I.C.2. Overall pharmacovigilance responsibilities within the EU regulatory network

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I.C.

The competent authorities in Member States and the Agency are responsible for the respective pharmacovigilance tasks and responsibilities imposed on them by Directive 2001/83/EC, Regulation (EC) No 726/2004 and the Commission Implementing Regulation (EU) No 520/2012 on the Performance of Pharmacovigilance Activities Provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC in order to ensure that appropriate action can be taken, when necessary.

For this purpose each competent authority in a Member State as well as the Agency shall operate a pharmacovigilance system [DIR 101(1)] and shall establish and use an adequate and effective quality system for performing their pharmacovigilance activities [IR Art 8(1)].

The Agency and the Member States shall cooperate to continuously develop pharmacovigilance systems capable of achieving high standards of public health protection for all medicinal products, regardless of the routes of marketing authorisation, including the use of collaborative approaches, to maximise use of resources available within the EU [REG Art 28e].

The requirement in I.B.11.2. according to which competent authorities shall keep accessible clear descriptions of the organisational structures, assignment of tasks and responsibilities as well as contact points [IR Art 14(1)], should relate to the interaction between competent authorities in Member States, the Agency, the European Commission, marketing authorisation holders and persons reporting information on the risks of medicinal products.

Guidance on the structures and processes to enable the competent authorities in Member States and the Agency to conduct the pharmacovigilance tasks and responsibilities is provided in the respective Modules of GVP.

I.C.2.1. Role of the competent authorities in Member States

Each Member State shall designate a competent authority for the performance of pharmacovigilance [DIR Art 101(3)]. This authority is usually the same as the competent authority responsible for granting national marketing authorisations.

Each competent authority in a Member State must operate a pharmacovigilance system for the fulfilment of their pharmacovigilance tasks and their participation in EU pharmacovigilance activities [DIR Art 101(1)]. In this context, the competent authority in a Member State is responsible for the safety monitoring of each medicinal product, independent of its route of authorisation, in the territory of that Member State. In particular, the competent authority in each Member State shall be responsible for monitoring data originating in their territory [IR Art 18(4)].

For nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure, the competent authority in a Member State is responsible for granting, varying, suspending and revoking a marketing authorisation. The pharmacovigilance tasks and responsibilities of competent authorities in Member States for each process in relation to such products, are detailed in the respective Modules of GVP.

For products authorised through the mutual recognition or the decentralised procedure, one Member State acts as the Reference Member State. For practical reasons, the competent authority of the Reference Member State should coordinate communication with the marketing authorisation holder on pharmacovigilance matters and monitor the compliance of the marketing authorisation holder with legal pharmacovigilance requirements. These arrangements do not replace the legal responsibilities of the marketing authorisation holder with respect to individual competent authorities and the Agency.

Nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure, may become subject to regulatory procedures at EU level on pharmacovigilance grounds. If a Commission Decision for a nationally authorised product exists as an outcome of such a procedure, the competent authorities in Member States are responsible for the implementation of the Commission Decision and also for its follow-up, unless exceptionally further action by the Agency and the European Commission has been foreseen in the Commission Decision reflecting the outcome of the regulatory procedure (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons).

The pharmacovigilance tasks and responsibilities of competent authorities in Member States in relation to centrally authorised products are also detailed in the respective Modules of GVP. They include the collaboration in signal detection (see Module IX) and implementation of Commission Decisions regarding risk management of centrally authorised products addressed to Member States (see Module V). Where urgent action is essential to protect human health or the environment, the competent authority in a Member State, on its own initiative or at the European Commission’s request, may suspend the use of a centrally authorised product in its territory (see Modules XII).

Competent authorities in Member States are responsible for pharmacovigilance inspections of organisations in their territory in relation to medicinal products. This is independent of the route of marketing authorisation as well as which competent authority granted the marketing authorisation for the respective medicinal product (see Module III).

In relation to the various aspects of the role described above, each Member State’s competent authority should ensure that all pharmacovigilance data are shared between competent authorities in other Member States, the European Commission and the Agency for each process in accordance with the legislation and the guidance in the respective GVP Modules.

I.C.2.2. Role of the European Commission

The European Commission is the competent authority for medicinal products authorised through the centralised procedure and is responsible for granting, varying, suspending and revoking their marketing authorisations by adoption of Commission Decisions on the basis of Opinions adopted by the Committee for Medicinal Products for Human Use (CHMP) (see I.C.2.3.3.).

Further, the European Commission adopts Commission Decisions in relation to nationally authorised medicinal products subject to regulatory procedures at EU level, including on pharmacovigilance grounds. The European Commission may also initiate such procedures (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons).

I.C.2.3. Role of the European Medicines Agency

I.C.2.3.1. General role of the Agency and the role of the Agency’s secretariat

The role of the Agency is to coordinate the monitoring of medicinal products for human use authorised in the EU and to provide advice on the measures necessary to ensure their safe and effective use, in particular, by coordinating the evaluation and implementation of legal pharmacovigilance requirements and the monitoring of such implementation. The tools established and maintained by the Agency for the coordination are presented in the GVP Modules for each process.

The Agency provides coordination and technical, scientific and administrative support to the Pharmacovigilance Risk Assessment Committee (PRAC) (see I.C.2.3.2.) and the Committee for Medicinal Products for Human Use (CHMP) (see I.C.2.3.3.) and coordination and technical and administrative support to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) (see I.C.2.3.4.), as well as coordination between the committees and the CMDh.

Pharmacovigilance for centrally authorised products is conducted by the Agency with the involvement of the Rapporteurs, the PRAC and the CHMP. The Agency should take the lead for communicating with the marketing authorisation holders of centrally authorised products. The respective responsibilities for each pharmacovigilance process are detailed in the GVP Modules.

For nationally authorised products, the Agency coordinates regulatory procedures at EU level on pharmacovigilance grounds through providing support to the CMDh and CHMP (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons).

The Agency also cooperates with other EU bodies as necessary.

Specific pharmacovigilance tasks of the Agency include:

  • running the EudraVigilance database [REG Art 57(d)];
  • monitoring selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances [REG Art 27] (see Module VI);
  • running processes for the EU coordination of the assessment of periodic safety update reports (see Module VII) and oversight of post-authorisation safety studies (see Module VIII);
  • tasks relating to signal detection [REG Art 28a(1)(c), IR Art 18–24] (see Module IX);
  • tracking of follow-up of safety concerns and other pharmacovigilance matters at EU level (see Module XII);
  • assisting Member States with the rapid communication of information on safety concerns to healthcare professionals and coordinating the safety announcements of the national competent authorities [REG Art 57(e)] (see Module XV);
  • distributing appropriate information on safety concerns to the general public, in particular by setting up and maintaining the European medicines web-portal [REG Art 57(f)] (see Module XV);
  • coordination of safety announcements between national competent authorities for active substances contained in medicinal products authorised in more than one Member State, including providing timetables for the publication of information [DIR 106a(3)] (see Module XV);

and specifically in relation to centrally authorised products:

I.C.2.3.2. Role of the Pharmacovigilance Risk Assessment Committee (PRAC)

The Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for providing recommendations to the Committee for Medicinal Products for Human Use (CHMP) and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) on any question relating to pharmacovigilance activities in respect of medicinal products for human use and on risk management systems, including the monitoring of the effectiveness of those risk management systems [REG Art 56(1)(aa)]. The Details on the responsibilities for each process are presented in the respective GVP Modules. The Mandate and Rules of Procedure of the PRAC are published on the Agency’s website.

I.C.2.3.3. Role of the Committee for Medicinal Products for Human Use (CHMP)

The Committee for Medicinal Products for Human Use (CHMP) is responsible for evaluating applications and formulating Opinions serving as a basis for granting, varying, suspending or withdrawing marketing authorisations for centrally authorised products. The CHMP also prepares Opinions on safety concerns emerging after a marketing authorisation has been granted for centrally authorised products or, for nationally authorised products, including those through the mutual recognition or the decentralised procedure, in the framework of regulatory procedures at EU level in which at least one centrally authorised product is involved (see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons), procedures for the assessment of periodic safety update reports (PSURs) (see Module VII) and procedures for post-authorisation safety studies (see Module VIII). For questions related to pharmacovigilance activities and risk management systems, the CHMP relies on the recommendations from the Pharmacovigilance Risk Assessment Committee (PRAC). The specific responsibilities of each party for each pharmacovigilance process are described in the GVP Modules. The Rules of Procedure of the CHMP are published on the Agency’s website.

I.C.2.3.4. Role of the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)

The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) is responsible for examining any question relating to marketing authorisations for medicinal products authorised through the mutual recognition or the decentralised procedure and questions on the variation of marketing authorisations granted by the Member States as well as questions arising for nationally authorised products from assessments of periodic safety update reports (see Module VII), post-authorisation safety studies (see Module VIII) and during regulatory procedures at EU level. The CMDh shall reach a position, based on a PRAC recommendation, on regulatory procedures at EU level when only nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure, are involved [DIR Art 107k](see see Chapter 3 of the Notice to Applicants and the Agency’s and HMA Procedural Advice on Referral Procedures for Safety Reasons). The responsibilities of the CMDh for each pharmacovigilance process are described in the respective GVP Modules. The Rules of Procedure of the CMDh and the Functions and Tasks for CMDh are published on the HMA website.

I.C.2.4. Specific quality system processes of the quality systems of competent authorities in Member States and the Agency

In applying the requirements set out in I.B.9.2. in the EU, the competent authorities in Member States and the Agency shall put in place the following additional specific quality system processes for:

  • monitoring and validating the use of terminology referred to in IR Art 25(1), either systematically or by regular random evaluation [IR Art 25(3)];
  • assessing and processing pharmacovigilance data in accordance with the timelines provided by legislation [IR Art 15(1)(b)];
  • ensuring effective communication within the EU regulatory network in accordance with the provisions on safety announcements in Article 106a of Directive 2001/83/EC [IR Art 15(1)(d)] (see Module XV);
  • guarantying that competent authorities in Member States and the Agency inform each other and the European Commission of their intention to make announcements relating to the safety of a medicinal product or an active substance contained in a medicinal product authorised in several Member State (see Modules XII and XV) [IR Art 15(1)(e)];
  • arranging for the essential documents describing their pharmacovigilance systems to be kept as long as the system exists and for at least further 5 years after they have been formally terminated [IR Art 16(2)];
  • ensuring that pharmacovigilance data and documents relating to individual authorised medicinal products are retained as long as the marketing authorisation exists or for at least further 10 years after the marketing authorisation has expired [IR Art 16(2)].

In this context, documents relating to a medicinal product include documents of a reference medicinal product where this is applicable.

The retention periods above apply unless the documents shall be retained for a longer period where EU or national law so requires [IR Art 16(2)].

During the retention periods referred to above, retrievability of the documents should be ensured.

Documents can be retained in electronic format, provided that the electronic system has been appropriately validated and appropriate arrangements exist for system security, access and back-up of data. If pharmacovigilance documents in paper format are transferred into an electronic format, the transfer process should ensure that all of the information present in the original format is retained in a legible manner and that the media used for storage will remain readable over time.

The legal requirements for record management (see I.B.10.) imply accessibility to the records from within the EU, preferably at a single point.

In addition to the above, competent authorities in Member States shall establish procedures for collecting and recording all suspected adverse reactions that occur in their territory (see Module VI) [IR Art 15(2)].

In addition to the above, the Agency shall establish procedures for literature monitoring in accordance with Article 27 of Regulation (EC) No 726/2004 (see Module VI) [IR Art 15(3)].

In addition to the quality system documentation in accordance with I.B.11. and I.B.11.2., competent authorities in Member States and the Agency shall clearly determine, and to the extent necessary, keep accessible the organisational structures and the distribution of tasks and responsibilities [IR Art 14(1)] as well as establish contact points [IR Art 14(1)], in particular to facilitate interaction between competent authorities in Member States, the Agency, marketing authorisation holders and persons reporting information on the risks of medicinal products as regards patients’ or public health. Quality audits of the Member States’ and Agency ‘s pharmacovigilance systems (see I.B.12.) shall be performed according to a common methodology [IR Art 17(1)]. The results of audits shall be reported by competent authorities in Member States in accordance with Article 101(2) of Directive 2001/83/EC and by the Agency in accordance with Article 28f of Regulation (EC) No 726/2004 (see Module IV).

I.C.2.5. Quality system requirements for pharmacovigilance tasks delegated or transferred by competent authorities in Member States

A competent authority in a Member State may delegate any pharmacovigilance task to another Member State subject to a written agreement of the latter Member State [DIR Art 103]. The written agreement should be reflected by exchange of letters, defining the scope of the delegation.

A competent authority in a Member State may transfer any or all of the pharmacovigilance tasks to another organisation, but the ultimate responsibility for the fulfilment of all pharmacovigilance tasks and responsibilities and the quality and integrity of the pharmacovigilance system always remains with the competent authority in a Member State.

Where tasks are transferred to another organisation, the competent authority in a Member State should ensure that the tasks are subject to a quality system compliant with the legal requirements applicable to their own organisation.

I.C.2.6. Transparency of the quality system of the EU regulatory network

The European Commission (EC) shall publish every three years a report on the performance of pharmacovigilance based on the reports submitted by the competent authorities in Member States (first EC report due on 21 July 2015) and by the Agency (first EC report due on 2 January 2014) on the results of their regular pharmacovigilance system audits (see Module IV) [DIR Art 101(2), Art 108b, REG Art 28f, Art 29].