Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the Council and Directive 2001/83/EC of the European Parliament and of the Council Text with EEA relevance

CHAPTER I

Pharmacovigilance system master file

Article 1

Structure of the pharmacovigilance system master file

All medicinal products for which the marketing authorisation holder obtained a marketing authorisation in accordance with Directive 2001/83/EC or Regulation (EC) No 726/2004 shall be covered by a pharmacovigilance system master file.

Article 2

Content of the pharmacovigilance system master file

The pharmacovigilance system master file shall contain at least all of the following elements:

(1) the following information relating to the qualified person responsible for pharmacovigilance: (a) a description of the responsibilities demonstrating that the qualified person responsible for pharmacovigilance has sufficient authority over the pharmacovigilance system in order to promote, maintain and improve compliance with pharmacovigilance tasks and responsibilities; (b) a summary curriculum vitae of the qualified person responsible for pharmacovigilance, including proof of registration with the Eudravigilance database; (c) contact details of the qualified person responsible for pharmacovigilance; (d) details of back-up arrangements to apply in the absence of the qualified person responsible for pharmacovigilance; (e) 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;

(2) a description of the organisational structure of the marketing authorisation holder, including the list of the site(s) where the following pharmacovigilance activities are undertaken: individual case safety report collection, evaluation, safety database case entry, periodic safety update report production, signal detection and analysis, preparation, implementation and maintenance of a risk management plan, pre- and post-authorisation study management, and management of safety variations of the terms of a marketing authorisation.

(3) a description of the location of, functionality of 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;

(4) a description of data handling and recording and of the process used for each of the following pharmacovigilance activities: (a) the continuous monitoring of the risk-benefit balance of the medicinal product(s), the result of that monitoring and the decision-making process for taking appropriate measures; (b) operation of the risk management system(s) and of the monitoring of the outcome of risk minimisation measures; (c) collection, assessment and reporting of individual case safety reports; (d) drafting and submission of periodic safety update reports; (e) procedures for communicating safety concerns and safety variations to the summary of product characteristics and package leaflet to healthcare professionals and the general public;

(5) a description of the quality system for the performance of pharmacovigilance activities, including all of the following elements: (a) a description of the management of human resources referred to in Article 10 containing the following elements: a description of the organisational structure for the performance of pharmacovigilance activities with a reference to the location of qualification records of the personnel; a summary description of the training concept, including a reference to the location of training files; instructions on critical processes; (b) a description of the record management system referred to in Article 12, including the location of the documents used for pharmacovigilance activities; (c) a description of the system for monitoring the performance of the pharmacovigilance system and for the compliance with Article 11;

(6) where applicable, a description of the activities and/or services subcontracted by the marketing authorisation holder in accordance with Article 6(1).

Article 3

Content of the Annex to the pharmacovigilance system master file

The pharmacovigilance system master file shall have an Annex containing the following documents:

(1) a list of medicinal products covered by the pharmacovigilance system master file, including the name of the medicinal product, the international non-proprietary name (INN) of the active substance(s), and the Member State(s) in which the authorisation is valid;

(2) a list of written policies and procedures for the purpose of complying with Article 11(1);

(3) the list of subcontracts referred to in Article 6(2);

(4) a list of the tasks that have been delegated by the qualified person for pharmacovigilance;

(5) a list of all scheduled and completed audits;

(6) where applicable, a list of the performance indicators referred to in Article 9;

(7) where applicable, a list of other pharmacovigilance system master files held by the same marketing authorisation holder;

(8) a logbook containing the information referred to in Article 5(4).

Article 4

Maintenance

Article 5

Form of the documents contained in the pharmacovigilance system master file

Article 6

Subcontracting

Without prejudice to the second sentence of paragraph 1 and to Article 11(2), the marketing authorisation holder shall include in the subcontracts the following elements:

(a) a clear description of the roles and responsibilities of the third parties to whom pharmacovigilance activities are subcontracted;

(b) obligation of third parties to exchange with the marketing authorisation holder safety data and the method for exchanging safety data, if relevant;

(c) arrangements for inspection and auditing process of third parties;

(d) obligation of the third parties to agree to be audited by or on behalf of the marketing authorisation holder and inspected by competent authorities.

This paragraph applies mutatis mutandis to the third parties that subcontract the tasks subcontracted to them by the marketing authorisation holder.

Article 7

Availability and location of the pharmacovigilance system master file

Where the pharmacovigilance system master file is kept in electronic form in accordance with Article 5(3), it is sufficient for the purposes of this Article that the data stored in electronic form is directly available at the site where the pharmacovigilance system master file is kept.

CHAPTER II

Minimum requirements for the quality systems for the performance of pharmacovigilance activities

Section 1

General provisions

Article 8

Quality system

The quality system shall be based on all of the following activities:

(a) quality planning: establishing structures and planning integrated and consistent processes;

(b) quality adherence: carrying out tasks and responsibilities in accordance with quality requirements;

(c) quality control and assurance: monitoring and evaluating how effectively the structures and processes have been established and how effectively the processes are being carried out;

(d) quality improvements: correcting and improving the structures and processes where necessary.

Article 9

Performance indicators

Section 2

Minimum requirements for the quality systems for the performance of pharmacovigilance activities by marketing authorisation holders

Article 10

Management of human resources

For the purposes of the first subparagraph, the market authorisation holder shall ensure that the qualified person responsible for pharmacovigilance has acquired adequate theoretical and practical knowledge for the performance of pharmacovigilance activities. Where the qualified person has not completed basic medical training in accordance with Article 24 of Directive 2005/36/EC of the European Parliament and of the Council of 7 September 2005 on the recognition of professional qualifications (²), the market authorisation holder shall ensure that the qualified person responsible for pharmacovigilance is assisted by a medically trained person. This assistance shall be duly documented.

Article 11

Compliance management

Specific quality system procedures and processes shall be in place in order to ensure the following:

(a) the continuous monitoring of pharmacovigilance data, the examination of options for risk minimisation and prevention and appropriate measures are taken by the marketing authorisation holder;

(b) the scientific evaluation by the marketing authorisation holder of all information on the risks of medicinal products, as referred to in the second subparagraph of Article 101(1) of Directive 2001/83/EC;

(c) the submission of accurate and verifiable data on serious and non-serious adverse reactions to the Eudravigilance database within the time limits provided for in the first and second subparagraphs respectively of Article 107(3) of Directive 2001/83/EC;

(d) the quality, integrity and completeness of the information submitted on the risks of medicinal products, including processes to avoid duplicate submissions;

(e) effective communication by the marketing authorisation holder with the national competent authorities and the Agency, including communication on new risks or changed risks, the pharmacovigilance system master file, risk management systems, risk minimisation measures, periodic safety update reports, corrective and preventive actions, and post-authorisation studies;

(f) the update of product information by the marketing authorisation holder in the light of scientific knowledge, including the assessments and recommendations made public via the European medicines web-portal, and on the basis of a continuous monitoring by the marketing authorisation holder of information published on the European medicines web-portal;

(g) appropriate communication by the marketing authorisation holder of relevant safety information to healthcare professionals and patients.

Article 12

Record management and data retention

Marketing authorisation holders shall put in place a record management system for all documents used for pharmacovigilance activities that ensures the retrievability of those documents as well as the traceability of the measures taken to investigate safety concerns, of the timelines for those investigations and of decisions on safety concerns, including their date and the decision-making process.

Marketing authorisation holders shall establish mechanisms enabling the traceability and follow-up of adverse reaction reports.

Pharmacovigilance data and documents relating to individual authorised medicinal products shall be retained as long as the product is authorised and for at least 10 years after the marketing authorisation has ceased to exist. However, the documents shall be retained for a longer period where Union law or national law so requires.

Article 13

Audit

Section 3

Minimum requirements for the quality systems for the performance of pharmacovigilance activities by national competent authorities and the Agency

Article 14

Management of human resources

The organisational structures and the distribution of tasks and responsibilities shall be clear and, to the extent necessary, accessible. Contact points shall be established.

Article 15

Compliance management

The national competent authorities and the Agency shall establish specific procedures and processes in order to achieve all of the following objectives:

(a) ensuring the evaluation of the quality, including completeness, of pharmacovigilance data submitted;

(b) ensuring the assessment of pharmacovigilance data and its processing within the timelines provided by Directive 2001/83/EC and Regulation (EC) No 726/2004;

(c) ensuring independence in the performance of pharmacovigilance activities;

(d) ensuring effective communication among national competent authorities and between the national competent authorities and the Agency as well as with patients, healthcare professionals, marketing authorisation holders and the general public;

(e) guaranteeing that the national competent authorities and the Agency inform each other and the Commission of their intention to make announcements relating to the safety of a medicinal product authorised in several Member States or an active substance contained in such a medicinal product in accordance with Article 106a of Directive 2001/83/EC;

(f) conducting inspections, including pre-authorisation inspections.

Article 16

Record management and data retention

They shall put in place a record management system for all documents used for pharmacovigilance activities that ensures the retrievability of those documents as well as the traceability of the measures taken to investigate safety concerns, of the timelines for those investigations and of decisions on safety concerns, including their date and the decision-making process.

Pharmacovigilance data and documents relating to individual authorised medicinal products shall be retained as long as the product is authorised and for at least 10 years after the marketing authorisation has expired. However, the documents shall be retained for a longer period where Union law or national law so requires.

Article 17

Audit

CHAPTER III

Minimum requirements for the monitoring of data in the Eudravigilance database

Article 18

General requirements

Article 19

Identification of changed risks and new risks

For the purposes of this chapter, ‘signal’ means information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, which is judged to be of sufficient likelihood to justify verificatory action.

For the purpose of monitoring data in the Eudravigilance database, only signals related to a suspected adverse reaction shall be considered.

Article 20

Methodology for determining the evidentiary value of a signal

Article 21

Signal management process

For the purposes of this Article, ‘signal validation’ means the process of evaluating the data supporting the detected signal in order to verify that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal.

Where it is considered that a signal validated by a national competent authority or the Agency requires further analysis, it shall be confirmed as soon as possible and no later than 30 days from its receipt as follows:

(a) where the signal concerns a product authorised in accordance with Directive 2001/83/EC, it shall be confirmed by the competent authority of a Member State in which the medicinal product is marketed or of any lead Member State or co-leader appointed in accordance with Article 22(1);

(b) where the signal concerns a product authorised in accordance with Regulation (EC) No 726/2004, it shall be confirmed by the Agency in collaboration with the Member States.

When analysing the validated signal, national competent authorities and the Agency may take into account other information available on the medicinal product.

Where the validity of the signal is not confirmed, special attention shall be paid to non-confirmed signals concerning a medicinal product where those signals are subsequently followed by new signals concerning the same medicinal product.

Article 22

Worksharing for signal management

The lead Member State shall monitor the Eudravigilance database and shall validate and confirm signals in accordance with Article 21(3) and (4) on behalf of the other Member States. The Member State appointed as co-leader shall assist the lead Member State in the fulfilment of its tasks.

Article 23

Signal detection support

The Agency shall support the monitoring of the Eudravigilance database by providing national competent authorities with access to the following information:

(a) data outputs and statistical reports allowing a review of all adverse reactions reported to the Eudravigilance database in relation to an active substance or a medicinal product;

(b) customised queries supporting the evaluation of individual case safety reports and case series;

(c) customised grouping and stratification of data enabling the identification of patient groups with a higher risk of occurrence of adverse reactions or with a risk of a more severe adverse reaction;

(d) statistical signal detection methods.

The Agency shall also ensure appropriate support for the use of the Eudravigilance database by marketing authorisation holders.

Article 24

Signal detection audit trail

CHAPTER IV

Use of terminology, formats and standards

Article 25

Use of internationally agreed terminology

For the classification, retrieval, presentation, risk-benefit evaluation and assessment, electronic exchange and communication of pharmacovigilance and medicinal product information, Member States, marketing authorisation holders and the Agency shall use the following terminology:

(a) the Medical Dictionary for Regulatory Activities (MedDRA) as developed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), multidisciplinary topic M1;

(b) the lists of Standard Terms published by the European Pharmacopoeia Commission;

(c) the terminology set out in EN ISO 11615:2017 Health Informatics, Identification of Medicinal Products (IDMP) standard, Data elements and structures for the unique identification and exchange of regulated medicinal product information;

(d) the terminology set out in EN ISO 11616:2017 Health Informatics, Identification of Medicinal Products (IDMP) standard, Data elements and structures for unique identification and exchange of regulated pharmaceutical product information;

(e) the terminology set out in EN ISO 11238:2018 Health Informatics, Identification of Medicinal Products (IDMP) standard, Data elements and structures for the unique identification and exchange of regulated information on substances;

(f) the terminology set out in EN ISO 11239:2023 Health Informatics, Identification of Medicinal Products (IDMP) standard, Data elements and structures for the unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation, routes of administration and packaging;

(g) the terminology set out in EN ISO 11240:2012 Health Informatics, Identification of Medicinal Products (IDMP) standard, Data elements and structures for the unique identification and exchange of units of measurement.

Article 26

Use of internationally agreed formats and standards