I.C.1. Overall pharmacovigilance responsibilities of the applicant and marketing authorisation holder in the EU

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I.C.

The marketing authorisation holder in the EU is responsible for the respective pharmacovigilance tasks and responsibilities laid down in 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 assure responsibility and liability for its authorised medicinal products and to ensure that appropriate action can be taken, when necessary.

For this purpose, the marketing authorisation holder shall operate a pharmacovigilance system [DIR 104(1)] and shall establish and use a quality system that is adequate and effective for performing its pharmacovigilance activities [IR Art 8(1)].

There may be circumstances where a marketing authorisation holder may establish more than one pharmacovigilance system, e.g. specific systems for particular types of products (e.g. vaccines, products available without medical prescription).

A description of the pharmacovigilance system shall be developed by the applicant for a marketing authorisation in the format of a pharmacovigilance system master file (PSMF) and be maintained by the marketing authorisation holder for all authorised medicinal products (see Module II). The applicant or the marketing authorisation holder is also responsible for developing and maintaining product-specific risk management systems (see Module V).

Guidance on the structures and processes on how the marketing authorisation holder should conduct the pharmacovigilance tasks and responsibilities is provided in the respective GVP Modules.

I.C.1.1. Responsibilities of the marketing authorisation holder in relation to the qualified person responsible for pharmacovigilance in the EU

As part of the pharmacovigilance system, the marketing authorisation holder shall have permanently and continuously at its disposal an appropriately qualified person responsible for pharmacovigilance in the EU (QPPV) [DIR Art 104(3)(a)].

The marketing authorisation holder shall submit the name and contact details of the QPPV to the competent authorities in Member States and the Agency [DIR Art 104(3) last paragraph]. Changes to this information should be submitted in accordance with Regulation (EC) No 1234/2008 on variations to the terms of marketing authorisation and the Communication from the Commission – Guideline on the Details of the Various Categories of Variations to the Terms of Marketing Authorisations for Medicinal Products for Human Use and Veterinary Medicinal Products.

The duties of the QPPV shall be defined in a job description [IR Art 10(2)]. The hierarchical relationship of the QPPV shall be defined in an organisational chart together with those of other managerial and supervisory staff [IR Art 10(2)].

Information relating to the QPPV shall be included in the pharmacovigilance systems master file (PSMF) [IR Art 2(1)] (see Module II).

Each pharmacovigilance system can have only one QPPV. A QPPV may be employed by more than one marketing authorisation holder, for a shared or for separate pharmacovigilance systems or may fulfil the role of QPPV for more than one pharmacovigilance system of the same marketing authorisation holder, provided that the QPPV is able to fulfil all obligations.

In addition to the QPPV, competent authorities in Member States are legally provided with the option to request the nomination of a pharmacovigilance contact person at national level reporting to the QPPV. Reporting in this context relates to pharmacovigilance tasks and responsibilities and not necessarily to line management. A contact person at national level may also be nominated as the QPPV.

The marketing authorisation holder shall ensure that the QPPV has sufficient authority to influence the performance of the quality system and the pharmacovigilance activities of the marketing authorisation holder [IR Art 10(2)]. The marketing authorisation holder should therefore ensure that the QPPV has access to the pharmacovigilance system master file (PSMF) as well as authority over it and is notified of any changes to it in accordance with Module II (see I.C.1.3). The authority over the pharmacovigilance system and the PSMF should allow the QPPV to implement changes to the system and to provide input into risk management plans (see Module V) as well as into the preparation of regulatory action in response to emerging safety concerns (see Module XII).

Overall, the marketing authorisation holder should ensure that structures and processes are in place, so that the QPPV can fulfil the responsibilities listed in I.C.1.3.. In order to do this, the marketing authorisation holder should ensure that mechanisms are in place so that the QPPV receives all relevant information and that the QPPV can access all information the QPPV considers relevant, in particular on:

emerging safety concerns and any other information relating to the benefit-risk evaluation of the medicinal products covered by the pharmacovigilance system;
ongoing or completed clinical trials and other studies the marketing authorisation holder is aware of and which may be relevant to the safety of the medicinal products;
information from sources other than from the specific marketing authorisation holder, e.g. from those with whom the marketing authorisation holder has contractual arrangements; and
the procedures relevant to pharmacovigilance which the marketing authorisation holder has in place at every level in order to ensure consistency and compliance across the organisation.

The outcome of the regular reviews of the quality system referred to in I.B.6. and I.B.12. and the measures introduced should be communicated by the managerial staff to the QPPV.

Compliance information should be provided to the QPPV on a periodic basis. Such information may also be used to provide assurance to the QPPV that commitments in the framework of risk management plans and post-authorisation safety systems are being adhered to.

The managerial staff should also inform the QPPV of scheduled pharmacovigilance audits. The QPPV should be able to trigger an audit where appropriate. The managerial staff should provide the QPPV with a copy of the corrective and preventive action plan following each audit relevant to the pharmacovigilance system the QPPV is responsible for, so that the QPPV can assure that appropriate corrective actions are implemented.

In particular with regard to its adverse reaction database (or other systems to collate adverse reaction reports), the marketing authorisation holder should implement a procedure to ensure that the QPPV is able to obtain information from the database, for example, to respond to urgent requests for information from the competent authorities or the Agency, at any time. If this procedure requires the involvement of other personnel, for example database specialists, then this should be taken into account in the arrangements made by the marketing authorisation holder for supporting the QPPV outside of normal working hours.

When a marketing authorisation holder intends to expand its product portfolio, for example, by acquisition of another company or by purchasing individual products from another marketing authorisation holder, the QPPV should be notified as early as possible in the due diligence process in order that the potential impact on the pharmacovigilance system can be assessed and the system be adapted accordingly. The QPPV may also have a role in determining what pharmacovigilance data should be requested from the other company, either pre- or post-acquisition. In this situation, the QPPV should be made aware of the sections of the contractual arrangements that relate to responsibilities for pharmacovigilance activities and safety data exchange and have the authority to request amendments.

When a marketing authorisation holder intends to establish a partnership with another marketing authorisation holder, organisation or person that has a direct or indirect impact on the pharmacovigilance system, the QPPV should be informed early enough and be involved in the preparation of the corresponding contractual arrangements (see I.C.1.5.) so that all necessary provisions relevant to the pharmacovigilance system are included.

I.C.1.2. Qualifications of the qualified person responsible for pharmacovigilance in the EU

The marketing authorisation holder shall ensure that the QPPV has acquired adequate theoretical and practical knowledge for the performance of pharmacovigilance activities [IR Art 10(1)]. The QPPV should have skills for the management of pharmacovigilance systems as well as expertise or access to expertise in relevant areas such as medicine, pharmaceutical sciences as well as epidemiology and biostatistics. Where the QPPV has not completed basic medical training in accordance with Article 24 of Directive 2005/36/EC, the marketing authorisation holder shall ensure that the QPPV is assisted by a medically trained person (i.e. in accordance with Article 24 of Directive 2005/36/EC) and this assistance shall be duly documented [IR Art 10(1)].

The expectation is that the applicant or marketing authorisation holder will assess the qualification of the QPPV prior to appointment by, for example, reviewing university qualifications, knowledge of EU pharmacovigilance requirements and experience in pharmacovigilance.

The applicant or marketing authorisation holder should provide the QPPV with training in relation to its pharmacovigilance system, which is appropriate for the role prior to the QPPV taking up the position and which is appropriately documented. Consideration should be given to additional training, as needed, of the QPPV in the medicinal products covered by the pharmacovigilance system.

I.C.1.3. Role of the qualified person responsible for pharmacovigilance in the EU

The qualified person responsible for pharmacovigilance in the EU (QPPV) is a natural person.

The QPPV appointed by the marketing authorisation holder shall be appropriately qualified (see I.C.1.2.) and shall be at the marketing authorisation holder’s disposal permanently and continuously (see I.C.1.1.) [DIR Art 104 (3)(a)]. The QPPV shall reside and operate in the EU [DIR Art 104 (3) last paragraph]. Following European Economic Area (EEA) agreements, the QPPV may also reside and operate in Norway, Iceland or Liechtenstein. Back-up procedures in the case of absence of the QPPV shall be in place [IR Art 2(1)(d)] and should be accessible through the QPPV’s contact details. The QPPV should ensure that the back-up person has all necessary information to fulfil the role.

The QPPV shall be responsible for the establishment and maintenance of the marketing authorisation holder’s pharmacovigilance system [DIR Art 104 (3) last paragraph] and therefore shall have sufficient authority to influence the performance of the quality system and the pharmacovigilance activities [IR Art 10(2)] and to promote, maintain and improve compliance with the legal requirements [IR Art 2(1)(a)]. Hence, the QPPV should have access to the pharmacovigilance system master file (PSMF) (see Module II) and be in a position of authority to ensure and to verify that the information contained in the PSMFis an accurate and up-to-date reflection of the pharmacovigilance system under the QPPV’s responsibility.

In relation to the medicinal products covered by the pharmacovigilance system, specific additional responsibilities of the QPPV should include:

having an overview of medicinal product safety profiles and any emerging safety concerns;
having awareness of any conditions or obligations adopted as part of the marketing authorisations and other commitments relating to safety or the safe use of the products;
having awareness of risk minimisation measures;
being aware of and having sufficient authority over the content of risk management plans;
being involved in the review and sign-off of protocols of post-authorisation safety studies conducted in the EU or pursuant to a risk management plan agreed in the EU;
having awareness of post-authorisation safety studies requested by a competent authority including the results of such studies;
ensuring conduct of pharmacovigilance and submission of all pharmacovigilance-related documents in accordance with the legal requirements and GVP;
ensuring the necessary quality, including the correctness and completeness, of pharmacovigilance data submitted to the competent authorities in Members States and the Agency;
ensuring a full and prompt response to any request from the competent authorities in Members States and from the Agency for the provision of additional information necessary for the benefitrisk evaluation of a medicinal product;
providing any other information relevant to the benefit-risk evaluation to the competent authorities in Members States and the Agency;
providing input into the preparation of regulatory action in response to emerging safety concerns (e.g. variations, urgent safety restrictions, and communication to patients and healthcare professionals);
acting as a single pharmacovigilance contact point for the competent authorities in Member States and the Agency on a 24-hour basis and also as a contact point for pharmacovigilance inspections.

This responsibility for the pharmacovigilance system means that the QPPV has oversight over the functioning of the system in all relevant aspects, including its quality system (e.g. standard operating procedures, contractual arrangements, database operations, compliance data regarding quality, completeness and timeliness of expedited reporting and submission of periodic update reports, audit reports and training of personnel in relation to pharmacovigilance). Specifically for the adverse reaction database, if applicable, the QPPV should be aware of the validation status of the database, including any failures that occurred during validation and the corrective actions that have been taken to address the failures. The QPPV should also be informed of significant changes that are made to the database (e.g. changes that could have an impact on pharmacovigilance activities).

The QPPV may delegate specific tasks, under supervision, to appropriately qualified and trained individuals, for example, acting as safety experts for certain products, provided that the QPPV maintains system oversight and overview of the safety profiles of all products. Such delegation should be documented.

I.C.1.4. Specific quality system processes of the marketing authorisation holder in the EU

In applying the requirements set out in I.B.9.1. in the EU, the marketing authorisation holder shall put in place the following additional specific quality system processes for ensuring:

the submission of adverse reaction data to EudraVigilance within the legal timelines [IR Art 11(c)];
the monitoring of the use of terminology referred to in IR Art 25(1) either systematically or by regular random evaluation [IR Art 25(3)];
the retention of minimum elements of the pharmacovigilance system master file (PSMF) (see IR Art 2 and Module II) as long as the system described in the PSMF exists and for at least further 5 years after it has been formally terminated by the marketing authorisation holder [IR Art 12(2)];
the retention of pharmacovigilance data and documents relating to individual authorised medicinal products as long as the marketing authorisation exists and for at least further 10 years after the marketing authorisation has ceased to exist [IR Art 12(2)];
that the product information is kept up-to-date by the marketing authorisation holder in the light of scientific knowledge, including the assessments and recommendations made public via the European medicines web-portal an on the basis of a continuous monitoring by the marketing authorisation holder of information published on the European medicines web-portal [IR Art 11(1)(g)].

The retention periods above apply unless the documents shall be retained for a longer period where EU or national law so requires [IR Art 12(2)].

During the retention period, 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 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.

Documents transferred in situations where the business of the marketing authorisation holder is taken over by another organisation should be complete.

I.C.1.5. Quality system requirements for pharmacovigilance tasks subcontracted by the marketing authorisation holder

The marketing authorisation holder may subcontract certain activities of the pharmacovigilance system to third parties [IR Art 6(1)], i.e. to another organisation or person (where the same requirements apply to a person as for an organisation). This may include the role of the QPPV. The marketing authorisation holder shall nevertheless retain full responsibility for the completeness and accuracy of the pharmacovigilance system master file (PSMF) (see Module II) [IR Art 6(1)]. 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 marketing authorisation holder.

Where a marketing authorisation holder has subcontracted some tasks of its pharmacovigilance tasks, it shall retain responsibility for ensuring that an effective quality system is applied in relation to those tasks [IR Art 11(2)]. All guidance provided in GVP is also applicable to the other organisation to which the tasks have been subcontracted.

When subcontracting tasks to another organisation, the marketing authorisation holder shall draw up subcontracts [IR Art 6(2)] and these should be detailed, up-to-date and clearly document the contractual arrangements between the marketing authorisation holder and the other organisation, describing arrangements for delegation and the responsibilities of each party. A description of the subcontracted activities and/or services shall be included in the pharmacovigilance system master file (PSMF) [IR Art 2(6)] and a list of the subcontracts shall be included in an annex to the PSMF, specifying the product(s) and territory(ies) concerned [IR Art 6(2)] (see Module II). The other organisation may be subject to inspection at the discretion of the competent or supervisory authority in the relevant Member State.

Contractual arrangements should be prepared with the aim of enabling compliance with the legal requirements by each party involved. When preparing contractual arrangements, the marketing authorisation holder should include sufficiently detailed descriptions of the delegated tasks, the related interactions and data exchange, together with, for example, agreed definitions, tools, assignments and timelines. The contractual arrangements should also contain clear information on the practical management of pharmacovigilance as well as related processes, including those for the maintenance of pharmacovigilance databases. Further, they should indicate which processes are in place for checking whether the agreed arrangements are being adhered to on an ongoing basis. In this respect, regular risk-based audits of the other organisation by the marketing authorisation holder or introduction of other methods of control and assessment are recommended.

With respect to centrally authorised products, contractual arrangements between different marketing authorisation holders should also be in place in relation to separately authorised medicinal products with the application of Article 82(1) of Regulation (EC) No 726/2004 in order to ensure conduct of pharmacovigilance on the basis of complete worldwide data sets.

For responsibilities of the marketing authorisation holder towards the QPPV in this context, see I.C.1.1.