EN    EN  
 EUROPEAN COMMISSION 
Brussels, XXX   
PhV […](2011) XXX  draft 
  
COMMISSION IMPLEMENTING REGULATION (EU) No …/.. 
of XXX  
on the performance of pharmacovigilance activities provided for in Regulation (EC) No 
726/2004 and Directive 2001/83/EC 
(Text with EEA relevance) 
  
EN 2   EN COMMISSION IMPLEMENTING REGULATION (EU) No …/.. 
of XXX 
on the performance of pharmac ovigilance activities provided for in Regulation (EC) No 
726/2004 and Directive 2001/83/EC 
(Text with EEA relevance) 
THE EUROPEAN COMMISSION, 
Having regard to the Treaty on the Functioning of the European Union, Having regard to Regulation (EC) No 726/2004 of the European Parliament and of the 
Council of 31 March 2004 laying down Community procedures for the authorisation and 
supervision of medicinal products for human a nd veterinary use and establishing a European 
Medicines Agency
1, and in particular Article 87a thereof, 
Having regard to Directive 2001/83/EC of the Eu ropean Parliament and of the Council of 6 
November 2001 on the Community code relati ng to medicinal products for human use2, and 
in particular Article 108 thereof, 
Whereas: (1) Regulation (EU) No 1235/2010 of the European  Parliament and of the Council of 15 
December 2010 amending, as regards pharmac ovigilance of medicinal products for 
human use, Regulation (EC) No 726/2004 laying down Comm unity procedures for the 
authorisation and supervision of medicinal products for human a nd veterinary use and 
establishing a European Medicines Ag ency, and Regulation (EC) No 1394/2007 on 
advanced therapy medicinal products
3 strengthened and rationa lised the monitoring of 
the safety of medicines that have been placed on the market in the Union. Similar 
provisions were introduced by Directive 2010/84/EU of the European Parliament and 
of the Council of 15 December 2010 ame nding, as regards pharmacovigilance, 
Directive 2001/83/EC on the Community c ode relating to medicinal products for 
human use4 into Directive 2001/83/EC. 
(2) Regulation (EU) No 1235/2010 and Directiv e 2010/84/EU introduced the concept of 
the pharmacovigilance system master file . In order to accurately reflect the 
pharmacovigilance system used by the marketing authorisation holder, the 
pharmacovigilance system master file shoul d contain key information and documents 
                                                 
1 OJ L 136, 30.4.2004, p.1. 
2 OJ L 311, 28.11.2001, p. 67. 
3 OJ L 348, 31.12.2010, p. 1. 
4 OJ L 348, 31.12.2010, p. 74.  
EN 3   EN covering all aspects of pharmacovigilance activities, including information on tasks 
that have been delegated. Through the pr oduction of the pharmacovigilance system 
master file, the marketing authorisation hol der and its qualif ied person responsible for 
pharmacovigilance should be able to gain assurance that a pharmacovigilance system 
has been implemented in accordance with th e requirements. At the same time it should 
enable competent authorities to verify compliance concerning all aspects of the 
system. 
(3) The information contained in the pharmacovigi lance master file should be maintained 
so as to reflect any modifications that have been made and ensure easy accessibility and availability by competent authori ties for the purpose of inspections. 
(4) As required by Directive 2001/83/EC a nd Regulation (EC) No 726/2004, minimum 
requirements should be established for the quality systems for the performance of 
pharmacovigilance activities. Those requirements should ensure that marketing 
authorisation holders, nationa l competent authorities and the European Medicines 
Agency (hereinafter 'the Agency') establis h an adequate and effective quality system, 
which provides for the necessary resource s being attributed to pharmacovigilance 
activities, an effective monitoring of  compliance and the accurate and proper 
documentation of all measures taken. Adhere nce to a well-defined quality system 
should ensure that all pharmacovigilance act ivities are conducted in such a way that 
they produce, with estimated likelihoods , results relevant for the purpose of 
pharmacovigilance. 
(5) As part of their quality system, national competent authorities and the Agency should 
establish contact points to f acilitate interaction between na tional competent authorities, 
the Agency, the Commission, marketing author isation holders and persons re porting 
information in accordance with Article 101(1) of Directive 2001/83/EC 
(6) Pharmacovigilance activities  rely increasingly on the pe riodic monitoring of large 
databases, such as the Eudravigilance data base. Whereas the Eudravigilance database 
is expected to be a major source of pharmacovigilance information, account should 
also be taken of pharmacovigilance inform ation coming from other sources, such as 
sources not directly supported by the Eudravigilance database. 
(7) Marketing authorisation hol ders, national competent au thorities and the Agency 
should continuously monitor the data in th e Eudravigilance database to determine 
whether there are new risks or whether ri sks have changed and whether those risks 
have an impact on the risk-benefit balance. In this context, it is necessary to establish 
common requirements for signal detection, to clarify the respective monitoring roles of 
marketing authorisation holders, national co mpetent authorities and the Agency, to 
clarify how signals are iden tified and to specify the overall signal management 
process. 
(8) As a general principle, signal detection should follow a structured and recognised 
methodology. However, the methodology ma y vary depending on the type of 
medicinal product it is  intended to cover. 
(9) The use of internationally agreed terminol ogy, format and standards should facilitate 
the interoperability of systems used for the performance of pharmacovigilance 
activities and avoids  the duplication of encoding activities concerning the same  
EN 4   EN information. It also allows for an easie r information exchange between regulatory 
authorities on an international level. 
(10) In order to simplify the reporting of su spected adverse reactions, the marketing 
authorisation holder and the Member States  should report those re actions only to the 
Eudravigilance database. The Eudravigila nce database should be equipped to 
immediately forward reports on suspected ad verse reactions received from marketing 
authorisation holders to the Member States on whose territo ry the reaction occurred. It 
is therefore necessary to establish a comm on electronic format for the transmission of 
suspected adverse reactions to be used by marketing authorisation holders and 
Member States when electronically submitti ng reports to the Eudravigilance database. 
(11) Periodic safety update reports are an importa nt instrument to monitor the development 
of the safety profile of a medicinal produc t after it has been placed on the Union 
market, including an integrated  (re-)evaluation of the risk-b enefit balance. In order to 
facilitate their processing and evaluation, common format and content requirements 
should be established. 
(12) Risk management plans are required for a ll new marketing authorisation applications. 
They contain a detailed description of the risk management system used by the 
marketing authorisation holder. In orde r to facilitate the production of risk 
management plans and their evaluation by th e competent authorities, common format 
and content requirements should be established.  
(13) In order to clarify their scope and content, it is necessary to provide for rules 
concerning non-interventional pos t-authorisation safety stud ies that are imposed on 
marketing authorisation holder by competent authorities and involve  the collection of 
data from patients or healthcare professionals. In this context it is also appropriate to 
establish the format of protocols, abstract s and final study reports for those studies in 
order to facilitate the approval a nd oversight of those studies by the 
Pharmacovigilance Risk Assessment Committee. 
(14) This Regulation shall apply w ithout prejudice to Directive 95/46/EC of the European 
Parliament and of the Council of 24 Oct ober 1995 on the protectio n of individuals 
with regard to the processing of personal data and on the free movement of such data5 
and Regulation (EC) No 45/2001 of the Europ ean Parliament and of the Council of 18 
December 2000 on the protection of individuals  with regard to the processing of 
personal data by the Community institutions  and bodies and on the free movement of 
such data6. The fundamental right to  protection of personal da ta should be fully and 
effectively guaranteed in all pharmacovigilance activities. 
(15) The measures provided for in this Regulati on are in accordance with the opinion of the 
Standing Committee for Medicina l Products for Human Use, 
                                                 
5 OJ L 281, 23.11.1995, p. 31. 
6 OJ L 8, 12.1.2001, p. 1.  
EN 5   EN HAS ADOPTED THIS REGULATION: 
Article 1 
General scope 
This Regulation lays down rules on the pe rformance of pharmacovigilance activities by 
marketing authorisation holders, national competent authorities and the Agency. 
Pharmacovigilance activities cover the whole life-cycle management of medicinal products 
for human use in relation to safety. 
Chapter 1 
Pharmacovigilance sy stem master file 
Article 2 
Scope of the pharmacovigil ance system master file 
1. The information in the pharmacovigilance system  master file shall be accurate and reflect 
the current system in place. 
2. The marketing authorisation holder ma y, where appropriate, use separate 
pharmacovigilance systems for different categorie s of medicinal products. Each such system 
shall be described in a separate pharmacovig ilance system master file. Those files shall 
cumulatively cover all medicinal products fo r which the marketing authorisation holder 
obtained a marketing authorisation in acco rdance with Directive 2001/83/EC or an 
authorisation in accordance with Regulation (EC) No 726/2004. 
Article 3 
Content of the pharmacovigilance system master file 
The pharmacovigilance system master  file shall contain at least all of the following elements:  
(1) Information relating to the qualified person responsible for pharmacovigilance 
including all the following elements: 
(a) a description of the res ponsibilities demonstrating that the qualified person 
responsible for pharmacovigilance ha s sufficient authority over the 
pharmacovigilance system in order to  promote, maintain and improve 
compliance; 
(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 qua lified person responsible  for pharmacovigilance; 
(d) details of back-up arrangements to appl y in the absence of the qualified person 
responsible for pharmacovigilance;   
EN 6   EN (e) responsibilities of the cont act person for pharmacovigi lance issues where such 
a person has been nominated at nati onal level in accord ance with Article 
104(4) of Directive 2001/83/EC , including contact details. 
(2) A description of the organisa tional structure of the marketing authorisation holder, 
including the list of the s ite(s) where the pharmacovigila nce activities are undertaken 
covering individual case safety report coll ection, evaluation, safe ty database case 
entry, periodic safety update report produc tion, signal detection and analysis, risk 
management plan management, pre- and post-authorisation study management, and 
management of safety varia tions to product particulars. 
(3) A description of the location of, functiona lity 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 handli ng, recording and the process,  concerning the following 
pharmacovigilance activities: 
(a) A description of the continuous mon itoring of the product risk-benefit 
profile(s), the result of that monito ring and the decision-making process for 
taking appropriate measures; 
(b) a description of the risk management sy stem(s) and of the monitoring of the 
outcome of risk minimisation measures; 
(c) collection, assessment and reporting of individual case safety reports; 
(d) drafting of periodic safety update report and submission; 
(e) procedures for communicating safety c oncerns 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 fo r the performance of pharmacovigilance 
activities, including all of the following elements: 
(a) a list of documented procedures and pr ocesses related to pharmacovigilance 
activities and interfaces with other functions, with details of how documentation can be accessed; 
(b) a description of the management of hum an resources containing the following 
elements: the organisational chart indicating the number  of persons involved in 
pharmacovigilance activities with a reference to the location of their qualification records; a list of the sites where the staff is located; a summary description of the training concept, including a reference to the location of 
training files; instructions  on critical processes; 
(c) documentation arrangements and the locat ion of any records in relation to 
pharmacovigilance activities in accordance with Article 13;  
EN 7   EN (d) a description of the system for monitoring the performance of the 
pharmacovigilance system and the comp liance of the main outputs of the 
system in accordance with Article 12. 
(6) Where applicable, a description of the ac tivities and/or services delegated by the 
marketing authorisation holder relating to  the fulfilment of pharmacovigilance 
obligations in accordance with Article 7(1). 
Article 4 
Content of the annex to the pharma covigilance system master file 
The pharmacovigilance system master file sh all have an Annex c ontaining the following 
documents: 
(1) A list of medicinal products  covered by the pharmacovigila nce system master file, 
including the name of the me dicinal product, the international non-proprietary name 
(INN) of the active substance(s), and the Me mber State(s) in which the authorisation 
is valid; 
(2) A list of contractual agreements covering de legated activities including the medicinal 
products and territory(ies) concerned in accordance with Article 7(2); 
(3) A list of the tasks that have been  delegated by the qualified person for 
pharmacovigilance; 
(4) A list of all scheduled and completed audits; 
(5) Where applicable, a list of the performance indicators re ferred to in Article 10; 
(6) Where applicable, a list of other pharmacovi gilance system master files held by the 
same marketing authorisation holder; 
(7) A logbook in accordance with Article 6(5). 
Article 5 
Maintenance 
1. The marketing authorisation holder shall keep the pharmacovi gilance master file up to 
date and, where necessary, revise it to take account of experience gained, technical and 
scientific progress and of am endments to Directive 2001/83/ EC and Regulation (EC) No 
726/2004. 
2. The pharmacovigilance system master file and its Annex shall be  version-controlled 
and shall indicate the date when  it was last reviewed by the ma rketing authorisation holder. 
3. Any deviations from the pharmacovigila nce procedures, their impact and their 
management shall be documented in the pharmac ovigilance system master file until resolved. 
4. Without prejudice to other requirements, the marketing authorisation holder shall 
notify immediately the Agency of any change in  the location of the pharmacovigilance system  
EN 8   EN master file or changes to the contact details and name of the qualifie d person responsible for 
pharmacovigilance. The Agency shall update th e Eudravigilance database referred to in 
Article 24(1) of Regulation (EC) No 726/2004 a nd, where necessary, the European medicines 
web-portal referred to in Article 26(1) of Regulation (EC) No 726/2004 accordingly. 
Article 6 
Form of the documents cont ained in the master file 
1. Pharmacovigilance system master file docum ents shall be complete and legible. If 
appropriate, information may be  provided in the form of ch arts or flow diagrams. All 
documents shall be indexed and archived so as to ensure their accurate and ready retrieval 
throughout the period for record-keeping. 
2. The particulars and documents of the pharm acovigilance system master file may be 
presented in modules in accordance with the sy stem delineated in detail in the guidance on 
good pharmacovigilance practices. 
3. The pharmacovigilance system master file may be stored in electronic form provided 
that the media used for storage remain readable over time and a clearly arranged printed copy can be made available for audits and inspections. 
4. The marketing authorisation holder shall record in the l ogbook referred to in Article 
4(7) any alteration of the content of the pharmac ovigilance master file made within the last 
five years, with the exception of the informati on referred to in Arti cle 3(1)(b) to (e) and 
Article 4. The marketing author isation holder shall i ndicate in the logbook the date, the person 
responsible for the alterati on and, where appropriate, th e reason for the alteration. 
Article 7 
Delegation 
1. The marketing authorisation holder ma y subcontract certai n activities of the 
pharmacovigilance system to third parties. It shall nevertheless retain full responsibility for 
the completeness and accuracy of the pha rmacovigilance system master file. 
2. The marketing authorisation holder shall dr aw up a list of its ex isting subcontracts 
between it and the third partie s referred to in paragraph 1, including the product(s) and 
territory(ies) concerned. 
Article 8 
Availability and Accessibility 
1. The pharmacovigilance system master file sh all be located either at the site in the 
Union where the main pharmacovigilance activitie s of the marketing authorisation holder are 
performed or at the site where the qualifi ed person responsible for pharmacovigilance 
operates.  
For the purpose of this Article, it is immaterial whether in accordance with Article 6(3) parts 
of the pharmacovigilance system master file are av ailable in electronic form only at the site 
where it is kept.  
EN 9   EN 2. The marketing authorisation holder shal l ensure that the qualified person for 
pharmacovigilance has permanent access to the pharmacovigilance system master file.  
3. The pharmacovigilance system master file  shall be permanently and immediately 
available for inspection at the site where it is kept. 
4. For the purpose of Article 23(4) of Di rective 2001/83/EC, the national competent 
authority may limit its request to specific part s or modules of the pharmacovigilance system 
master file and the marketing authorisation hol der shall bear the costs of submitting the copy 
of the pharmacovigilance system master file. 
5. The national competent authority and the Agency may request the marketing 
authorisation holder to submit a copy of the logbook at re gular intervals. 
Chapter 2 
Minimum requirements for th e quality systems for the 
performance of pharma covigilance activities 
SECTION 1 
GENERAL PROVISIONS  
Article 9 
Scope of the quality system  
1. Marketing authorisation holders, the nati onal competent authorities and the Agency 
shall establish and follow a quality system that is adequate and effective for performing their pharmacovigilance activities. 
2. The quality system shall cover organisationa l structure, responsibilities, procedures, 
processes and resources and shall include ap propriate resource management, compliance 
management and record management. 
3. The quality system shall be based on the following: (a) establishing structures and planning inte grated and consistent  processes (quality 
planning); 
(b) carrying out tasks and responsib ilities (quality control); 
(c) monitoring and evaluating how effectively th e structures and processes have been 
established and how effectively the pro cesses are being carri ed out (quality 
assurance); and 
(d) correcting and improving the structures and processes and the ca rrying out of those 
processes as necessary (quality improvements).  
EN 10   EN 4. All elements, requirements and provisions adopted for the quality system shall be 
documented in a systematic and orderly ma nner in the form of written policies and 
procedures, such as quality plans, quality manuals and quality records. 
5. All persons involved in the procedures  and processes of the quality systems 
established by the national competent authoriti es and the Agency for the performance of 
pharmacovigilance activities shall be respons ible for the good functioning of those quality 
systems and shall ensure a systematic approach towards quality and towards the implementation and maintenance of the quality system. Those quality systems shall form an integral part of the pharmacovigilance system. 
Article 10 
Performance indicators 
1. The marketing authorisati on holder, national competent authorities and the Agency 
may use performance indicators to con tinuously monitor the good performance of 
pharmacovigilance activities. If they are used , those indicators shall be documented. For 
marketing authorisation holders this shall be  done in an annex to the pharmacovigilance 
system master file. 
2. The Agency may publish a list of perf ormance indicators on the basis of a 
recommendation of the Pharmacovigilance Risk Assessment Committee. 
SECTION 2 
MINIMUM REQUIREMENTS FOR THE QUALITY SYSTEMS FOR THE 
PERFORMANCE OF PHARMACOVIGILANCE ACTIVITIES BY MARKETING 
AUTHORISATION HOLDERS  
Article 11 
Management of human resources 
1. The marketing authorisation holder shall have a sufficient number of competent and 
appropriately qualified and trained person nel available for the performance of 
pharmacovigilance activities.  
For the purposes of the first subparagraph, the ma rket authorisation hold er shall ensure that 
the qualified person responsible for pharmacovig ilance has acquired ade quate theoretical and 
practical knowledge for the pe rformance of pharmacovigilan ce activities. If the qualified 
person has not completed basic medical training  in accordance with Artic le 24 of Directive 
2005/36/EC of the European Parliament and of the Council7, the market authorisation holder 
shall ensure that the qualified person respons ible for pharmacovigilance is assisted by a 
medically trained person. 
2. The duties of the managerial and supervis ory staff, including the qualified person 
responsible for pharmacovigilance, shall be defi ned in job descriptions. Their hierarchical 
                                                 
7 OJ L 255, 30.9.2005, p. 22.  
EN 11   EN relationships shall be defined in an organi sational chart. For that purpose, the market 
authorisation holder shall ensure that the qua lified person responsible for pharmacovigilance 
has sufficient authority to influence the performance of the quality system and the pharmacovigilance activiti es of the marketing authorisation holder. 
3. All personnel involved in the performan ce of pharmacovigilance activities shall 
receive initial and continued tr aining in relation to their role and responsibilities. The 
marketing authorisation holder shall keep training plans and reco rds for documenting, 
maintaining and developing the competences of personnel and make them available for audit 
or inspection. 
4. The marketing authorisation holder shall pr ovide appropriate inst ructions on processes 
for dealing with urgent situati ons, including busin ess continuity. 
Article 12 
Compliance management 
1. Specific quality system procedures and processes shall be in place in order to: 
(a) ensure that that pharmacovigilance data ar e continuously monitored, that options for 
risk minimisation and prevention are consid ered and that appropriate measures are 
taken as necessary, whereby the marketing au thorisation holder shall follow up such 
information, as appropriate, independent  of its source, including information 
spontaneously reported by patients or health care professionals, published in medical 
literature, or arising in the cont ext of a post-auth orisation study; 
(b) ensure that all information on the risks of medicinal products, as referred to in the 
second subparagraph of Article 101(1) of  Directive 2001/83/EC, is evaluated 
scientifically; 
(c) ensure that data on serious and non-seri ous adverse reactions are submitted to the 
Eudravigilance database within the times stipulated by Article 107 of Directive 2001/83/EC, whereby the marketing authoris ation holder shall establish operating 
procedures in order to obtain accurate and verifiable data and processes that ensure 
the quality, integrity and completeness of the information submitted, including processes to avoid duplicate s ubmissions and to validate si gnals in accordance with 
Article 25(4); 
(d) ensure effective communication with the national competent authorities and the 
Agency, including communication on ne w 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; 
(e) ensure that the product information is ke pt up to date with current scientific 
knowledge, including the assessments a nd recommendations ma de public via the 
European medicines web-portal, whereby th e marketing authorisation holder shall 
continuously check the European medicine s web-portal for any relevant updates, 
including consultati ons and notifications of procedures;  
EN 12   EN (f) ensure appropriate communication of rele vant safety information to healthcare 
professionals and patients. 
2. Where a marketing authorisation holde r has delegated certain tasks of its 
pharmacovigilance activities, it shall retain responsibility for ensuring that an effective quality 
system is applied in relation to those tasks. 
Article 13 
Record management and data retention 
1. A quality system shall be in place for mainta ining a record management system for all 
documents used for pharmacovigilance activi ties, ensuring the retrievability of these 
documents as well as the traceability of how sa fety concerns have been investigated, the 
timelines for these investigations and how and when decisions have been taken. All 
pharmacovigilance information shall be recorded, handled and stored so as to allow accurate 
reporting, interpretation and verification of th e information. In this context, marketing 
authorisation holders shall establish mechan isms enabling the traceability and follow-up of 
adverse reaction reports while complyi ng with data protection legislation. 
2. Marketing authorisation holders shall arra nge for essential documents describing the 
pharmacovigilance system to be kept  for at least five years after the system as described in the 
pharmacovigilance system master file has ceas ed to exist. Pharmacovigilance data and 
documents relating to authorised medicinal products shall be reta ined as long as the product is 
authorised and for at least 10 years after the marketing authorisation has ceased to exist. 
However, the documents may be retained fo r a longer period if re quired by applicable 
regulatory requirement s or national law. 
3. Documentation arrangements, including the location of records, shall be documented 
in the pharmacovigilance system master file. 
Article 14 
Audit 
1. Risk-based audits of the qua lity system shall be perfor med at regular intervals to 
assure that the quality system complies with the established quality system requirements and 
to determine its effectiveness.  Audits shall be conducted by individuals who have no direct 
involvement in or responsibility for the matters or processes being audited. 
2. Corrective action(s), including a follow-up a udit of deficient matters, shall be taken 
when necessary. A report shall be made of the results of each quality audit and any follow-up 
audits carried out. Such reports  shall be reviewed by the ma nagement responsible for the 
matters audited. The dates and results of qu ality audits and follo w-up audits shall be 
documented.  
EN 13   EN SECTION 3 
MINIMUM REQUIREMENTS FOR THE QUALITY SYSTEMS FOR THE PERFORMANCE 
OF PHARMACOVIGILANCE ACTIVITIES BY NATIONAL COMPETENT AUTHORITIES 
AND THE AGENCY  
Article 15 
Management of human resources 
1. National competent authorities and the Ag ency shall have a sufficient number of 
competent and appropriately qualified and traine d personnel available for the performance of 
pharmacovigilance activities. 
The organisational structures a nd the distribution of tasks and responsibilities shall be clear 
and, to the extent necessary, accessible.  Contact points shall be established. 
2. All personnel involved in the performan ce of pharmacovigilance activities shall 
receive initial and continued training. The natio nal competent authorities and the Agency shall 
keep training plans and records for doc umenting, maintaining and developing the 
competences of personnel and shall make them available for audit. 
3. Appropriate instructions on processes for dealing with urgent situations, including 
business continuity, shall be provided by the national competent authorities and by the 
Agency to their personnel. 
Article 16 
Compliance management 
1. National competent authorities and the Agen cy shall establish specific procedures and 
processes in order to achieve all of the following objectives: 
(a) ensuring the evaluation of the quality, incl uding completeness, of pharmacovigilance 
data submitted; 
(b) ensuring the assessment of pharmacovigilan ce data and its processing in accordance 
with the timelines provided by Direc tive 2001/83/EC and Regulation (EC) No 
726/2004; 
(c) guaranteeing independence in the perfor mance of pharmacovigilance activities; 
(d) ensuring effective communication between the different national competent 
authorities and the Agency as well as with patients, healthcare professionals, marketing authorisation holde rs 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 such  a medicinal product; 
(f) conducting inspections, including pr e-authorisation inspections.  
EN 14   EN (g) For the purposes of point (e), the national competent authorities and the Agency shall 
inform each other and the Commission at  least 24 hours before making the public 
safety announcement, unless urgent publ ic announcements are required for the 
protection of public health.  
2. In addition to the quality system procedures referred to in paragraph 1, national 
competent authorities shall have procedures fo r collecting and recording all suspected adverse 
reactions that occur in their territory. 
3. The Agency shall have additional procedur es for literature monitoring in accordance 
with Article 27 of Regulation (EC) No 726/2004. 
Article 17 
Record management and data retention 
1. The national competent authorities and the Agency shall record all pharmacovigilance 
information and ensure that it is handled and stored so as to  allow for accurate reporting, 
interpretation and verifica tion of that information.  
They shall put in place a record manageme nt system for all documents used for 
pharmacovigilance activities  that ensures the retrievability of those documents as well as the 
traceability of the measures take n to investigate safety concerns, of the timelines for those 
investigations and of decisions on safety co ncerns, including their date and the decision-
making process. 
2. The national competent authorities and th e Agency shall arrange for the essential 
documents describing their pharmacovigilance system  to be kept for at least five years after 
the system has ceased to exist. Pharmacovigila nce data and documents relating to authorised 
medicinal products shall be reta ined as long as the product is authorised and for at least 10 
years after the marketing authorisation has expi red. However, the documents may be retained 
for a longer period where that is re quired by Union or national law. 
Article 18 
Audit 
1. Risk-based audits of the quality system shall be performed according to a common 
methodology, at regular in tervals, to ensure that the quality system complies with the 
requirements set out in Articles 9 and 15 to 17 and to ensure its effectiveness. Audits shall be 
conducted by individuals who have no direct invol vement in or responsib ility for the matters 
or processes being audited. The dates and results of quality audits and follow-up audits shall be documented. 
2. Corrective action, including a follow-up audi t of deficient matters, shall be taken 
where necessary.  
EN 15   EN Chapter 3 
Minimum requirements for the mo nitoring of data in the 
Eudravigilance database 
Article 19 
General 
1. The Agency and national competent authoriti es shall cooperate in  the monitoring of 
the data available in the Eudravigilance database. 
2. Marketing authorisation holders shall monito r the data available in the Eudravigilance 
database to the extent that th ey have access to the database. 
Article 20 
Changed risks/new risks 
1. The identification of new risks or change d risks shall be base d on the detection and 
analysis of the relevant signals.  
A signal consists of 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 lik elihood to justif y verificatory 
action. 
For the purpose of monitoring data in the Eudrav igilance database, only signals related to an 
adverse reaction shall be considered. 
2. The detection of a signal shall be based on a multidisciplinary approach. Signal 
detection within the Eudravigilance database shall be complemented by statistical analysis. After consultation with the Pharmacovigilan ce Risk Assessment Committee the Agency may 
publish a list of medical events that have to be taken into account for the detection of a signal. 
Article 21 
Methodology 
1. In order to determine the evidentiary value contained in  a signal, a structured and 
recognised methodology shall be applied taking account  of the clinical relevance, quantitative 
strength of the association, the consistency of the data, the exposure–response relationship, 
the biological plausibility, e xperimental findings, possible analogies and the nature and 
quality of the data. 
2. Different types of factors may be taken into  account for the priori tisation of signals, in 
particular whether the association or medicinal product is new, factors related to the strength 
of the association, factors related to the se riousness of the reacti on involved and factors 
related to the documentation of repor ts to the Eudravigilance database.  
EN 16   EN 3. The Pharmacovigilance Risk Assessment Co mmittee shall perform a regular review of 
the methodology(ies) to be used and pub lish recommendations, as appropriate. 
Article 22 
Signal management process 
1. The signal management proces s consist of the set of activities to determine whether, 
based on an examination of individual case sa fety reports, aggregated data from active 
surveillance systems or studies, literature info rmation or other data sources, there are new 
risks associated with an active substance or  a medicinal product or whether risks have 
changed. It shall include signal detection, signal validation, signal confirmation, signal 
analysis and prioritisation, signal as sessment, and recommendation for action. 
Signal validation is the process of evaluating th e data supporting the detected signal in order 
to verify that the available documentation contains sufficient evidence demonstrating the existence of a new poten tially causal association,  or a new aspect of a known association, and 
therefore to justify further assessment of the signal. 
2. Marketing authorisation holde rs, national competent author ities and the Agency shall 
ensure continuous monitoring of the Eudravigil ance database with a frequency proportionate 
to the identified risk, the potential risks and the need  for additional information. 
3. National competent authorities shall specif ically monitor data originating in their 
territory. 
4. Where a marketing authorisation holder detects a new signal as a result of the 
monitoring referred to in para graph 2, it shall validate it a nd shall forthwith inform the 
Agency and national competent authorities. 
5. Any validated signal that has been co mmunicated by the marketing authorisation 
holder in accordance with paragraph 4 shall be c onfirmed within 15 days of receipt where it is 
considered that further analysis  is required. For the purpose of this analysis, other information 
available on the medicinal product may be taken into account. Where the validity of the signal is not confirmed within this period no further action shall be required. However, special 
attention shall be paid to non-confirmed signals in the case of subsequent signals. 
Where the signal concerns a product authorised in accordance with Directive 2001/83/EC, the 
signal may be confirmed by any national competen t authority of any Member State in which 
the medicinal product is marketed or of any le ad Member-State or co -leader appointed in 
accordance with Article 23(1). For products author ised in accordance with Regulation (EC) 
No 726/2004, the signal shall be confirmed by th e Agency in collaboration with the Member 
States. 
6. Without prejudice to paragraphs 4 and 5, national competent authorities and the 
Agency shall validate and confirm any signal that  has been detected by th em in the course of 
their continuous monitoring of  the Eudravigilance database. 
7. Any confirmed signal shall be entered in  the tracking system administered by the 
Agency and shall be transmitted to the Phar macovigilance Risk Assessment Committee for 
the initial analysis and prioritisation of signals in accordance  with Article 107h(2) of Directive 
2001/83/EC and Article 28a(2) of  Regulation (EC) No 726/2004.  
EN 17   EN 8. The Agency shall inform forthwith the marketing authorisati on concerned of the 
conclusions of the Pharmacovig ilance Risk Assessment Committee. 
Article 23 
Worksharing for signal management 
1. For medicinal products authorised in acco rdance with Directive 2001/83/EC in more 
than one Member State and for active substanc es contained in several medicinal products 
where at least one marketing au thorisation has been granted in accordance with Directive 
2001/83/EC, Member States may agree within th e coordination group provided for by Article 
27 of Directive 2001/83/EC to appoi nt a lead Member State that  monitors the Eudravigilance 
database on behalf of other Member States and validates and confirms signals in accordance 
with Article 22(5) and (6). The lead Memb er State may be supported by another Member 
State, as a co-leader. Any such appointment sh all be reviewed at le ast every four years. 
2. When appointing a lead Member State and as appropriate a co-l eader, the coordination 
group may take into account whether any Member State is acting as reference Member State, 
in accordance with Ar ticle 28(1) of Direct ive 2001/83/EC, or as a rapporteur for the 
assessment of periodic safety update reports in  accordance with Article 107(e) of Directive 
2001/83/EC. 
3. The Agency shall publish on the European  medicines web-porta l a list of active 
substances that are subject to worksharing in  accordance with this provision and the lead 
Member State and co-leader appointed for monito ring those substances in the Eudravigilance 
database. 
4. Without prejudice to paragraph 1, all Member States remain responsible for 
monitoring the data in the Eudravigilance data base in accordance with Article 107h(1)(c) and 
Article 107h(3) of Directive 2001/83/EC. 
5. For medicinal products authorised in accordance with Regulation (EC) No 726/2004, 
the Agency shall be supported for the monitori ng of data in the Eudravigilance database, as 
appropriate, by the rapporteur appointed by  the Pharmacovigilance Risk Assessment 
Committee in accordance with Article 62(1) of Regulation (EC) No 726/2004. 
Article 24 
Signal detection support 
The Agency shall support the monitoring of  the Eudravigilance database by providing 
national competent authorities and marketing authorisation holders, as appropriate, with 
access to of the following elements: 
(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 supporti ng the evaluation of individua l case safety reports and 
case series;  
EN 18   EN (c) customised grouping and stratification of data  enabling the identification of patient 
groups with a higher risk of occurrence of a dverse reactions or with a risk of a more 
severe adverse reaction; 
(d) statistical signal detection methods. 
Article 25 
Signal detection audit trail 
1. The national competent authorities and the Agen cy shall keep an audit trail of their signal 
detection activities conducted in the Eudravigila nce database and of th e relevant queries and 
their results.  
2. The audit trail shall allow traceability of how signals have been detected and how validated 
and confirmed signals have been assessed. 
Chapter 4 
Use of terminology 
Article 26 
Use of internationally agreed terminology 
1. For the classification, retrieval, presenta tion, risk-benefit evaluation and assessment, 
electronic exchange and communication of  pharmacovigilance and medicinal product 
information, Member States, marketing authoris ation holders and the Agency shall apply the 
following internationally agreed terminology:  
(a) the Medical Dictionary for Regulatory Ac tivities (MedDRA) as developed by the 
International Conference on Harmonisa tion 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 ISO EN 11615, H ealth Informatics, Identification of 
Medicinal Products (IDMP) standard, ‘Dat a elements and structures for unique 
identification and exchange of regul ated medicinal product information’; 
(d) the terminology set out in ISO EN 11616 H ealth Informatics, Identification of 
Medicinal Products (IDMP) standard, ‘Dat a elements and structures for unique 
identification and exchange of regulated  pharmaceutical product information’; 
(e) the terminology set out in ISO EN 11238 H ealth Informatics, Identification of 
Medicinal Products (IDMP) standard, ‘Dat a elements and structures for unique 
identification and exchange of regul ated information on substances’; 
(f) the terminology set out in ISO EN 11239 H ealth Informatics, Identification of 
Medicinal Products (IDMP) standard, ‘Dat a elements and structures for unique 
identification and exchange of regulated information on pharmaceutical dose forms, 
units of presentation and routes of administration’;  
EN 19   EN (g) the terminology set out in ISO EN 11240 H ealth Informatics, Identification of 
Medicinal Products (IDMP) standard, ‘Dat a elements and structures for unique 
identification and exchange of units of measurement’. 
2. The terminology referred to in paragraph 1( c) to (g) shall be applied as from six 
months after the Management Board of the Ag ency has published the relevant announcement, 
taking into account the recommendations of the Pharmacovigilance Risk Assessment Committee. This announcement shall be publishe d on the European medicines web-portal. 
3. In the event that a required term is not available, Member States, national competent 
authorities or marketing author isation holders shall make a re quest for the addition of a new 
term to the organisation that is responsible for maintaining the terminology and inform the 
Agency accordingly. Until the newly required term  is confirmed, the next best term shall be 
utilised. 
4. The use of terminology shall be monitored a nd validated, either systematically or by 
regular random evaluation. Data entry staff shal l be instructed in the use of the terminology, 
and their proficiency shall be verified. 
Article 27 
Use of internationally agreed formats and standards 
1. For the description, retrie val, presentation, risk-benef it evaluation and assessment, 
electronic exchange and communication of  pharmacovigilance and medicinal product 
information, the following internationally agreed  formats and standards shall be applied by 
Member States, marketing authoris ation holders and the Agency:  
(a) ISO EN 27953-2 Health Informatics, ‘Individual Case Safety Reports’ for the 
electronic transmission of su spected adverse reactions; 
(b) ISO EN 11615, Health Informatics, Iden tification of Medici nal Products (IDMP) 
standard, ‘Data elements and structures for unique identification and exchange of 
regulated medicinal product information’; 
(c) ISO EN 11616, Health Informatics, Iden tification of Medici nal Products (IDMP) 
standard ‘Data elements and structures for unique identification and exchange of 
regulated pharmaceutical product information’; 
(d) ISO EN 11238, Health Informatics, Iden tification of Medici nal Products (IDMP) 
standard, ‘Data elements and structures for unique identification and exchange of 
regulated information on substances’; 
(e) ISO EN 11239, Health Informatics, Iden tification of Medici nal Products (IDMP) 
standard, ‘Data elements and structures for unique identification and exchange of 
regulated information on pharmaceutical dose fo rms, units of presentation and routes 
of administration’; 
(f) ISO EN 11240, Health Informatics, Iden tification of Medici nal Products (IDMP) 
standard, ‘Data elements and structures for unique identification and exchange of 
units of measurement’;  
EN 20   EN The formats and standards referred to in (a) to (f ) shall be applied as from six months after the 
Management Board of the Agency has publishe d the relevant announcement, taking into 
account the recommendations of the Pharmac ovigilance Risk Assessment Committee. This 
announcement shall be published on th e European medicines web-portal. 
2. Until the date of application of the formats and standards referred to in paragraph 1(a) 
to (f) the following formats and standards shall be applied: 
(a) the Extended Eudravigilance Medicinal Product Report Message (XEVPRM), where 
XEVPRM refers to the format for the elec tronic submission of information on all 
medicinal products for human use authorised  in the Union in accordance with Article 
57(2), second sub-paragraph of Regulati on (EC) No 726/2004, as published by the 
Agency; 
(b) ICH E2B(R2) ‘Maintenance of the ICH guideline on clinical safety data 
management: data elements for transmissi on of Individual Case Safety Reports’; 
(c) ICH M2 standard ‘Electronic Transmissi on of Individual Case Safety Reports 
Message Specification’. 
Chapter 5 
Transmission of suspected adverse reactions 
Article 28 
Individual Case Safety Reports 
Individual case safety report refers to the form at and content for the reporting of one or more 
suspected adverse reactions to a medicinal product that occur in a single patient at a specific 
point in time. A valid individua l case safety report for expedited reporting shall include at 
least an identifiable reporter, an identifiable pa tient, at least one suspect adverse reaction and 
a suspect medicinal product. 
Article 29 
Content of electronic transmission of suspected adverse reactions 
1. Member States and marketing authorisation holders shall ensure that all individual 
cases are well documented and individual case safety reports are as complete as possible when transmitted electronically to the Eudravig ilance database, providing all the information 
available upon initial recei pt and any subsequent follow-up w ith the reporter in an accurate 
and reliable manner. 
2. Member States and marketing authorisati on holders shall record sufficient details 
necessary for obtaining follow-up information on adverse reaction repor ts as outlined in 
Articles 107a(1), (2) and 107(4) of Directive 2010/83/EC. The fo llow-up of reports shall be 
adequately documented. 
3. Pseudonymisation may be applied by Member  States and marketing authorisation 
holders as appropriate, thereby replacing identif iable health data such as name and address  
EN 21   EN with pseudonyms, though without  impairing the information fl ow in the Eudravigilance 
system. 
4. For the electronic reporting of suspect ed adverse reactions, Member States and 
marketing authorisation holders  shall provide all available information on each individual 
case, in particular: 
(a) Administrative information: report type , date and a world-wide unique case 
identification number as well as unique sender identification and sender type. The 
date the report was first received from the source and the date of  the receipt of the 
most recent information, using a fully 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; 
(b) Literature reference in acco rdance with the ‘Vancouver style’ as developed by the 
International Committee of Medical Journal Editors8 for adverse reactions reported 
in the world-wide literature, including a comprehensive English summary of the 
article. Upon request of the Agency, a c opy of the relevant li terature taking into 
account copyright restrictions a nd, if required, a full translat ion of the article must be 
provided by the marketing authorisation hol der that transmitted the initial report; 
(c) Study type, study name and the sponsor st udy number or study registration number 
for reports from studies not covered by EU legislation on clinical trials, namely 
Directive 2001/20/EC of the European Par liament 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 implementati on of good clinical prac tice in the conduct 
of clinical trials on medicinal products for human use9; 
(d) Primary source(s), which refer(s) to the pe rson(s) reporting the facts: information 
identifying the reporter, including prim ary-source country and qualification; 
(e) 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 gestati on period at time of exposure; 
(f) Relevant medical history and concurrent conditions; 
(g) Medicinal product(s) suspected to be re lated to the occurrence of the adverse 
reaction, including interacti ng medicinal products. Medi cinal product(s) shall be 
reported by the name in accordance with Article 1(20) of Directive 2001/83/EC. Where this is not available, they shall be  reported by the active substance(s) and any 
other characteristics that allow for the identification of the medicinal product(s) such as: name of the marketing authorisation holder, marketing authorisation number, 
country of marketing authorisation, pharm aceutical form and (parent) route(s) of 
administration, indication(s) for use in the case, dose administered, start date and end 
                                                
 
8 International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted 
to biomedical journals. N Engl J Med 1997; 336:309-15. 
9 OJ L 121, 1.5.2001, p. 34.  
EN 22   EN date of administration, actio ns taken with the medicina l product(s), effect of the 
dechallenge and rechallenge fo r suspect medicinal products; 
(h) For biological medicinal produc t(s), the batch number(s) and the expiry date shall be 
reported. A follow-up procedure must be in place to obtain this information if not 
available in the initial report; 
(i) Concomitant medicinal products not suspected to be related to the occurrence of the 
adverse reaction and past-medical drug ther apy for the patient (and for the parent), 
where applicable. The reporting of this info rmation must follow the principles set out 
above under point (g); 
(j) Suspected adverse reaction(s) : start date and end date of the suspected adverse 
reaction(s) and/or duration, se riousness, outcome of the su spected adverse reaction(s) 
at the time of last observation, time in tervals between suspect medicinal product 
administration and start of a dverse reaction and the origin al reporter’s words and/or 
short phrases used to describe the reaction(s); 
(k) Results of tests and procedures relevant  to the investigation of the patient; 
(l) Date and reported cause of death, including  autopsy-determined causes, in the event 
of the death of the patient; 
(m) A case narrative, where possible, providing all relevant inform ation for individual 
cases with the exception of non-serious a dverse reactions. The information shall be 
presented in a logical time sequence, in the chronology of  the patient’s experience 
including clinical course, therapeutic m easures, outcome and follow-up information 
obtained. Any relevant autopsy or post-mor tem findings must also be summarised in 
the narrative; 
(n) Reason for nullification or amendment fo r nullification and amendment reports. 
5. For narrative and textual desc riptions, where reported in an  official language in the EU 
other than English, an English summary with the initial verbat im text shall be provided. 
Member States may report case narratives in th eir official language or languages. For these 
reports, case translations shoul d be provided when re quested by the Agency or other Member 
States for the evaluation of potential signals . For suspected adverse reactions originating 
outside the EU, English shall be used for adverse reaction reporting. 
Article 30 
Format of electronic transmission of suspected adverse reactions 
Member States and marketing authorisation holders shall use the agreed format and 
terminology for electronic transmissi on of suspected adverse reactions.  
EN 23   EN Chapter 6 
Risk management plans 
Article 31 
Content of Risk management plans 
1. The risk management plan shall: 
(a) identify or characterise the safety prof ile of the medicinal product(s) concerned; 
(b) indicate how to characterise further the safety profile of the medicinal product(s) 
concerned; 
(c) document measures to prevent or minimise the risks associated with the medicinal 
product, including an assessment of the e ffectiveness of those interventions; 
(d) document post-authorisation obligations that have been imposed as a condition of the 
marketing authorisation. 
Products containing the same active substa nce and belonging to the same marketing 
authorisation holder should be included, if appropriate, in one risk management plan. 
Where reference is made in a risk management plan to post-authorisati on studies it shall be 
indicated whether a study is in itiated, managed or financed by the marketing authorisation 
holder voluntarily or pursuant to obligations imposed by the na tional competent authorities. 
All post-authorisation obligations shall be listed  in the summary of the risk management plan 
together with a timeframe. 
2. A summary of the risk management plan  shall be made publicly available in 
accordance with Article 106(c) of  Directive 2001/83/EC and Ar ticle 26(1)(c) of Regulation 
(EC) No 726/2004 as amended. The summary sh all include key elements of the risk 
management plan with a specific focus on risk minimisation activities. With regard to the 
safety specification of the medicinal produc t concerned, it should contain important 
information on potential and identified  risks as well as missing information. 
Article 32 
Updates of the risk management plan 
1. A risk management plan previously submitted for a medicinal product shall be 
resubmitted whenever it is updated. On request the new submission may be limited to the modules concerned by the update. 
2. Each submission of the risk management plan  shall have a distinct version number and 
be dated.  
EN 24   EN Article 33 
Format of Risk management plans 
The risk management plans shall be submitted in accordance with Annex I. 
Chapter 7 
Periodic Safety Update Reports 
Article 34 
Content of periodic safety update reports 
1. Under Article 107b of Directive 2001/83/EC , periodic safety update reports submitted 
by the marketing authorisation holder shall contai n a scientific evaluati on of the risk–benefit 
balance of the medicinal product, to  be based on all available data. 
2. A periodic safety update report shall c ontain cumulative data starting from the 
granting of the marketing authorisation or, wher e appropriate, the inte rnational birth date, 
though with the focus on new information emerging in the period since the data lock point of the last periodic safe ty update report. 
3. Periodic safety update reports shall provi de an accurate estimation of the population 
exposed to the medicinal product , including all data  relating to the volume of sales and 
volume of prescriptions. This estimation of exposure should be accompanied by a qualitative 
and quantitative analysis of actual use, including how it may differ from indicated use based 
on all data available to the marketing authorisation holder, including the results of observational or drug utilisation studies. 
4. Results of assessments of the effectiveness of risk minimisation activities relevant to 
the risk–benefit assessment shall be included. 
5. Detailed listings of indi vidual cases, including case narr atives, may not be included 
routinely, but shall be provided in  the relevant risk evaluation s ection of the periodic safety 
update report where integral to the scientific analysis of a signal or safety concern in the 
relevant risk evaluation section. 
6. Based on the evaluation of the cumulative safe ty data and the risk-benefit analysis, the 
marketing authorisation holde r may conclude the periodic safety update report with 
considerations as to the need for changes an d/or actions, including implications for the 
approved summary of product charac teristics for the product(s) fo r which the periodic safety 
update report is submitted. 
7. Unless otherwise specified in the list of  Union reference date s and frequency of 
submission, a single periodic sa fety update report may prepar ed for all medicinal products 
containing the same active substance and author ised for one marketing authorisation holder, 
including all indications, routes of admi nistration, dosage forms and dosing regimens, 
irrespective of whether authoris ed under different names and through separate procedures. 
Where relevant, data relating to  a particular indication, dosage form, route of administration 
or dosing regimen should be presented in a sepa rate section within th e body of the periodic  
EN 25   EN safety update report and any safety concerns  addressed accordingl y, without preparing a 
separate periodic safe ty update report. 
8. Unless otherwise specified in the list of  Union reference date s and frequency of 
submission, the marketing authorisation holder shall either submit a stand-alone periodic 
safety update report fo r the combination of active substances auth orised for the same 
marketing authorisation holder, with cross-refere nces to the single-substance periodic safety 
update report(s), or provide the combination data  within one of the si ngle-substance periodic 
safety update reports. 
Article 35 
Format of periodic safety update reports 
Electronic periodic safety update reports sh all be submitted in acco rdance with Annex II. 
Chapter 8 
Post-authorisation safety studies 
Article 36 
Scope 
1. These provisions apply to non-interventi onal post-authorisati on safety studies 
initiated, managed or financed by a marketing authorisation holder under  obligations imposed 
by a national competent authority, the Agency or  the Commission in accordance with Articles 
21a and 22a of Directive 2001/83/EC and Ar ticles 10 and 10a of Regulation (EC) No 
726/2004. 
2. ‘Start of data collection’ means the date  from which information on the first study 
subject is first recorded in th e study dataset or, in the case of the secondary use of data, the 
date on which data extraction starts. 
3. ‘End of data collection’ means the date on which the analytical dataset is first 
completely available. 
4. All studies as referred to in paragraph 1 shall have a written study protocol. Prior to 
the start of data collection, the marketing authorisation holder must ensure that information on the study, including the study protoc ol, is notified to the Agency  or the national competent 
authority, as applicable, and that the Member  State in which the study is conducted is 
informed. The marketing authorisation holder must  ensure that this information includes an 
English translation of the title and abstract of the study protocol. The study protocol shall be 
amended as needed throughout the course of th e study. Any substantial amendments to the 
protocol shall be submitted, before their im plementation, in accordan ce with Article 107o of 
Directive 2001/83/EC. 
5. Unless a written waiver has been granted, the marketing authorisation holder shall, 
within 12 months of the end of data collec tion, submit the final st udy report, including a 
public abstract, to the Agency or the nati onal competent authority, as applicable. The 
marketing authorisation holder shal l ensure that an English transl ation of the abstract of the  
EN 26   EN final study report is submitted. The abstract of the final study report shall include a summary 
of the study methods 
6. The marketing authorisation holder shall ensure that all study information is handled 
and stored in such a way that it can be accura tely reported, interpreted and verified, while the 
confidentiality of the reco rds of the study subjects rema ins protected. The marketing 
authorisation holder shall ensure that the anal ytical dataset and statistical programmes used 
for generating the data included in the final stud y report are kept in el ectronic format and are 
available for auditing and inspection. 
7. The Agency may publish appropriate templa tes for the protocol, abstract and final 
study report. 
Article 37 
Format of post-authori sation safety studies 
Protocols, abstracts and final study reports for non- interventional post-au thorisation safety 
studies shall be submitted in accordance with Annex III. 
Chapter 9 
Final provisions 
Article 38 
Data protection 
1. This Regulation shall be without prejudi ce to the obligations of national competent 
authorities and marketing author isation holders relating to thei r processing of personal data 
under Directive 95/46/EC or the obligations of the Agency re lating to its processing of 
personal data under Regulation (EC) No 45/2001. 
2. At each stage in the storage and processing  of pharmacovigilance data, measures shall 
be taken to ensure data security and confiden tiality. For that purpose, access to documents and 
to databases shall be strictly limited to aut horised personnel. The auth orised personnel shall 
ensure the medical and administrative confidentiality of the data. They shall ensure that the fundamental right to protection of personal data is fully and effectively guaranteed in all 
pharmacovigilance activities, in conformity w ith Union legislation on the protection of 
personal data. The processing of personal data may be justified only where the processing of 
identifiable health data is necessary and only where the parties involve d assess this necessity 
at each stage of the pharmacovigilance process. 
3. Where the Agency processes pharmacovigila nce data pursuant to this Regulation, it 
shall comply with Regulation (EC) No 45/2001. 
Article 39 
This Regulation shall enter into force on the twentieth day following that of its publication in 
the Official Journal of  the European Union .  
EN 27   EN It shall apply from 2 July 2012. 
However, Articles 28 to 37 shall apply from [6 months from the entry into force of this 
Regulation].  
This Regulation shall be binding in  its entirety and directly applicable in all Member States. 
Done at Brussels, 
 For the Commission 
 The President  
EN 28   EN Annex I — Risk management plans  
Format of the risk management plan 
1. The risk management plan consists of seven parts, which ma y be subdivided, and 
includes the following modules: 
Part I: Product(s) Overview Part II: Safety Specification 
Module SI: Epidemiology of the in dications and target population 
Module SII: Non-clinical part  of the Safety Specification 
Module SIII: Clinical trial exposure Module SIV: Populations not studied in clinical trials Module SV: Post-Authorisation Experience Module SVI: Additional EU requireme nts for the Safety Specification 
Module SVII: Identified and potential risks 
Module SVIII: Summary of the safety concerns 
Part III: Pharmacovigilance Plan (incl uding post-authorisatio n safety studies) 
Part IV: Plans for post-authorisation efficacy studies Part V: Risk minimisation measures (includi ng evaluation of the e ffectiveness of risk 
minimisation activities) 
Part VI: Summary of the risk management plan 
Part VII: Annexes 2. Where a risk management plan concerns di fferent medicinal produc ts, a separate Part 
VI shall be provided for each medicinal product.  
EN 29   EN Annex II — Electronic period ic safety update reports  
Format of the periodic  safety update reports 
1. The periodic safety update report shall be  submitted electronically with the following 
modular structure: 
• Title page including signature 
• Executive Summary 
• Table of contents 
1. Introduction 2. Worldwide marketing approval status 3. Actions taken in the reporting interval for safety reasons 
4. Changes to reference safety information 5. Estimated exposure and use patterns 
5.1. Cumulative subject exposur e in clinical trials 
5.2. Cumulative and interval patient exposure from marketing experience 
6. Data in summary tabulations 
6.1. Reference information 6.2. Cumulative summary tabulations of se rious adverse events from clinical 
trials 
6.3. Cumulative and interval summary ta bulations from post-marketing data 
Sources 
7. Summaries of significant fi ndings from clinical trials during the reporting interval 
7.1. Completed clinical trials 7.2. Ongoing clinical trials 7.3. Long-term follow-up 7.4. Other therapeutic us e of medicinal product 
7.5. New safety data related to fixed combination therapies 
8. Findings from non-interventional studies 9. Information from other clinical trials and sources  
EN 30   EN 10. Non-clinical data 
11. Literature 12. Other periodic reports 13. Lack of efficacy in controlled clinical trials 14. Late-breaking information 15. Overview on signals: New, ongoing or closed 16. Signal and risk evaluation 
16.1. Summaries of safety concerns 16.2. Signal evaluation 16.3. Evaluation of risks and new information 16.4. Characterisation of risks 16.5. Effectiveness of risk minimisation (if applicable) 
17. Benefit evaluation 
17.1. Important baseline efficacy and effectiveness information 17.2. Newly identified information on efficacy and effectiveness 17.3. Characterisation of benefits 
18. Integrated benefit-risk analys is for authorised indications 
18.1. Benefit-risk context – Medical need and important alternatives 
18.2. Benefit-risk analysis evaluation 
19. Conclusions and actions 20. Appendices to the periodi c safety update report 
2. The Agency may publish appropriate templates on the individual modules.  
EN 31   EN Annex III — Protocols, abstracts and final st udy reports for post-authorisation safety 
studies  
1. Format of the study protocol 
1. Title: informative title  including a commonly used term indicating the study design and the 
medicinal product, substance or drug class conc erned, and a sub-title wi th a version identifier 
and the date of the last version. 
2. Marketing authorisation holder. 3. Responsible parties including a list of all collaborating primary institutions and other 
relevant study sites. 
4. Abstract: stand-alone summary of the study protocol, includi ng the following sub-sections: 
• Title with subtitles including version a nd date of the protocol and name and 
affiliation of the main author 
• Rationale and background 
• Research question and objectives 
• Study design 
• Population 
• Variables 
• Data sources 
• Study size 
• Data analysis 
• Milestones. 
5. Amendments and updates: any substantial amendment and update to the study protocol 
after the start of data collec tion, including a justific ation for the amendm ent 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 da tes for the following milestones: 
• Start of data collection 
• End of data collection 
• Study progress report(s) as referred to in  Article 107m(5) of Directive 2001/83/EC 
• Interim report(s) of study results, if applicable  
EN 32   EN • Final report of study results. 
7. Rationale and background: description of the safe ty hazard(s), the safety profile or the risk 
management measures that led to the study be ing imposed as an obligation for a marketing 
authorisation. 
8. Research question and objectives in accord ance with the decision of the competent 
authority that imposed th e study as an obligation. 
9. Research methods: description of  the research methods, including: 
• Study design 
• Setting: study population defined in term s of persons, place, time period, and 
selection criteria, including the rati onale for any inclusion and exclusion 
criteria. If any sampling from a sour ce population is undertaken, a description 
of the source population and details of  sampling methods should be provided. 
Where the study design is a systematic revi ew or a meta-analysis, the criteria 
for the selection and eligibility of studies should be explained. 
• Variables 
• Data sources: strategies and data sources for determining exposures, outcomes 
and all other variables rele vant to the study objectiv es. Where the study will 
use an existing data source, such as el ectronic health records, any information 
on the validity of the recording and codi ng of the data should be reported. In 
the case of a systematic review or meta-analysis, the search strategy and processes and any methods for confirmi ng data from investigators should be 
described. 
• Study size: Any projected study size, pr ecision sought for study estimates and 
any calculation of the study size that can minimally detect a pre-specified risk 
with a pre-specified power. 
• Data management 
• Data analysis 
• Quality control 
• Limitations of the research methods. 
10. Protection of human subjects : safeguards in order to comp ly with natio nal and Union 
requirements for ensuring the well-being and righ ts of participants in  non-interventional post-
authorisation safety studies. 
11. Management and reporting of adverse events/a dverse reactions while the study is being 
conducted 
12. Plans for disseminating a nd communicating study results 
13. References  
EN 33   EN 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, if relevant, an evalua tion of the impact of study results on the risk–
benefit balance of the product) 
11. Marketing authorisation holder 
12. Name(s) and affiliation(s) of principal investigator(s) 
3. Format of the final study report 
1. Title: title including a commonl y used term indicating the study design; sub-titles with date 
of final report and name and affiliation of main author. 
2. Abstract: stand-alone summary in accord ance with section 2 of this Annex. 
3. Marketing authorisation holder: name and ad dress 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 collabo rating primary institutions and other relevant 
study sites. 
5. Milestones: dates for the following milestones: 
• Start of data collection (planned and actual dates) 
• End of data collection (p lanned and actual dates) 
• Study progress report(s) 
• Interim report(s) of study results, if applicable 
• Final report of study results  (planned and actual date)  
EN 34   EN • Any other important milest one applicable to the study, including data of study 
registration in the elec tronic study register. 
6. Rationale and background: description of the sa fety concern(s) that led to the study being 
initiated, and critical review of relevant published and unpu blished data evaluating pertinent 
information and gaps in knowledge th at 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 th e case of a system atic review or 
meta-analysis, study characteristics used as criteria for eligibil ity, with rationale. 
9.3. Subjects: any source population and elig ibility criteria for study subjects. 
Sources and methods for selection of par ticipants should be provided, including, 
where relevant, methods for case ascertainment , as well as number of and reasons for 
dropouts. 
9.4. Variables: all outcomes, exposures, pr edictors, potential c onfounders, and effect 
modifiers, including operational definitions . Diagnostic criteria should be provided, 
if applicable. 
9.5. Data sources and measurement: for each vari able of interest, sources of data and 
details of methods of assessment and measur ement. 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 should be reported. In the case of a systematic 
review or meta-analysis, de scription of all informati on 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 a ny study size calcul ation and any method 
for attaining projected study size. 
9.8. Data transformation: transformations, calculations or operations on the data, 
including how quantitative data were handl ed in the analyses and which groupings 
were chosen and why. 
9.9. Statistical methods : description of: 
• main summary measures 
• all statistical methods  applied to the study  
EN 35   EN • any methods used to examine subgroups and interactions 
• how missing data were addressed 
• any sensitivity analyses 
• any amendment to the plan of data anal ysis included in the study protocol, with 
rationale for the change. 
9.10. Quality control: mechanisms to en sure data quality and integrity. 
10. Results: comprising the following sub-sections: 
10.1. Participants: numbers of study subjects at  each stage of study.  In the case of a 
systematic review or meta-analysis, nu mber of studies screened, assessed for 
eligibility and included in the review w ith reasons for exclusion at each stage. 
10.2. Descriptive data: characteristics of st udy participants, information on exposures 
and potential confounders and number of par ticipants 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 estimate s and, if applicable, confounder-adjusted 
estimates and their precision. If relevant , estimates of rela tive risk should 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 present findi ngs, and, if 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 directi on and magnitude of pot ential biases should 
be discussed. 
11.3. Interpretation: interpre tation of results, considering objectives, limitations, 
multiplicity of analyses, results from sim ilar studies and other relevant evidence. 
11.4. Generalisability 
12. References