority or the Pharmacovigilance Risk Assessment Advisory Committee within 12 months of the last patient visit unless a written waiver has been given. The marketing authorization holder has to consider whether the results of the study have an impact on the terms of the marketing authorization and is required if necessary to submit an application to vary the marketing authorization.

Other areas where differences still have to be resolved among national officials include a risk management system covering all products; the setting up and maintenance of national safety Web portals; and direct reporting to the Eudravigilance database by the marketing authorization holder and by patients.

The next crucial stage in this process will be the first opinion from the European Parliament, but this is not expected until the autumn, since the new parliament elected in June will not start work until July, and then takes an extended summer break.

* Proposal for a Regulation of the European Parliament and of the Council amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency and Proposal for a Directive of the European Parliament and of the Council amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.