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Dokument 02012R0520-20250812
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)
Konsolidirano besedilo: 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)
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)
This consolidated text may not include the following amendments:
| Amending act | Amendment type | Subdivision concerned | Date of effect |
|---|---|---|---|
| 32025R1466 | Modified by | article 34 paragraph 3 | 12/02/2026 |
| 32025R1466 | Modified by | article 6 paragraph 4 | 12/02/2026 |
| 32025R1466 | Modified by | article 13 paragraph 1 | 12/02/2026 |
| 32025R1466 | Modified by | annex II part III point 16.5 | 12/02/2026 |
| 32025R1466 | Modified by | article 2 point 2 | 12/02/2026 |
| 32025R1466 | Modified by | article 26 paragraph 1 point (a) | 12/02/2026 |
| 32025R1466 | Modified by | article 21 paragraph 3 | 12/02/2026 |
| 32025R1466 | Modified by | article 28 paragraph 3 point (i) | 12/02/2026 |
| 32025R1466 | Modified by | article 36 paragraph 5 | 12/02/2026 |
| 32025R1466 | Modified by | article 11 paragraph 1 point (d) | 12/02/2026 |
| 32025R1466 | Modified by | article 6 paragraph 3 | 12/02/2026 |
| 32025R1466 | Modified by | article 13 paragraph 1a | 12/02/2026 |
| 32025R1466 | Modified by | annex III part 3 point 5 point (f) | 12/02/2026 |
| 32025R1466 | Modified by | article 4 paragraph 3 | 12/02/2026 |
| 32025R1466 | Modified by | article 28 paragraph 3 point (b) | 12/02/2026 |
| 32025R1466 | Modified by | article 25 paragraph 2 | 12/02/2026 |
| 32025R1466 | Modified by | article 19 paragraph 1 unnumbered paragraph 3 | 12/02/2026 |
| 32025R1466 | Modified by | article 17 paragraph 1 | 12/02/2026 |
| 32025R1466 | Modified by | article 26 paragraph 2 | 12/02/2026 |
| 32025R1466 | Modified by | article 23 unnumbered paragraph 2 | 12/02/2026 |
| 32025R1466 | Modified by | article 25 paragraph 1 | 12/02/2026 |
| 32025R1466 | Modified by | article 21 paragraph 4 | 12/02/2026 |
| 32025R1466 | Modified by | article 28 paragraph 1 unnumbered paragraph 2 | 12/02/2026 |
02012R0520 — EN — 12.08.2025 — 001.001
This text is meant purely as a documentation tool and has no legal effect. The Union's institutions do not assume any liability for its contents. The authentic versions of the relevant acts, including their preambles, are those published in the Official Journal of the European Union and available in EUR-Lex. Those official texts are directly accessible through the links embedded in this document
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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 (OJ L 159 20.6.2012, p. 5) |
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COMMISSION IMPLEMENTING REGULATION (EU) 2025/1466 of 22 July 2025 |
L 1466 |
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23.7.2025 |
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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:
the following information relating to the qualified person responsible for pharmacovigilance:
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;
a summary curriculum vitae of the qualified person responsible for pharmacovigilance, including proof of registration with the Eudravigilance database;
contact details of the qualified person responsible for pharmacovigilance;
details of back-up arrangements to apply in the absence of the qualified person responsible for pharmacovigilance;
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 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, risk management plan management, pre- and post-authorisation study management, and management of safety variations to the terms of a marketing authorisation;
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;
a description of data handling and recording and of the process used for each of the following pharmacovigilance activities:
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;
operation of the risk management system(s) and of the monitoring of the outcome of risk minimisation measures;
collection, assessment and reporting of individual case safety reports;
drafting and submission of periodic safety update reports;
procedures for communicating safety concerns and safety variations to the summary of product characteristics and package leaflet to healthcare professionals and the general public;
a description of the quality system for the performance of pharmacovigilance activities, including all of the following elements:
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;
a description of the record management system referred to in Article 12, including the location of the documents used for pharmacovigilance activities;
a description of the system for monitoring the performance of the pharmacovigilance system and for the compliance with Article 11;
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:
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;
a list of written policies and procedures for the purpose of complying with Article 11(1);
the list of subcontracts referred to in Article 6(2);
a list of the tasks that have been delegated by the qualified person for pharmacovigilance;
a list of all scheduled and completed audits;
where applicable, a list of the performance indicators referred to in Article 9;
where applicable, a list of other pharmacovigilance system master files held by the same marketing authorisation holder;
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
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
Article 8
Quality system
The quality system shall be based on all of the following activities:
quality planning: establishing structures and planning integrated and consistent processes;
quality adherence: carrying out tasks and responsibilities in accordance with quality requirements;
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;
quality improvements: correcting and improving the structures and processes where necessary.
Article 9
Performance indicators
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:
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;
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;
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;
the quality, integrity and completeness of the information submitted on the risks of medicinal products, including processes to avoid duplicate submissions and to validate signals in accordance with Article 21(2);
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;
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;
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
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:
ensuring the evaluation of the quality, including completeness, of pharmacovigilance data submitted;
ensuring the assessment of pharmacovigilance data and its processing within the timelines provided by Directive 2001/83/EC and Regulation (EC) No 726/2004;
ensuring independence in the performance of pharmacovigilance activities;
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;
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;
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 an 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.
▼M1 —————
Where it is considered that a validated signal requires further analysis, it shall be confirmed as soon as possible and no later than 30 days from its receipt as follows:
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);
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:
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;
customised queries supporting the evaluation of individual case safety reports and case series;
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;
statistical signal detection methods.
The Agency shall also ensure appropriate support for the monitoring 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 apply the following terminology:
the Medical Dictionary for Regulatory Activities (MedDRA) as developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), multidisciplinary topic M1;
the lists of Standard Terms published by the European Pharmacopoeia Commission;
the terminology set out in EN ISO 11615:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of regulated medicinal product information’ (ISO/FDIS 11615:2012);
the terminology set out in EN ISO 11616:2012 Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of regulated pharmaceutical product information’ (ISO/FDIS 11616:2012);
the terminology set out in EN ISO 11238:2012 Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of regulated information on substances’ (ISO/FDIS 11238:2012);
the terminology set out in EN ISO 11239:2012 Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation and routes of administration’ (ISO/FDIS 11239:2012);
the terminology set out in EN ISO 11240:2012 Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of units of measurement’ (ISO/FDIS 11240:2012).
Article 26
Use of internationally agreed formats and standards
For the description, retrieval, presentation, risk-benefit evaluation and assessment, electronic exchange and communication of pharmacovigilance and medicinal product information, national competent authorities, marketing authorisation holders and the Agency shall apply the following formats and standards:
the Extended Eudravigilance Medicinal Product Report Message (XEVPRM), which is the format for the electronic submission of information on all medicinal products for human use authorised in the Union in accordance with the second subparagraph of Article 57(2) of Regulation (EC) No 726/2004, as published by the Agency;
ICH E2B(R2) ‘Maintenance of the ICH guideline on clinical safety data management: data elements for transmission of Individual Case Safety Reports’;
ICH M2 standard ‘Electronic Transmission of Individual Case Safety Reports Message Specification’.
For the purpose of paragraph 1 national competent authorities, marketing authorisation holders and the Agency may also apply the following formats and standards:
EN ISO 27953-2:2011 Health Informatics, Individual case safety reports (ICSRs) in pharmacovigilance — Part 2: Human pharmaceutical reporting requirements for ICSR (ISO 27953-2:2011);
EN ISO 11615:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of regulated medicinal product information’ (ISO/FDIS 11615:2012);
EN ISO 11616:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard ‘Data elements and structures for unique identification and exchange of regulated pharmaceutical product information’ (ISO/FDIS 11616:2012);
EN ISO 11238:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of regulated information on substances’ (ISO/FDIS 11238:2012);
EN ISO 11239:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation and routes of administration’ (ISO/FDIS 11239:2012);
EN ISO 11240:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard, ‘Data elements and structures for unique identification and exchange of units of measurement’ (ISO/FDIS 11240:2012).
CHAPTER V
Transmission of reports of suspected adverse reactions
Article 27
Individual case safety reports
Individual case safety reports shall be used for reporting to the Eudravigilance database suspected adverse reactions to a medicinal product that occur in a single patient at a specific point in time.
Article 28
Content of the individual case safety report
In the case of expedited reporting, the individual case safety report shall include at least an identifiable reporter, an identifiable patient, one suspected adverse reaction and the medicinal product(s) concerned.
When reporting suspected adverse reactions, Member States and marketing authorisation holders shall provide all available information on each individual case, including the following:
administrative information: report type, date and a worldwide unique case identification number as well as unique sender identification and sender type; the date on which the report was first received from the source and the date of receipt of the most recent information, using a precise date; other case identifiers and their sources, as well as references to additional available documents held by the sender of the individual case safety report, where applicable;
literature reference in accordance with the ‘Vancouver style’ as developed by the International Committee of Medical Journal Editors ( 3 ) for adverse reactions reported in the worldwide literature, including a comprehensive English summary of the article;
study type, study name and the sponsor’s study number or study registration number for reports from studies not covered by Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use ( 4 );
information on the primary source(s): information identifying the reporter, including Member State of residence and professional qualifications;
information identifying the patient (and parent in the case of a parent-child report), including age at the time of the onset of the first reaction, age group, gestation period when reaction/event was observed in the foetus, weight, height or gender, last menstrual date and/or gestation period at time of exposure;
relevant medical history and concurrent conditions;
the name, as defined in Article 1(20) of Directive 2001/83/EC, of the medicinal product(s) suspected to be related to the occurrence of the adverse reaction, including interacting medicinal products or, where the name is not known, the active substance(s) and any other characteristics that allow for the identification of the medicinal product(s), including the name of the marketing authorisation holder, marketing authorisation number, country of marketing authorisation, pharmaceutical form and (parent) route(s) of administration, indication(s) for use in the case, dose administered, start date and end date of administration, actions taken with the medicinal product(s), effect of the dechallenge and rechallenge for suspect medicinal products;
for biological medicinal product(s), the batch number(s);
concomitant medicinal products, identified in accordance with point (g), which are not suspected to be related to the occurrence of the adverse reaction and past-medical drug therapy for the patient (and for the parent), where applicable;
information on the suspected adverse reaction(s): start date and end date of the suspected adverse reaction(s) or duration, seriousness, outcome of the suspected adverse reaction(s) at the time of last observation, time intervals between suspect medicinal product administration and start of adverse reaction, the original reporter’s words or short phrases used to describe the reaction(s) and Member State or third-country of occurrence of the suspected adverse reaction;
results of tests and procedures relevant to the investigation of the patient;
date and reported cause of death, including autopsy-determined causes, in the event of death of the patient;
a case narrative, where possible, providing all relevant information for individual cases with the exception of non-serious adverse reactions;
reasons for nullifying or amending an individual case safety report.
For the purposes of point (b), upon request of the Agency, the marketing authorisation holder that transmitted the initial report shall provide a copy of the relevant article taking into account copyright restrictions, and a full translation of that article into English.
For the purposes of point (h), a follow-up procedure shall be in place to obtain the batch number where it is not indicated in the initial report.
For the purposes of point (m), the information shall be presented in a logical time sequence, in the chronology of the patient’s experience including clinical course, therapeutic measures, outcome and follow-up information obtained; any relevant autopsy or post-mortem findings shall also be summarised in the narrative.
Member States may report case narratives in their official language(s). For those reports, case translations shall be provided where requested by the Agency or other Member States for the evaluation of potential signals.
English shall be used for the reporting of suspected adverse reactions originating outside the Union.
Article 29
Format of electronic transmission of suspected adverse reactions
Member States and marketing authorisation holders shall use the formats provided for in Article 26 and the terminology provided for in Article 25 for the electronic transmission of suspected adverse reactions.
CHAPTER VI
Risk management plans
Article 30
Content of the risk management plan
The risk management plan established by the marketing authorisation holder shall contain the following elements:
an identification or characterisation of the safety profile of the medicinal product(s) concerned;
an indication of how to characterise further the safety profile of the medicinal product(s) concerned;
a documentation of measures to prevent or minimise the risks associated with the medicinal product, including an assessment of the effectiveness of those interventions;
a documentation of post-authorisation obligations that have been imposed as a condition of the marketing authorisation.
Article 31
Summary of the risk management plan
Article 32
Updates of the risk management plan
Article 33
Format of the risk management plan
The risk management plan shall be in the format set out in Annex I.
CHAPTER VII
Periodic safety update reports
Article 34
Content of periodic safety update reports
Article 35
Format of periodic safety update reports
CHAPTER VIII
Post-authorisation safety studies
Article 36
Scope
Article 37
Definitions
For the purposes of this chapter, the following definitions shall apply:
‘Start of data collection’ means the date from which information on the first study subject is first recorded in the study dataset or, in the case of the secondary use of data, the date from which data extraction starts;
‘End of data collection’ means the date from which the analytical dataset is completely available.
Article 38
Format of post-authorisation safety studies
Protocols, abstracts and final study reports for non-interventional post-authorisation safety studies shall be submitted in the format set out in Annex III.
CHAPTER IX
Final provisions
Article 39
Data protection
This Regulation shall apply without prejudice to the obligations of national competent authorities and marketing authorisation holders relating to their processing of personal data under Directive 95/46/EC or the obligations of the Agency relating to its processing of personal data under Regulation (EC) No 45/2001.
Article 40
Transitional provisions
Article 41
Entry into force and application
This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.
It shall apply from 10 July 2012.
This Regulation shall be binding in its entirety and directly applicable in all Member States.
ANNEX I
Risk management plans
Format of the risk management plan
The risk management plan shall consist of the following modules:
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Part I: |
Product(s) overview |
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Part II: |
Safety specification |
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Module SI: |
Epidemiology of the indication(s) and target population(s) |
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Module SII: |
Non-clinical part of the safety specification |
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Module SIII: |
Clinical trial exposure |
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Module SIV: |
Populations not studied in clinical trials |
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Module SV: |
Post-authorisation experience |
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Module SVI: |
Additional EU requirements for the safety specification |
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Module SVII: |
Identified and potential risks |
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Module SVIII: |
Summary of the safety concerns |
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Part III: |
Pharmacovigilance plan (including post-authorisation safety studies) |
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Part IV: |
Plans for post-authorisation efficacy studies |
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Part V: |
Risk minimisation measures (including evaluation of the effectiveness of risk minimisation activities) |
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Part VI: |
Summary of the risk management plan |
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Part VII: |
Annexes |
ANNEX II
Format of the electronic periodic safety update reports
The periodic safety update report shall consist of the following modules:
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Part I |
Title page including signature |
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Part II |
Executive Summary |
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Part III |
Table of contents |
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1. |
Introduction |
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2. |
Worldwide marketing authorisation status |
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3. |
Actions taken in the reporting interval for safety reasons |
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4. |
Changes to reference safety information |
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5. |
Estimated exposure and use patterns |
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5.1. |
Cumulative subject exposure in clinical trials |
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5.2. |
Cumulative and interval patient exposure from marketing experience |
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6. |
Data in summary tabulations |
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6.1. |
Reference information |
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6.2. |
Cumulative summary tabulations of serious adverse events from clinical trials |
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6.3. |
Cumulative and interval summary tabulations from post-marketing data sources |
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7. |
Summaries of significant findings from clinical trials during the reporting interval |
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7.1. |
Completed clinical trials |
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7.2. |
Ongoing clinical trials |
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7.3. |
Long-term follow-up |
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7.4. |
Other therapeutic use of medicinal product |
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7.5. |
New safety data related to fixed combination therapies |
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8. |
Findings from non-interventional studies |
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9. |
Information from other clinical trials and sources |
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10. |
Non-clinical data |
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11. |
Literature |
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12. |
Other periodic reports |
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13. |
Lack of efficacy in controlled clinical trials |
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14. |
Late-breaking information |
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15. |
Overview on signals: New, ongoing or closed |
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16. |
Signal and risk evaluation |
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16.1. |
Summaries of safety concerns |
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16.2. |
Signal evaluation |
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16.3. |
Evaluation of risks and new information |
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16.4. |
Characterisation of risks |
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16.5. |
Effectiveness of risk minimisation (if applicable) |
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17. |
Benefit evaluation |
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17.1. |
Important baseline efficacy and effectiveness information |
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17.2. |
Newly identified information on efficacy and effectiveness |
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17.3. |
Characterisation of benefits |
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18. |
Integrated benefit-risk analysis for authorised indications |
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18.1. |
Benefit-risk context — Medical need and important alternatives |
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18.2. |
Benefit-risk analysis evaluation |
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19. |
Conclusions and actions |
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20. |
Appendices to the periodic safety update report |
ANNEX III
Protocols, abstracts and final study reports for post-authorisation safety studies
1. Format of the study protocol
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1. |
Title: informative title including a commonly used term indicating the study design and the medicinal product, substance or drug class concerned, and a sub-title with a version identifier and the date of the last version. |
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2. |
Marketing authorisation holder. |
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3. |
Responsible parties including a list of all collaborating institutions and other relevant study sites. |
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4. |
Abstract: stand-alone summary of the study protocol, including the following subsections:
(a)
title with subtitles including version and date of the protocol and name and affiliation of the main author;
(b)
rationale and background;
(c)
research question and objectives;
(d)
study design;
(e)
population;
(f)
variables;
(g)
data sources;
(h)
study size;
(i)
data analysis;
(j)
milestones. |
|
5. |
Amendments and updates: any substantial amendment and update to the study protocol after the start of data collection, including a justification for the amendment or update, the date of the change, and a reference to the section of the protocol where the change has been made. |
|
6. |
Milestones: table with planned dates for the following milestones:
(a)
start of data collection;
(b)
end of data collection;
(c)
study progress report(s) as referred to in Article 107m(5) of Directive 2001/83/EC;
(d)
interim report(s) of study results, if applicable;
(e)
final report of study results. |
|
7. |
Rationale and background: description of the safety hazard(s), the safety profile or the risk management measures that led to the study being imposed as an obligation for a marketing authorisation. |
|
8. |
Research question and objectives in accordance with the decision of the national competent authority that imposed the study as an obligation. |
|
9. |
Research methods: description of the research methods, including:
(a)
study design;
(b)
setting: study population defined in terms of persons, place, time period, and selection criteria, including the rationale for any inclusion and exclusion criteria. Where any sampling from a source population is undertaken, a description of the source population and details of sampling methods shall be provided. Where the study design is a systematic review or a meta-analysis, the criteria for the selection and eligibility of studies shall be explained;
(c)
variables;
(d)
data sources: strategies and data sources for determining exposures, outcomes and all other variables relevant to the study objectives. Where the study will use an existing data source, such as electronic health records, any information on the validity of the recording and coding of the data shall be reported. In the case of a systematic review or meta-analysis, the search strategy and processes and any methods for confirming data from investigators shall be described;
(e)
study size: any projected study size, precision sought for study estimates and any calculation of the study size that can minimally detect a pre-specified risk with a pre-specified interpretative power;
(f)
data management;
(g)
data analysis;
(h)
quality control;
(i)
limitations of the research methods. |
|
10. |
Protection of human subjects: safeguards in order to comply with national and Union requirements for ensuring the well-being and rights of participants in non-interventional post-authorisation safety studies. |
|
11. |
Management and reporting of adverse events/adverse reactions and other medically important events while the study is being conducted. |
|
12. |
Plans for disseminating and communicating study results. |
|
13. |
References. |
2. Format of the abstract of the final study report
|
1. |
Title, with subtitles including date of the abstract and name and affiliation of main author. |
|
2. |
Keywords (not more than five keywords indicating the main study characteristics). |
|
3. |
Rationale and background. |
|
4. |
Research question and objectives. |
|
5. |
Study design. |
|
6. |
Setting. |
|
7. |
Subjects and study size, including dropouts. |
|
8. |
Variables and data sources. |
|
9. |
Results. |
|
10. |
Discussion (including, where relevant, an evaluation of the impact of study results on the risk–benefit balance of the product). |
|
11. |
Marketing authorisation holder. |
|
12. |
Names and affiliations of principal investigators. |
3. Format of the final study report
|
1. |
Title: title including a commonly used term indicating the study design; sub-titles with date of final report and name and affiliation of the main author. |
|
2. |
Abstract: stand-alone summary referred to in Section 2 of this Annex. |
|
3. |
Marketing authorisation holder: name and address of the marketing authorisation holder. |
|
4. |
Investigators: names, titles, degrees, addresses and affiliations of the principal investigator and all co-investigators, and list of all collaborating primary institutions and other relevant study sites. |
|
5. |
Milestones: dates for the following milestones:
(a)
start of data collection (planned and actual dates);
(b)
end of data collection (planned and actual dates);
(c)
study progress reports;
(d)
interim reports of study results, where applicable;
(e)
final report of study results (planned and actual date);
(f)
any other important milestone applicable to the study, including date of study registration in the electronic study register. |
|
6. |
Rationale and background: description of the safety concerns that led to the study being initiated, and critical review of relevant published and unpublished data evaluating pertinent information and gaps in knowledge that the study is intended to fill. |
|
7. |
Research question and objectives. |
|
8. |
Amendments and updates to the protocol: list of any substantial amendments and updates to the initial study protocol after the start of data collection, including a justification for each amendment or update. |
|
9. |
Research methods 9.1. Study design: key elements of the study design and rationale for this choice. 9.2. Setting: setting, locations, and relevant dates for the study, including periods of recruitment, follow-up, and data collection. In the case of a systematic review or meta-analysis, study characteristics used as criteria for eligibility, with rationale. 9.3. Subjects: any source population and eligibility criteria for study subjects. Sources and methods for selection of participants shall be provided, including, where relevant, methods for case ascertainment, as well as number of and reasons for dropouts. 9.4. Variables: all outcomes, exposures, predictors, potential confounders, and effect modifiers, including operational definitions. Diagnostic criteria shall be provided, where applicable. 9.5. Data sources and measurement: for each variable of interest, sources of data and details of methods of assessment and measurement. If the study has used an existing data source, such as electronic health records, any information on the validity of the recording and coding of the data shall be reported. In the case of a systematic review or meta-analysis, description of all information sources, search strategy, methods for selecting studies, methods of data extraction and any processes for obtaining or confirming data from investigators. 9.6. Bias. 9.7. Study size: study size, rationale for any study size calculation and any method for attaining projected study size. 9.8. Data transformation: transformations, calculations or operations on the data, including how quantitative data were handled in the analyses and which groupings were chosen and why. 9.9. Statistical methods: description of the following items:
(a)
main summary measures;
(b)
all statistical methods applied to the study;
(c)
any methods used to examine subgroups and interactions;
(d)
how missing data were addressed;
(e)
any sensitivity analyses;
(f)
any amendment to the plan of data analysis included in the study protocol, with rationale for the change. 9.10. Quality control: mechanisms to ensure data quality and integrity. |
|
10. |
Results: comprising the following subsections:
10.1.
Participants: numbers of study subjects at each stage of study. In the case of a systematic review or meta-analysis, number of studies screened, assessed for eligibility and included in the review with reasons for exclusion at each stage.
10.2.
Descriptive data: characteristics of study participants, information on exposures and potential confounders and number of participants with missing data. In the case of a systematic review or meta-analysis, characteristics of each study from which data were extracted.
10.3.
Outcome data: numbers of study subjects across categories of main outcomes.
10.4.
Main results: unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision. Where relevant, estimates of relative risk shall be translated into absolute risk for a meaningful time period.
10.5.
Other analyses.
10.6.
Adverse events and adverse reactions. |
|
11. |
Discussion 11.1. Key results: key results with reference to the study objectives, prior research in support of and conflicting with the findings of the completed post-authorisation safety study, and, where relevant, the impact of the results on the risk–benefit balance of the product. 11.2. Limitations: limitations of the study taking into account circumstances that may have affected the quality or integrity of the data, limitations of the study approach and methods used to address them, sources of potential bias and imprecision, and validation of the events. Both the direction and magnitude of potential biases shall be discussed. 11.3. Interpretation: interpretation of results, considering objectives, limitations, multiplicity of analyses, results from similar studies and other relevant evidence. 11.4. Generalisability. |
|
12. |
References. |
( 1 ) OJ L 334, 24.11.2008, p. 7.
( 2 ) OJ L 255, 30.9.2005, p. 22.
( 3 ) International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. N Engl J Med 1997; 336:309-15.
( 4 ) OJ L 121, 1.5.2001, p. 34.