II.B.4. Information to be contained in the pharmacovigilance system master file

Location:
II.B.
In force from:
31.03.2017

The PSMF shall contain at least all of the documents listed in Article 2 of Commission Implementing Regulation (EU) No 520/2012.

The PSMF shall include documents to describe the pharmacovigilance system. The content of the PSMF should reflect the global availability of safety information for medicinal products authorised in the EU. The content shall be indexed to allow for efficient navigation around the document and follow the modular system described in the following sections and the annex headings described in II.B.6.1. The main principle for the structure of the content of the PSMF is that the primary topic sections contain information that is fundamental to the description of pharmacovigilance system. Detailed information is required to fully describe the system, and, since this may change frequently, it should be referred to and contained in the Annexes. The control associated with change of content is described in section II.B.5.

It is accepted that, where no marketing authorisation (and master file) previously existed in the EU, there may be information that cannot be initially provided, for example, compliance information, however, descriptions of what will be implemented should be provided instead.

II.B.4.1. PSMF section on qualified person responsible for pharmacovigilance (QPPV)

For the QPPV, contact details shall be provided in the marketing authorisation application [DIR Art 8(3)(ia)] and/or via the Article 57 database.

The information relating to the QPPV provided in the PSMF [IR Art 2(1)] shall include:

  • a description of the responsibilities guaranteeing that the qualified person has sufficient authority over the pharmacovigilance system in order to promote, maintain and improve compliance;
  • a summary curriculum vitae with the key information on the role of the qualified person responsible for pharmacovigilance, including proof of registration with the EudraVigilance database;
  • contact details;
  • details of back-up arrangements to apply in the absence of the qualified person responsible for pharmacovigilance; and
  • responsibilities of the contact person for pharmacovigilance issues where such a person has been nominated at national level in accordance with Article 104(4) of Directive 2001/83/EC, including contact details.

A list of tasks that have been delegated by the qualified person for pharmacovigilance shall also be included in the Annexes (see II.B.4.8.). This should outline the activities that are delegated and to whom, and include the access to a medically qualified person if applicable (GVP Module I and [IR Art 10(1)]). This list may be supplied as a copy of a written procedural document provided the required content is covered.

The details provided in relation to the QPPV should also include the description of the QPPV qualifications, experience and registrations relevant to pharmacovigilance (including registration with EudraVigilance). The contact details supplied should include name, postal address, telephone, fax and e-mail and represent the usual working address of the QPPV, which may therefore be different to a marketing authorisation holder address. If the QPPV is employed by a third party, even if the usual working address is an office of the marketing authorisation holder, this should be indicated and the name of the company the QPPV works for provided.

II.B.4.2. PSMF section on the organisational structure of the marketing authorisation holder

A description of the organisational structure of the marketing authorisation holder relevant to the pharmacovigilance system must be provided. The description should provide a clear overview of the company(ies) involved, the main pharmacovigilance departments and the relationship(s) between organisations and operational units relevant to the fulfilment of pharmacovigilance obligations. This should include third parties. Specifically, the PSMF shall describe:

  • The organisational structure of the marketing authorisation holder(s), showing the position of the QPPV in the organisation.
  • The site(s) where the pharmacovigilance functions are undertaken covering individual case safety report collection, evaluation, safety database case entry, periodic safety update report production, signal detection and analysis, risk management plan management, pre- and post-authorisation study management, and management of safety variations to product particulars [IR Art 2(2)].

Diagrams may be particularly useful; the name of the department or third party should be indicated.

Delegated activities

The PSMF, where applicable, shall contain a description of the activities and/or services subcontracted by the marketing authorisation holder [IR Art 2 (6)] relating to the fulfillment of pharmacovigilance obligations. This includes arrangements with other parties in any country, Worldwide and if applicable, to the pharmacovigilance system applied to products authorised in the EU.

Links with other organisations, such as co-marketing agreements and contracting of pharmacovigilance activities should be outlined. A description of the location and nature of contracts and agreements relating to the fulfilment of pharmacovigilance obligations should be provided. This may be in the form of a list/table to show the parties involved, the roles undertaken and the concerned product(s) and territories. The list should be organised according to: service providers (e.g. medical information, auditors, patient support programme providers, study data management, etc.), commercial arrangements (distributors, licensing partners, co-marketing etc.) and other technical providers (hosting of computer systems etc.). Individual contractual agreements shall be made available at the request of national competent authorities and the Agency or during inspection and audit and the list provided in the Annexes (see II.B.4.8.).

II.B.4.3. PSMF section on the sources of safety data

The description of the main units for safety data collection should include all parties responsible, on a global basis, for solicited and spontaneous case collection for products authorised in the EU. This should include medical information sites as well as affiliate offices and may take the form of a list describing the country, nature of the activity and the product(s) (if the activity is product specific) and providing a contact point (address, telephone and e-mail) for the site. The list may be located in the Annexes of the PSMF. Information about third parties (licence partners or local distribution/marketing arrangements) should also be included in the section describing contracts and agreements (see II.B.4.2. and II.B.4.8.).

Flow diagrams indicating the main stages, timeframes and parties involved may be used. However represented, the description of the process for ICSRs from collection to reporting to competent authorities should indicate the departments and/or third parties involved.

For the purposes of inspection and audit of the pharmacovigilance system, sources include data arising from study sources, including any studies, registries, surveillance or support programmes sponsored by the marketing authorisation holder through which ICSRs could be reported. MAHs should be able to produce and make available a list of such sources to support inspection, audit and QPPV oversight. In the interests of harmonisation, it is recommended that the list should be comprehensive for products authorised in the EU, irrespective of indication, product presentation or route of administration. The list should describe, on a worldwide basis, the status of each study/programme, the applicable country(ies), the product(s) and the main objective. It should distinguish between interventional and non-interventional studies and should be organised per active substance. The list should be comprehensive for all studies/programmes and should include ongoing studies/programmes as well as studies/programmes completed in the last two years and may be located in an Annex or provided separately.

II.B.4.4. PSMF section on computerised systems and databases

The location, functionality and operational responsibility for computerised systems and databases used to receive, collate, record and report safety information and an assessment of their fitness for purpose shall be described in the PSMF [IR Art 2(3)].

Where multiple computerised systems/databases are used, the applicability of these to pharmacovigilance activities should be described in such a way that a clear overview of the extent of computerisation within the pharmacovigilance system can be understood. The validation status of key aspects of computer system functionality should also be described; the change control, nature of testing, back-up procedures and electronic data repositories vital to pharmacovigilance compliance should be included in summary, and the nature of the documentation available described. For paperbased systems (where an electronic system may only be used for expedited submission of ICSRs), the management of the data, and mechanisms used to assure the integrity and accessibility of the safety data, and in particular the collation of information about adverse drug reactions, should be described.

II.B.4.5. PSMF section on pharmacovigilance processes

An essential element of any pharmacovigilance system is that there are clear written procedures in place. GVP Module I describes the required minimum set of written procedures for pharmacovigilance. A description of the procedural documentation available (standard operating procedures, manuals, at a global and/or National level etc.), the nature of the data held (e.g. the type of case data retained for ICSRs) and an indication of how records are held (e.g. safety database, paper file at site of receipt) should be provided in the PSMF.

A description of the process, data handling and records for the performance of pharmacovigilance, covering the following aspects shall be included in the PSMF:

  • Continuous monitoring of product risk-benefit profile(s) applied and the result of evaluation and the decision making process for taking appropriate measures; this should include signal generation, detection and evaluation. This may also include several written procedures and instructions concerning safety database outputs, interactions with clinical departments etc;
  • Risk management system(s) and monitoring of the outcome of risk minimisation measures; several departments may be involved in this area and interactions should be defined in written procedures or agreements;
  • ICSR collection, collation, follow-up, assessment and reporting; the procedures applied to this area should clarify what are local and what are global activities;
  • PSUR scheduling, production and submission, if applicable (see GVP Module VII);
  • Communication of safety concerns to consumers, healthcare professionals and the competent authorities;
  • Implementation of safety variations to the summary of product characteristics (SmPC) and patient information leaflets; procedures should cover both internal and external communications [based on IR Art 2(4)].

In each area, the marketing authorisation holder should be able to provide evidence of a system that supports appropriate and timely decision making and action.

The description must be accompanied by the list of processes referred to in Article 11(1) of Commission Implementing Regulation (EU) No 520/2012 under the topic compliance management, as well as interfaces with other functions. Interfaces with other functions include, but are not limited to, the roles and responsibilities of the QPPV, responding to competent authority requests for information, literature searching, safety database change control, safety data exchange agreements, safety data archiving, pharmacovigilance auditing, quality control and training. The list, which may be located in the Annexes, should comprise the procedural document reference number, title, effective date and document type (for all standard operating procedures, work instructions, manuals etc.). Procedures belonging to service providers and other third parties should be clearly identified. Documents relating to specific local/country procedures need not be listed, but a list may be requested on a per country basis. If no or only some countries use specific local procedures, this should be indicated (and the names of the applicable countries provided).

II.B.4.6. PSMF section on pharmacovigilance system performance

The PSMF should contain evidence of the ongoing monitoring of performance of the pharmacovigilance system including compliance of the main outputs of pharmacovigilance. The PSMF should include a description of the monitoring methods applied and contain as a minimum:

  • An explanation of how the correct reporting of ICSRs is assessed. In the annex, figures/graphs should be provided to show the timeliness of 15-day and 90-day reporting over the past year;
  • A description of any metrics used to monitor the quality of submissions and performance of pharmacovigilance. This should include information provided by competent authorities regarding the quality of ICSR reporting, PSURs or other submissions;
  • An overview of the timeliness of PSUR reporting to competent authorities in the EU (the annex should reflect the latest figures used by the marketing authorisation holder to assess compliance);
  • An overview of the methods used to ensure timeliness of safety variation submissions compared to internal and competent authority deadlines, including the tracking of required safety variations that have been identified but not yet been submitted;
  • Where applicable, an overview of adherence to risk management plan commitments, or other obligations or conditions of marketing authorisation(s) relevant to pharmacovigilance.

Targets for the performance of the pharmacovigilance system shall be described and explained. A list of performance indicators must be provided in the Annex to the PSMF [IR Art 3(6) and Art 9], alongside the results of (actual) performance measurements.

II.B.4.7. PSMF section on quality system

A description of the quality management system should be provided, in terms of the structure of the organisation and the application of the quality to pharmacovigilance. This shall include:

Document and Record Control

A description of the archiving arrangements for electronic and/or hardcopy versions of the PSMF should be provided, as well as an overview of the procedures applied to other quality system and pharmacovigilance records and documents (see also GVP Module I).

Procedural documents

  • A general description of the types of documents used in pharmacovigilance (standards, operating procedures, work instructions etc), the applicability of the various documents at global, regional or local level within the organisation, and the controls that are applied to their accessibility, implementation and maintenance.
  • Information about the documentation systems applied to relevant procedural documents under the control of third parties.

A list of specific procedures and processes related to the pharmacovigilance activities and interfaces with other functions, with details of how the procedures can be accessed must be provided [IR Art 2(5)(a)] and the detailed guidance for the inclusion of these is in section II.B.4.5.

Training

  • A description of the resource management for the performance of pharmacovigilance activities:
    • the organisational chart giving the number of people (full time equivalents) involved in pharmacovigilance activities, which may be provided in the section describing the organisational structure (see II.B.4.3.)
  • Information about sites where the personnel are located (this is described under sections II.B.4.2. and II.B.4.3.) whereby the sites are provided in the PSMF in relation to the organisation of specific pharmacovigilance activities and in the Annexes which provide the list of site contacts for sources of safety data. However, a description should be provided in order to explain the training organisation in relation to the personnel and site information;
  • A summary description of the training concept, including a reference to the location training files.

Staff should be appropriately trained for performing pharmacovigilance related activities and this includes not only staff within pharmacovigilance departments but also any individual that may receive safety reports.

Auditing

Information about quality assurance auditing of the pharmacovigilance system should be included in the PSMF. A description of the approach used to plan audits of the pharmacovigilance system and the reporting mechanism and timelines should be provided, with a current list of the scheduled and completed audits concerning the pharmacovigilance system maintained in the annex referred to II.B.4.8. [IR Art 3(5)]. This list should describe the date(s) (of conduct and of report), scope and completion status of audits of service providers, specific pharmacovigilance activities or sites undertaking pharmacovigilance and their operational interfaces relevant to the fulfilment of the obligations in the Directive 2001/83/EC, and cover a rolling 5 year period.

The PSMF shall also contain a note associated with any audit where significant findings are raised. This means that the presence of findings that fulfil the EU criteria for major or critical findings must be indicated (see GVP Module IV). The audit report must be documented within the quality system; in the PSMF it is sufficient to provide a brief description of the corrective and/or preventative action(s) associated with the significant finding, the date it was identified and the anticipated resolution date(s), with cross reference to the audit report and the documented corrective and preventative action plan(s). In case corrective and preventative action plan(s) have not yet been agreed for a particular audit or finding, the PSMF should include the note required and stating that “corrective and preventative action plan(s) are to be agreed”. In the annex, in the list of audits conducted, those associated with unresolved notes in the PSMF, should be identified. The note and associated corrective and preventative action(s), shall be documented in the PSMF until the corrective and/or preventative action(s) have been fully implemented, that is, the note is only removed once corrective action and/or sufficient improvement can be demonstrated or has been independently verified [DIR Art 104(2)]. The addition, amendment or removal of the notes must therefore be recorded in the logbook.

As a means of managing the pharmacovigilance system, and providing a basis for audit or inspection, the PSMF should also describe the process for recording, managing and resolving deviations from the quality system. The master file shall also document deviations from pharmacovigilance procedures, their impact and management until resolved [IR Art 4(3)]. This may be documented in the form of a list referencing a deviation report, and its date and procedure concerned.

II.B.4.8. Annex to the PSMF

An annex to the PSMF shall contain the following documents:

  • A list of medicinal products covered by the PSMF including the name of the medicinal product, the international non-proprietary name of the active substance(s), and the Member State(s) in which the authorisation is valid [IR Art 3];

The list of medicinal products authorised in the EU should also include the authorisation number(s) including, per authorisation:

    • the type of procedure for authorisation and procedure number (e.g. centrally authorised, nationally authorised products, including those authorised through the mutual recognition or the decentralised procedure);
    • the Rapporteur country or Reference Member State;
    • the presence on the market in the EU [DIR Art 23(a), REG Art 13(4)];
    • other (non EU) territories where the product is authorised or on the market

The list should be organised per active substance and, where applicable, should indicate what type of product specific safety monitoring requirements exist (for example risk minimisation measures contained in the risk management plan or laid down as conditions of the marketing authorisation, non-standard PSUR periodicity, referral under Article 31 of Directive 2001/83/EC, or included in the list described in Article 23 of Regulation (EC) No 726/2004). The monitoring information may be provided as a secondary list.

For marketing authorisations that are included in a different pharmacovigilance system, for example, because the MAH has more than one pharmacovigilance system or third party agreements exist to delegate the system, reference to the additional PSMF(s) should also be provided as a separate list in the Annexes, such that, for a MAH, the entire product portfolio can be related to the set of PSMFs.

Where pharmacovigilance systems are shared, all products that utilise the pharmacovigilance system should be included, so that the entire list of products covered by the file is available. The products lists may be presented separately, organised per MAH. Alternatively, a single list may be used, which is supplemented with the name of the MAH(s) for each product, or a separate note can be included to describe the product(s) and the MAH(s) covered;