Regulation No 1235/2010 and Directive 2010/84/EU have substantially amended the pharmacovigilance requirements, as laid down in previous European legislation, by strengthening and consolidating the pharmacovigilance system.
Prior to this legislation, divergent actions by Member States in relation to safety issues pertaining to medicinal products were creating obstacles to the free movement of medicinal products.
Overview of major changes
2.1 Pharmacovigilance system master file (‘PSMF’)
Under the new rules, marketing authorisation (MA) applicants and MA holders (MAH) are required to maintain and make available upon request a PSMF. This facilitates the harmonisation and strengthening of pharmacovigilance activities. The specifications of the PSMF are described in a new guidance document and apply irrespective of the organisational structure of the MAH, including any delegation of activities or their location.
The contents of the PSMF must detail the global availability of safety information for medicinal products. In addition, the information on pharmacovigilance is not confined to local or regional activities. The PSMF location must be within the EU, along with the residence and location at which the qualified person for pharmacovigilance (QPPV) carries out his or her tasks.
PSMF requirements apply automatically to medicinal products authorised after July 2, 2012. Those authorised before this date, will apply as from either the date of renewal of their MA or, whichever is earlier, from July 2, 2015 for centrally authorised medicinal products or July 21, 2015 for others.
2.2 Definition of adverse reaction
A new definition of adverse reaction has been adopted which is broader in scope than previously. It now covers noxious and unintended effects resulting not only from the authorised use of a medicinal product in normal doses, but also from medicinal errors and uses outside the terms of the marketing authorisation (off-label use), as well as the misuse and abuse of the medicinal product.
2.3 Specific conditions relating to pharmacovigilance affecting MA
Additional measures relating to pharmacovigilance can be adopted by the competent authorities. In particular, those authorities may now issue a MA subject to one or more conditions specifically related to pharmacovigilance, and lay down deadlines for the fulfilment thereof. These conditions may consist of including additional measures in the risk management system; conducting post-authorisation safety or efficacy studies; complying with stricter obligations on the recording or reporting of suspected adverse reactions. More generally, the competent authority may lay down ‘any other conditions or restrictions with regard to the safe and effective use of the medicinal product’. This leaves it a relatively broad margin of discretion.
After a MA has been granted, the competent authority may also impose an obligation on the MAH to conduct post-authorisation safety or efficacy studies. If the same safety concerns apply to more than one medicinal product, the competent authority may, following consultation with the Pharmacovigilance Risk Assessment Advisory Committee (PRAC), encourage the performance of a joint post-authorisation safety study. The MAH is given the opportunity to present written observations in response to the imposition of the obligation, provided he so requests within 30 days of receipt of the written notification of the obligation.
2.4 PSUR requirements
An approach to periodic safety update reports (PSURs) that is more proportionate to the risks posed by medicinal products has been adopted. In particular, routine reporting will not be required for certain types of ‘lower risk’ products. However, in the interests of public health, the competent authorities may require periodic PSURs for such medicinal products when concerns arise.
2.5 Setup of interconnected web-portals
Transparency has been improved, with the upcoming establishment of a European medicines web-portal maintained by the EMA. This will be linked to national web-portals, the objective of which is to facilitate the exchange of, and access to, pharmacovigilance information as well as the reporting through those web-portals. Alternative reporting media must, however, remain available.
A new EMA committee
The new legislation puts the PRAC in place within the EMA. This committee will provide pharmacovigilance assessments and recommendations on the safety of medicines at European level.
Among others activities, the PRAC will issue recommendations on risk management systems, the monitoring of their effectiveness and the imposition of post-authorisation efficacy studies.
GVP guidelines
Good pharmacovigilance practice guidelines (GVP) are due to replace Eudralex Volume 9A. The GVP are divided into sixteen modules and apply to all medicinal products, irrespective of the MA granting procedure.
So far, seven modules have been released by the EMA, and pending the completion of public consultations, the complete set is scheduled to be available by early 2013.
Until the availability of all modules, Eudralex Volume 9A remains the reference.
The new pharmacovigilance rules tend towards increasing transparency and closer follow-up on the safety and efficacy of medicinal products marketed in Europe. The level of implication of all stakeholders increases, as well as accessibility to information. Overall, the collection of data and the assessment of pharmacovigilance issues is better coordinated. This will make the European pharmacovigilance system one of the most elaborate in the world.
The burden of relying on the MAH is heavier than before, at least for innovative products. The competent authorities can now impose post-authorisation studies on marketing authorisation holders, and only practice will show how often, and under which circumstances, this will be utilised.
New web-portals dedicated to pharmacovigilance information should ensure a European pharma market in which all stakeholders will be more, and better, informed than ever on pharmacovigilance issues.
Marc Martens is a partner and Nicolas Carbonnelle is an associate at Bird & Bird LLP.
They are both based in Brussels. They can be contacted on +32 2 282 60 00 or via www.twobirds.com