Pharmacovigilance and Drug Safety

A marketing authorisation for a medicinal product in more than one Member State in the EU must be sought via one of three procedures: either the “Centralised Procedure”, determined by Regulation (EC) No 726/2004, the “Mutual Recognition Procedure” or the new “Decentralised Procedure”, regulated by Directive 2001/83/EC.

In addition, national authorisations allow for products to be marketed in individual countries in the EU. A product may be authorised in several Member States by a number of national authorisations, or one of these may be used as the basis for a Mutual Recognition Procedure. The regulatory agency of the country concerned has the responsibility for monitoring and assessing the safety of products with national authorization.

Centralised Procedure

This is administered by the EMEA. It consists of one application which, if approved, grants marketing authorisation for all countries within the European Union (and the European Economic Area, i.e. the EU countries plus Iceland, Norway and Liechtenstein).The European Commission is the responsible authority for the products which come to the market through the centralised procedure. The procedure is available to all new, or innovative pharmaceuticals, and is obligatory for biotechnology medicines. It is used for products containing new substances for which the therapeutic indication is the treatment of serious disease.

The regulatory agency of a Member State is appointed as Rapporteur and carries out the initial assessment of the application for Marketing Authorisation; another agency is appointed as Co-Rapporteur. These countries remain responsible for taking the lead in the monitoring and assessment of safety of the product when it is subsequently marketed.

Mutual Recognition Procedure

Here, the marketing authorisation in one Member State, the ‘Reference Member State’, is “mutually recognised” by other ‘Concerned Member States’. There is a 90 day assessment period after which Member States grant a marketing authorisation with an identical summary of product characteristics to that in the Reference Member State, provided that they accept the assessment of the product. If a Member State raises objections and does not recognise the original marketing authorisation the matter may be referred to the EMEA for discussion among the parties: if this fails, binding arbitration is imposed.

Decentralised Procedure

This process can apply where an authorisation does not yet exist in any of the Member States. Identical dossiers are submitted in all Member States where a marketing authorisation is sought. A Reference Member State, selected by the applicant, prepares a preliminary assessment report within 120 days and sends it to the Concerned Member States. They then approve the assessment or the application will continue into a facilitation or, if this fails, a binding arbitration procedure applies.

Organization of safety monitoring

After approval in the EU, the company holding the marketing authorisation is required by regulation to continue monitoring safety. It must enter reports of suspected ADRs on a validated safety database and review the data for signals of possible new adverse reactions or other concerns. Any change to the balance of benefits and risks must be reported to the regulatory authorities, in addition to the reporting of individual cases and periodic safety update reports.

For products with national marketing authorisation in the EU, the regulatory authority in the Member State where the product is marketed has responsibility for reviewing safety by examining the safety reports that it receives from the company and directly from health professionals working in that country. The national regulatory authority also reviews PSURs from companies. It enters the case reports it receives onto the Eudravigilance database, held by EMEA.

For mutual recognition and centrally authorised products, the responsibility for monitoring safety rests with the EU regulatory authority that acted as Rapporteur or Reference Member State. However, each national regulatory authority will still receive local reports of adverse reactions from companies and health professionals and must enter these onto the Eudravigilance database. The EMEA acts as a coordinating body for the safety activities for centrally authorised and mutual recognition products, but the safety reviews are performed by assessors in the Member State regulatory authorities.

The Committee on Medicinal Products for Human use (CHMP) – comprised of representatives of each of the EU regulatory authorities – is involved at intervals with review of the PSURs for centrally authorised products and with safety issues arising post-marketing. These are channelled through its Pharmacovigilance Working Party (PhVWP), which comprises pharmacovigilance representatives from each Member State.

Legislation provides mechanisms for referral of important safety issues potentially affecting public health throughout Europe to the CHMP by the PhVWP. There are complex procedures for examining the benefit-risk balance of products if there are major safety concerns, and for making recommendations to the European Commission for suspending or revoking marketing authorisation.

There are two main strands to the assessment of safety of marketed medicines: spontaneous reporting and post-authorisation studies. However, it should be pointed out that company-sponsored research may be continuing in countries  where the product is not yet marketed, in order to obtain marketing authorisation there. Safety information from those studies is required by regulation to be reported to the competent authorities where the drug is marketed. In the same way, studies may be set up looking at new indications for the marketed drug, or use in new populations, or with different dosage forms. All of these may generate data on adverse reactions that is relevant to the marketed product and which is legally required to be forwarded by the sponsor company to the competent regulatory authorities.