20.6.

2012 EN Official Journal of the European Union L 159/5

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)

THE EUROPEAN COMMISSION, marketing authorisation holder, the pharmacovigilance

system master file should contain key information and
documents covering all aspects of pharmacovigilance
Having regard to the Treaty on the Functioning of the European activities, including information on tasks that have been
Union, subcontracted. It should contribute to the appropriate
planning and conduct of audits by the marketing auth­
orisation holder and the supervision of pharmaco­
Having regard to Regulation (EC) No 726/2004 of the European vigilance activities by the qualified person responsible
Parliament and of the Council of 31 March 2004 laying down for pharmacovigilance. At the same time it should
Community procedures for the authorisation and supervision of enable national competent authorities to verify
medicinal products for human and veterinary use and estab­ compliance concerning all aspects of the system.
lishing a European Medicines Agency (1), and in particular
Article 87a thereof,
(4) The information contained in the pharmacovigilance
system master file should be maintained so as to reflect
Having regard to Directive 2001/83/EC of the European any modifications that have been made and ensure easy
Parliament and of the Council of 6 November 2001 on the accessibility and availability by national competent auth­
Community code relating to medicinal products for human orities for the purpose of inspections.
use (2), and in particular Article 108 thereof,

(5) Quality systems should form an integral part of the phar­

Whereas: macovigilance system. The minimum requirements for
the quality system for the performance of pharmaco­
vigilance activities should ensure that marketing authori­
(1) Regulation (EU) No 1235/2010 of the European sation holders, national competent authorities and the
Parliament and of the Council of 15 December 2010 European Medicines Agency (hereinafter ‘the Agency’)
amending, as regards pharmacovigilance of medicinal establish an adequate and effective quality system,
products for human use, Regulation (EC) No 726/2004 which provides for an effective monitoring of compliance
laying down Community procedures for the authori­ and the accurate and proper documentation of all
sation and supervision of medicinal products for measures taken. They should also ensure that
human and veterinary use and establishing a European marketing authorisation holders, national competent
Medicines Agency, and Regulation (EC) No 1394/2007 authorities and the Agency have at their disposal
on advanced therapy medicinal products (3) strengthened sufficient competent, appropriately qualified and trained
and rationalised the monitoring of the safety of staff.
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 (6) Adherence to a well-defined quality system should ensure
Council of 15 December 2010 amending, as regards that all pharmacovigilance activities are conducted in
pharmacovigilance, Directive 2001/83/EC on the such a way that they are likely to produce the desired
Community code relating to medicinal products for results or quality objectives for the fulfilment of phar­
human use (4) into Directive 2001/83/EC. macovigilance tasks.

(2) Pharmacovigilance activities cover the whole life-cycle

management of medicinal products for human use in (7) As part of their quality system, national competent auth­
relation to safety. orities and the Agency should establish contact points to
facilitate interaction between national competent auth­
orities, the Agency, the Commission, marketing authori­
(3) Regulation (EU) No 1235/2010 and Directive sation holders and persons reporting information on the
2010/84/EU introduced the concept of the pharmaco­ risks of medicinal products, as referred to in the second
subparagraph of Article 101(1) of Directive 2001/83/EC.
vigilance system master file. In order to accurately
reflect the pharmacovigilance system used by the
(8) If marketing authorisation holders, national competent
(1 ) OJ L 136, 30.4.2004, p. 1.
(2 ) OJ L 311, 28.11.2001, p. 67. authorities and the Agency use performance indicators
(3 ) OJ L 348, 31.12.2010, p. 1. to monitor the good performance of pharmacovigilance
(4 ) OJ L 348, 31.12.2010, p. 74. activities, those indicators should be documented.
L 159/6 EN Official Journal of the European Union 20.6.2012

(9) Pharmacovigilance activities rely increasingly on the facilitate their processing and evaluation, common
periodic monitoring of large databases, such as the format and content requirements should be established.
Eudravigilance database. Whereas the Eudravigilance
database is expected to be a major source of pharmaco­
vigilance information, account should also be taken of
pharmacovigilance information coming from other (15) Risk management plans are required for all new
sources. marketing authorisation applications. They contain a
detailed description of the risk management system
used by the marketing authorisation holder. In order to
facilitate the production of risk management plans and
(10) Marketing authorisation holders, national competent their evaluation by the competent authorities, common
authorities and the Agency should continuously format and content requirements should be established.
monitor the data in the Eudravigilance database to
determine whether there are new risks or whether risks
have changed and whether those risks have an impact on
the risk-benefit balance of the medicinal product. They
should validate and confirm signals, as appropriate, based (16) Where competent authorities have concerns as to the
on an examination of individual case safety reports, safety of a medicinal product, they should be able to
aggregated data from active surveillance systems or impose on marketing authorisation holders the
studies, literature information or other data sources. It obligation to conduct post-authorisation safety studies.
is therefore necessary to establish common requirements The marketing authorisation holder should submit a
for signal detection, to clarify the respective monitoring draft protocol before those studies are conducted.
roles of marketing authorisation holders, national Moreover, the marketing authorisation holder should
competent authorities and the Agency, to clarify how provide, at the appropriate stage, a study abstract and a
signals are validated and confirmed where appropriate final study report. It is appropriate to provide that the
and to specify the signal management process. protocol, the abstract and the final study report follow a
common format in order to facilitate the approval and
oversight of those studies by the Pharmacovigilance Risk
Assessment Committee or the competent authorities in
case of studies to be conducted in only one Member
(11) As a general principle, signal detection should follow a
State that requests the study according to Article 22a
recognised methodology. However, the methodology
of Directive 2001/83/EC.
may vary depending on the type of medicinal product
it is intended to cover.

(17) This Regulation should apply without prejudice to

(12) The use of internationally agreed terminology, format Directive 95/46/EC of the European Parliament and of
and standards should facilitate the interoperability of the Council of 24 October 1995 on the protection of
systems used for the performance of pharmacovigilance individuals with regard to the processing of personal data
activities and avoids the duplication of encoding activities and on the free movement of such data (1) and Regu­
concerning the same information. It should also allow for lation (EC) No 45/2001 of the European Parliament and
an easier information exchange between regulatory auth­ of the Council of 18 December 2000 on the protection
orities on an international level. of individuals with regard to the processing of personal
data by the Community institutions and bodies and on
the free movement of such data (2). The fundamental
right to protection of personal data should be fully and
(13) In order to simplify the reporting of suspected adverse effectively guaranteed in all pharmacovigilance activities.
reactions, the marketing authorisation holder and the The purpose of safeguarding public health constitutes a
Member States should report those reactions only to substantial public interest and consequently the
the Eudravigilance database. The Eudravigilance database processing of personal data should be justified if iden­
should be equipped to immediately forward reports on tifiable personal data are processed only where necessary
suspected adverse reactions received from marketing and only where the parties involved assess this necessity
authorisation holders to the Member States on whose at every stage of the pharmacovigilance process. National
territory the reaction occurred. It is therefore necessary competent authorities and marketing authorisation
to establish a common electronic format for the trans­ holders may apply pseudonymisation where appropriate,
mission of suspected adverse reaction reports by thereby replacing identifiable personal data with pseu­
marketing authorisation holders and Member States to donyms.
the Eudravigilance database.

(18) The measures provided for in this Regulation are in

(14) Periodic safety update reports are an important accordance with the opinion of the Standing
instrument to monitor the development of the safety Committee for Medicinal Products for Human Use,
profile of a medicinal product after it has been placed
on the Union market, including an integrated (re-) (1) OJ L 281, 23.11.1995, p. 31.
evaluation of the risk-benefit balance. In order to (2) OJ L 8, 12.1.2001, p. 1.
20.6.2012 EN Official Journal of the European Union L 159/7

HAS ADOPTED THIS REGULATION: report production, signal detection and analysis, risk
management plan management, pre- and post-authorisation
study management, and management of safety variations to
CHAPTER I
the terms of a marketing authorisation;
Pharmacovigilance system master file
Article 1 (3) a description of the location of, functionality of and oper­
ational responsibility for computerised systems and
Structure of the pharmacovigilance system master file databases used to receive, collate, record and report safety
1. The information in the pharmacovigilance system master information and an assessment of their fitness for purpose;
file shall be accurate and reflect the pharmacovigilance system
in place. (4) a description of data handling and recording and of the
process used for each of the following pharmacovigilance
2. The marketing authorisation holder may, where appro­ activities:
priate, use separate pharmacovigilance systems for different
categories of medicinal products. Each such system shall be (a) the continuous monitoring of the risk-benefit balance of
described in a separate pharmacovigilance system master file. the medicinal product(s), the result of that monitoring
and the decision-making process for taking appropriate
All medicinal products for which the marketing authorisation measures;
holder obtained a marketing authorisation in accordance with
Directive 2001/83/EC or Regulation (EC) No 726/2004 shall be
(b) operation of the risk management system(s) and of the
covered by a pharmacovigilance system master file.
monitoring of the outcome of risk minimisation
measures;
Article 2
Content of the pharmacovigilance system master file (c) collection, assessment and reporting of individual case
safety reports;
The pharmacovigilance system master file shall contain at least
all of the following elements:
(d) drafting and submission of periodic safety update
reports;
(1) the following information relating to the qualified person
responsible for pharmacovigilance:
(e) procedures for communicating safety concerns and
safety variations to the summary of product character­
(a) a description of the responsibilities demonstrating that
istics and package leaflet to healthcare professionals and
the qualified person responsible for pharmacovigilance
the general public;
has sufficient authority over the pharmacovigilance
system in order to promote, maintain and improve
compliance with pharmacovigilance tasks and responsi­ (5) a description of the quality system for the performance of
bilities; pharmacovigilance activities, including all of the following
elements:
(b) a summary curriculum vitae of the qualified person
responsible for pharmacovigilance, including proof of (a) a description of the management of human resources
registration with the Eudravigilance database; referred to in Article 10 containing the following
elements: a description of the organisational structure
(c) contact details of the qualified person responsible for for the performance of pharmacovigilance activities
pharmacovigilance; with a reference to the location of qualification
records of the personnel; a summary description of
the training concept, including a reference to the
(d) details of back-up arrangements to apply in the absence location of training files; instructions on critical
of the qualified person responsible for pharmacovigi­ processes;
lance;

(b) a description of the record management system referred

(e) responsibilities of the contact person for pharmaco­ to in Article 12, including the location of the
vigilance issues where such a person has been documents used for pharmacovigilance activities;
nominated at national level in accordance with
Article 104(4) of Directive 2001/83/EC, including
contact details; (c) a description of the system for monitoring the
performance of the pharmacovigilance system and for
the compliance with Article 11;
(2) a description of the organisational structure of the
marketing authorisation holder, including the list of the
site(s) where the following pharmacovigilance activities are (6) where applicable, a description of the activities and/or
undertaken: individual case safety report collection, evalu­ services subcontracted by the marketing authorisation
ation, safety database case entry, periodic safety update holder in accordance with Article 6(1).
L 159/8 EN Official Journal of the European Union 20.6.2012

Article 3 change in the location of the pharmacovigilance system master

file or changes to the contact details and name of the qualified
Content of the Annex to the pharmacovigilance system person responsible for pharmacovigilance. The Agency shall
master file update the Eudravigilance database referred to in Article 24(1)
The pharmacovigilance system master file shall have an Annex of Regulation (EC) No 726/2004 and, where necessary, the
containing the following documents: European medicines web-portal referred to in Article 26(1) of
Regulation (EC) No 726/2004 accordingly.

(1) a list of medicinal products covered by the pharmaco­

vigilance system master file, including the name of the Article 5
medicinal product, the international non-proprietary name
(INN) of the active substance(s), and the Member State(s) in Form of the documents contained in the
which the authorisation is valid; pharmacovigilance system master file
1. Pharmacovigilance system master file documents shall be
(2) a list of written policies and procedures for the purpose of complete and legible. Where appropriate, information may be
complying with Article 11(1); provided in the form of charts 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.
(3) the list of subcontracts referred to in Article 6(2);

(4) a list of the tasks that have been delegated by the qualified 2. The particulars and documents of the pharmacovigilance
person for pharmacovigilance; system master file may be presented in modules in accordance
with the system delineated in detail in the guidance on good
pharmacovigilance practices.
(5) a list of all scheduled and completed audits;

3. The pharmacovigilance system master file may be stored

(6) where applicable, a list of the performance indicators in electronic form provided that the media used for storage
referred to in Article 9; remain readable over time and a clearly arranged printed copy
can be made available for audits and inspections.
(7) where applicable, a list of other pharmacovigilance system
master files held by the same marketing authorisation
holder; 4. The marketing authorisation holder shall record in the
logbook referred to in point 8 of Article 3 any alteration of
the content of the pharmacovigilance system master file made
(8) a logbook containing the information referred to in within the last five years, with the exception of the information
Article 5(4). referred to in point 1(b) to (e) of Article 2 and in Article 3. The
marketing authorisation holder shall indicate in the logbook the
Article 4 date, the person responsible for the alteration and, where appro­
priate, the reason for the alteration.
Maintenance
1. The marketing authorisation holder shall keep the phar­
Article 6
macovigilance system master file up to date and, where
necessary, revise it to take account of experience gained, of Subcontracting
technical and scientific progress and of amendments to
Directive 2001/83/EC and Regulation (EC) No 726/2004. 1. The marketing authorisation holder may subcontract
certain activities of the pharmacovigilance system to third
parties. It shall nevertheless retain full responsibility for the
2. The pharmacovigilance system master file and its Annex completeness and accuracy of the pharmacovigilance system
shall be subject to version control and shall indicate the date master file.
when it was last updated by the marketing authorisation holder.

2. The marketing authorisation holder shall draw up a list of

3. Any deviations from the pharmacovigilance procedures,
its existing subcontracts between it and the third parties referred
their impact and their management shall be documented in
to in paragraph 1, specifying the product(s) and territory(ies)
the pharmacovigilance system master file until resolved.
concerned.

4. Without prejudice to the requirements set out in

Commission Regulation (EC) No 1234/2008 of 24 November Article 7
2008 concerning the examination of variations to the terms of
marketing authorisations for medicinal products for human use Availability and location of the pharmacovigilance system
and veterinary medicinal products (1), the marketing authori­ master file
sation holder shall notify immediately the Agency of any 1. The pharmacovigilance system master file shall be located
either at the site in the Union where the main pharmaco­
(1) OJ L 334, 24.11.2008, p. 7. vigilance activities of the marketing authorisation holder are
20.6.2012 EN Official Journal of the European Union L 159/9

performed or at the site in the Union where the qualified person (d) quality improvements: correcting and improving the
responsible for pharmacovigilance operates. structures and processes where necessary.

2. The marketing authorisation holder shall ensure that the

4. All elements, requirements and provisions adopted for the
qualified person for pharmacovigilance has permanent access to
quality system shall be documented in a systematic and orderly
the pharmacovigilance system master file.
manner in the form of written policies and procedures, such as
quality plans, quality manuals and quality records.
3. The pharmacovigilance system master file shall be perma­
nently and immediately available for inspection at the site where
it is kept. 5. All persons involved in the procedures and processes of
the quality systems established by the national competent auth­
Where the pharmacovigilance system master file is kept in elec­ orities and the Agency for the performance of pharmaco­
tronic form in accordance with Article 5(3), it is sufficient for vigilance activities shall be responsible for the good functioning
the purposes of this Article that the data stored in electronic of those quality systems and shall ensure a systematic approach
form is directly available at the site where the pharmaco­ towards quality and towards the implementation and main­
vigilance system master file is kept. tenance of the quality system.

4. For the purposes of Article 23(4) of Directive Article 9

2001/83/EC, the national competent authority may limit its
request to specific parts or modules of the pharmacovigilance Performance indicators
system master file and the marketing authorisation holder shall 1. The marketing authorisation holder, national competent
bear the costs of submitting the copy of the pharmacovigilance authorities and the Agency may use performance indicators to
system master file. continuously monitor the good performance of pharmaco­
vigilance activities.
5. The national competent authority and the Agency may
request the marketing authorisation holder to submit a copy
of the logbook referred to in point 8 of Article 3 at regular 2. The Agency may publish a list of performance indicators
intervals. on the basis of a recommendation of the Pharmacovigilance
Risk Assessment Committee.
CHAPTER II

Minimum requirements for the quality systems for the Section 2

performance of pharmacovigilance activities Minimum requirements for the quality
systems for the performance of
Section 1
pharmacovigilance activities by marketing
General provisions authorisation holders
Article 8 Article 10
Quality system Management of human resources
1. Marketing authorisation holders, the national competent 1. The marketing authorisation holder shall have sufficient
authorities and the Agency shall establish and use a quality competent and appropriately qualified and trained personnel
system that is adequate and effective for the performance of available for the performance of pharmacovigilance activities.
their pharmacovigilance activities.
For the purposes of the first subparagraph, the market auth­
2. The quality system shall cover organisational structure, orisation holder shall ensure that the qualified person
responsibilities, procedures, processes and resources, appropriate responsible for pharmacovigilance has acquired adequate theor­
resource management, compliance management and record etical and practical knowledge for the performance of phar­
management. macovigilance activities. Where the qualified person has not
completed basic medical training in accordance with Article 24
3. The quality system shall be based on all of the following of Directive 2005/36/EC of the European Parliament and of the
activities: Council of 7 September 2005 on the recognition of profes­
sional qualifications (1), the market authorisation holder shall
(a) quality planning: establishing structures and planning inte­ ensure that the qualified person responsible for pharmaco­
grated and consistent processes; vigilance is assisted by a medically trained person. This
assistance shall be duly documented.
(b) quality adherence: carrying out tasks and responsibilities in
accordance with quality requirements; 2. The duties of the managerial and supervisory staff,
including the qualified person responsible for pharmacovigi­
(c) quality control and assurance: monitoring and evaluating lance, shall be defined in job descriptions. Their hierarchical
how effectively the structures and processes have been relationships shall be defined in an organisational chart. The
established and how effectively the processes are being
carried out; (1) OJ L 255, 30.9.2005, p. 22.
L 159/10 EN Official Journal of the European Union 20.6.2012

marketing authorisation holder shall ensure that the qualified (g) appropriate communication by the marketing authorisation
person responsible for pharmacovigilance has sufficient holder of relevant safety information to healthcare profes­
authority to influence the performance of the quality system sionals and patients.
and the pharmacovigilance activities of the marketing authori­
sation holder.
2. Where a marketing authorisation holder has subcontracted
some of its pharmacovigilance tasks, it shall retain responsibility
3. All personnel involved in the performance of pharmaco­ for ensuring that an effective quality system is applied in
vigilance activities shall receive initial and continued training in relation to those tasks.
relation to their role and responsibilities. The marketing auth­
orisation holder shall keep training plans and records for docu­
menting, maintaining and developing the competences of Article 12
personnel and make them available for audit or inspection. Record management and data retention
1. Marketing authorisation holders shall record all pharmaco­
4. The marketing authorisation holder shall provide appro­ vigilance information and ensure that it is handled and stored
priate instructions on the processes to be used in case of so as to allow for accurate reporting, interpretation and verifi­
urgency, including business continuity. cation of that information.

Article 11 Marketing authorisation holders shall put in place a record

management system for all documents used for pharmaco­
Compliance management
vigilance activities that ensures the retrievability of those
1. Specific quality system procedures and processes shall be documents as well as the traceability of the measures taken to
in place in order to ensure the following: investigate safety concerns, of the timelines for those investi­
gations and of decisions on safety concerns, including their date
and the decision-making process.
(a) the continuous monitoring of pharmacovigilance data, the
examination of options for risk minimisation and
prevention and appropriate measures are taken by the Marketing authorisation holders shall establish mechanisms
marketing authorisation holder; enabling the traceability and follow-up of adverse reaction
reports.

(b) the scientific evaluation by the marketing authorisation

holder of all information on the risks of medicinal 2. Marketing authorisation holders shall arrange for the
products, as referred to in the second subparagraph of elements referred to in Article 2 to be kept for at least five
Article 101(1) of Directive 2001/83/EC; years after the system as described in the pharmacovigilance
system master file has been formally terminated by the
marketing authorisation holder.
(c) the submission of accurate and verifiable data on serious
and non-serious adverse reactions to the Eudravigilance
database within the time limits provided for in the first Pharmacovigilance data and documents relating to individual
and second subparagraphs respectively of Article 107(3) authorised medicinal products shall be retained as long as the
of Directive 2001/83/EC; 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
(d) the quality, integrity and completeness of the information law or national law so requires.
submitted on the risks of medicinal products, including
processes to avoid duplicate submissions and to validate
signals in accordance with Article 21(2); Article 13
Audit
(e) effective communication by the marketing authorisation 1. Risk-based audits of the quality system shall be performed
holder with the national competent authorities and the at regular intervals to ensure that the quality system complies
Agency, including communication on new risks or with the quality system requirements set out in Articles 8, 10,
changed risks, the pharmacovigilance system master file, 11 and 12 and to determine its effectiveness. Those audits shall
risk management systems, risk minimisation measures, be conducted by individuals who have no direct involvement in
periodic safety update reports, corrective and preventive or responsibility for the matters or processes being audited.
actions, and post-authorisation studies;

2. Corrective action(s), including a follow-up audit of defi­

(f) the update of product information by the marketing auth­ ciencies, shall be taken where necessary. A report on the results
orisation holder in the light of scientific knowledge, of the audit shall be drawn up for each audit and follow-up
including the assessments and recommendations made audit. The audit report shall be sent to the management
public via the European medicines web-portal, and on the responsible for the matters audited. The dates and results of
basis of a continuous monitoring by the marketing auth­ audits and follow-up audits shall be documented in accordance
orisation holder of information published on the European with the second subparagraph of Article 104(2) of Directive
medicines web-portal; 2001/83/EC.
20.6.2012 EN Official Journal of the European Union L 159/11

Section 3 2. In addition to the procedures referred to in paragraph 1,

national competent authorities shall establish procedures for
Minimum requirements for the quality collecting and recording all suspected adverse reactions that
systems for the performance of occur in their territory.
pharmacovigilance activities by national
competent authorities and the Agency
3. The Agency shall establish procedures for the monitoring
Article 14 of medical literature in accordance with Article 27 of Regu­
Management of human resources lation (EC) No 726/2004.

1. The national competent authorities and the Agency shall

have sufficient competent and appropriately qualified and Article 16
trained personnel available for the performance of pharmaco­ Record management and data retention
vigilance activities.
1. The national competent authorities and the Agency shall
The organisational structures and the distribution of tasks and record all pharmacovigilance information and ensure that it is
responsibilities shall be clear and, to the extent necessary, handled and stored so as to allow for accurate reporting, inter­
accessible. Contact points shall be established. pretation and verification of that information.

2. All personnel involved in the performance of pharmaco­ They shall put in place a record management system for all
vigilance activities shall receive initial and continued training. documents used for pharmacovigilance activities that ensures
The national competent authorities and the Agency shall keep the retrievability of those documents as well as the traceability
training plans and records for documenting, maintaining and of the measures taken to investigate safety concerns, of the
developing the competences of personnel and shall make them timelines for those investigations and of decisions on safety
available for audit. concerns, including their date and the decision-making process.

3. Appropriate instructions on the processes to be used in 2. The national competent authorities and the Agency shall
case of urgency, including business continuity, shall be provided arrange for the essential documents describing their pharmaco­
by the national competent authorities and by the Agency to vigilance system to be kept for at least five years after the
their personnel. system has been formally terminated.

Article 15 Pharmacovigilance data and documents relating to individual

Compliance management authorised medicinal products shall be retained as long as the
product is authorised and for at least 10 years after the
1. The national competent authorities and the Agency shall marketing authorisation has expired. However, the documents
establish specific procedures and processes in order to achieve shall be retained for a longer period where Union law or
all of the following objectives: national law so requires.

(a) ensuring the evaluation of the quality, including Article 17

completeness, of pharmacovigilance data submitted;
Audit
(b) ensuring the assessment of pharmacovigilance data and its 1. Risk-based audits of the quality system shall be performed
processing within the timelines provided by Directive at regular intervals according to a common methodology to
2001/83/EC and Regulation (EC) No 726/2004; ensure that the quality system complies with the requirements
set out in Articles 8, 14, 15 and 16 and to ensure its effec­
(c) ensuring independence in the performance of pharmaco­ tiveness.
vigilance activities;
2. Corrective action, including a follow-up audit of defi­
(d) ensuring effective communication among national ciencies, shall be taken where necessary. The audit report shall
competent authorities and between the national competent be sent to the management responsible for the matters audited.
authorities and the Agency as well as with patients, The dates and results of audits and follow-up audits shall be
healthcare professionals, marketing authorisation holders documented.
and the general public;
CHAPTER III
(e) guaranteeing that the national competent authorities and the
Agency inform each other and the Commission of their Minimum requirements for the monitoring of data in the
intention to make announcements relating to the safety of Eudravigilance database
a medicinal product authorised in several Member States or Article 18
an active substance contained in such a medicinal product
in accordance with Article 106a of Directive 2001/83/EC; General requirements
1. The Agency and national competent authorities shall
(f) conducting inspections, including pre-authorisation inspec­ cooperate in the monitoring of the data available in the Eudra­
tions. vigilance database.
L 159/12 EN Official Journal of the European Union 20.6.2012

2. Marketing authorisation holders shall monitor the data Article 21

available in the Eudravigilance database to the extent that they
have access to that database. Signal management process
1. The signal management process shall include the
3. Marketing authorisation holders, the national competent following activities: signal detection, signal validation, signal
authorities and the Agency shall ensure the continuous moni­ confirmation, signal analysis and prioritisation, signal
toring of the Eudravigilance database with a frequency propor­ assessment, and recommendation for action.
tionate to the identified risk, the potential risks and the need for
additional information. For the purposes of this Article, ‘signal validation’ means the
process of evaluating the data supporting the detected signal in
4. The competent authority of each Member State shall be order to verify that the available documentation contains
responsible for monitoring the data originating in the territory sufficient evidence demonstrating the existence of a new poten­
of that Member State. tially causal association, or a new aspect of a known associ­
ation, and therefore justifies further analysis of the signal.
Article 19
2. Where a marketing authorisation holder detects a new
Identification of changed risks and new risks signal when monitoring the Eudravigilance database, it shall
1. The identification of new risks or changed risks shall be validate it and shall forthwith inform the Agency and national
based on the detection and analysis of the signals concerning a competent authorities.
medicinal product or an active substance.
3. Where it is considered that a validated signal requires
For the purposes of this chapter, ‘signal’ means information further analysis, it shall be confirmed as soon as possible and
arising from one or multiple sources, including observations no later than 30 days from its receipt as follows:
and experiments, which suggests a new potentially causal
association, or a new aspect of a known association between (a) where the signal concerns a product authorised in
an intervention and an event or set of related events, either accordance with Directive 2001/83/EC, it shall be
adverse or beneficial, which is judged to be of sufficient like­ confirmed by the competent authority of a Member State
lihood to justify verificatory action. in which the medicinal product is marketed or of any lead
Member State or co-leader appointed in accordance with
For the purpose of monitoring data in the Eudravigilance Article 22(1);
database, only signals related to an adverse reaction shall be
considered. (b) where the signal concerns a product authorised in
accordance with Regulation (EC) No 726/2004, it shall be
2. The detection of a signal shall be based on a multidis­ confirmed by the Agency in collaboration with the Member
ciplinary approach. Signal detection within the Eudravigilance States.
database shall be complemented by statistical analysis, where
appropriate. After consultation with the Pharmacovigilance
When analysing the validated signal, national competent auth­
Risk Assessment Committee, the Agency may publish a list of
orities and the Agency may take into account other information
medical events that have to be taken into account for the
available on the medicinal product.
detection of a signal.

Article 20 Where the validity of the signal is not confirmed, special

attention shall be paid to non-confirmed signals concerning a
Methodology for determining the evidentiary value of a medicinal product where those signals are subsequently
signal followed by new signals concerning the same medicinal
product.
1. National competent authorities, marketing authorisation
holders and the Agency shall determine the evidentiary value
of a signal by using a recognised methodology taking into 4. Without prejudice to paragraphs 2 and 3, national
account the clinical relevance, quantitative strength of the competent authorities and the Agency shall validate and
association, the consistency of the data, the exposure–response confirm any signal that they have detected during their
relationship, the biological plausibility, experimental findings, continuous monitoring of the Eudravigilance database.
possible analogies and the nature and quality of the data.
5. Any confirmed signal shall be entered in the tracking
2. Different types of factors may be taken into account for system administered by the Agency and shall be transmitted
the prioritisation of signals, in particular whether the association to the Pharmacovigilance Risk Assessment Committee for the
or medicinal product is new, factors related to the strength of initial analysis and prioritisation of signals in accordance with
the association, factors related to the seriousness of the reaction Article 107h(2) of Directive 2001/83/EC and Article 28a(2) of
involved and factors related to the documentation of reports to Regulation (EC) No 726/2004.
the Eudravigilance database.
6. The Agency shall inform forthwith the marketing auth­
3. The Pharmacovigilance Risk Assessment Committee shall orisation holder(s) concerned of the conclusions of the Phar­
regularly review the methodology(ies) used and publish recom­ macovigilance Risk Assessment Committee of the assessment of
mendations, as appropriate. any confirmed signal.
20.6.2012 EN Official Journal of the European Union L 159/13

Article 22 (c) customised grouping and stratification of data enabling the

identification of patient groups with a higher risk of
Worksharing for signal management occurrence of adverse reactions or with a risk of a more
1. For medicinal products authorised in accordance with severe adverse reaction;
Directive 2001/83/EC in more than one Member State and
for active substances contained in several medicinal products
where at least one marketing authorisation has been granted (d) statistical signal detection methods.
in accordance with Directive 2001/83/EC, Member States may
agree within the coordination group provided for by Article 27
of Directive 2001/83/EC to appoint a lead Member State and, The Agency shall also ensure appropriate support for the moni­
where appropriate, a co-leader. Any such appointment shall be toring of the Eudravigilance database by marketing authori­
reviewed at least every four years. sation holders.

The lead Member State shall monitor the Eudravigilance Article 24

database and shall validate and confirm signals in accordance
with Article 21(3) and (4) on behalf of the other Member States. Signal detection audit trail
The Member State appointed as co-leader shall assist the lead
1. The national competent authorities and the Agency shall
Member State in the fulfilment of its tasks.
keep an audit trail of their signal detection activities conducted
in the Eudravigilance database and of the relevant queries and
their results.
2. When appointing a lead Member State and as appropriate
a co-leader, the coordination group may take into account
whether any Member State is acting as reference Member
State in accordance with Article 28(1) of Directive 2001/83/EC 2. The audit trail shall allow traceability of how signals have
or as a rapporteur for the assessment of periodic safety update been detected and of how validated and confirmed signals have
reports in accordance with Article 107e of that Directive. been assessed.

3. The Agency shall publish on the European medicines web- CHAPTER IV

portal a list of the active substances that are subject to work­ Use of terminology, formats and standards
sharing in accordance with this Article and the lead Member
State and co-leader appointed for monitoring those substances Article 25
in the Eudravigilance database. Use of internationally agreed terminology
1. For the classification, retrieval, presentation, risk-benefit
4. Without prejudice to paragraph 1, all Member States shall evaluation and assessment, electronic exchange and communi­
remain responsible for monitoring the data in the Eudra­ cation of pharmacovigilance and medicinal product
vigilance database in accordance with Article 107h(1)(c) and information, Member States, marketing authorisation holders
Article 107h(3) of Directive 2001/83/EC. and the Agency shall apply the following terminology:

5. For medicinal products authorised in accordance with (a) the Medical Dictionary for Regulatory Activities (MedDRA)
Regulation (EC) No 726/2004, the Agency shall be assisted in as developed by the International Conference on Harmon­
the monitoring of data in the Eudravigilance database by the isation of Technical Requirements for Registration of Phar­
rapporteur appointed by the Pharmacovigilance Risk maceuticals for Human Use (ICH), multidisciplinary topic
Assessment Committee in accordance with Article 62(1) of M1;
Regulation (EC) No 726/2004.

(b) the lists of Standard Terms published by the European Phar­

Article 23 macopoeia Commission;
Signal detection support
The Agency shall support the monitoring of the Eudravigilance (c) the terminology set out in EN ISO 11615:2012, Health
database by providing national competent authorities with Informatics, Identification of Medicinal Products (IDMP)
access to the following information: standard, ‘Data elements and structures for unique identifi­
cation and exchange of regulated medicinal product
information’ (ISO/FDIS 11615:2012);
(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; (d) the terminology set out in EN ISO 11616:2012 Health
Informatics, Identification of Medicinal Products (IDMP)
standard, ‘Data elements and structures for unique identifi­
(b) customised queries supporting the evaluation of individual cation and exchange of regulated pharmaceutical product
case safety reports and case series; information’ (ISO/FDIS 11616:2012);
L 159/14 EN Official Journal of the European Union 20.6.2012

(e) the terminology set out in EN ISO 11238:2012 Health (b) ICH E2B(R2) ‘Maintenance of the ICH guideline on clinical
Informatics, Identification of Medicinal Products (IDMP) safety data management: data elements for transmission of
standard, ‘Data elements and structures for unique identifi­ Individual Case Safety Reports’;
cation and exchange of regulated information on substances’
(ISO/FDIS 11238:2012);

(c) ICH M2 standard ‘Electronic Transmission of Individual Case

Safety Reports Message Specification’.
(f) the terminology set out in EN ISO 11239:2012 Health
Informatics, Identification of Medicinal Products (IDMP)
standard, ‘Data elements and structures for unique identifi­
cation and exchange of regulated information on phar­
maceutical dose forms, units of presentation and routes of 2. For the purpose of paragraph 1 national competent auth­
administration’ (ISO/FDIS 11239:2012); orities, marketing authorisation holders and the Agency may
also apply the following formats and standards:

(g) the terminology set out in EN ISO 11240:2012 Health

Informatics, Identification of Medicinal Products (IDMP) (a) EN ISO 27953-2:2011 Health Informatics, Individual case
standard, ‘Data elements and structures for unique identifi­ safety reports (ICSRs) in pharmacovigilance — Part 2:
cation and exchange of units of measurement’ (ISO/FDIS Human pharmaceutical reporting requirements for ICSR
11240:2012). (ISO 27953-2:2011);

2. Member States, national competent authorities or (b) EN ISO 11615:2012, Health Informatics, Identification of
marketing authorisation holders shall request the International Medicinal Products (IDMP) standard, ‘Data elements and
Conference on Harmonisation of Technical Requirements for structures for unique identification and exchange of
Registration of Pharmaceuticals for Human Use, the European regulated medicinal product information’ (ISO/FDIS
Pharmacopoeia Commission, the European Committee for Stan­ 11615:2012);
dardisation or the International Organisation for Standardisation
to add a new term to the terminology referred to in paragraph
1, where necessary. In such a case, they shall inform the Agency
accordingly. (c) 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
3. Member States, marketing authorisation holders and the 11616:2012);
Agency shall monitor the use of the terminology referred to in
paragraph 1 either systematically or by regular random evalu­
ation.
(d) 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
Article 26
11238:2012);
Use of internationally agreed formats and standards
1. For the description, retrieval, presentation, risk-benefit
evaluation and assessment, electronic exchange and communi­
cation of pharmacovigilance and medicinal product (e) EN ISO 11239:2012, Health Informatics, Identification of
information, national competent authorities, marketing authori­ Medicinal Products (IDMP) standard, ‘Data elements and
sation holders and the Agency shall apply the following formats structures for unique identification and exchange of
and standards: regulated information on pharmaceutical dose forms, units
of presentation and routes of administration’ (ISO/FDIS
11239:2012);

(a) the Extended Eudravigilance Medicinal Product Report

Message (XEVPRM), which is the format for the electronic
submission of information on all medicinal products for (f) EN ISO 11240:2012, Health Informatics, Identification of
human use authorised in the Union in accordance with Medicinal Products (IDMP) standard, ‘Data elements and
the second subparagraph of Article 57(2) of Regulation structures for unique identification and exchange of units
(EC) No 726/2004, as published by the Agency; of measurement’ (ISO/FDIS 11240:2012).
20.6.2012 EN Official Journal of the European Union L 159/15

CHAPTER V tation of good clinical practice in the conduct of clinical

trials on medicinal products for human use (2);
Transmission of reports of suspected adverse reactions
Article 27 (d) information on the primary source(s): information iden­
Individual case safety reports tifying the reporter, including Member State of residence
and professional qualifications;
Individual case safety reports shall be used for reporting to the
Eudravigilance database suspected adverse reactions to a (e) information identifying the patient (and parent in the case
medicinal product that occur in a single patient at a specific of a parent-child report), including age at the time of the
point in time. onset of the first reaction, age group, gestation period
when reaction/event was observed in the foetus, weight,
Article 28 height or gender, last menstrual date and/or gestation
period at time of exposure;
Content of the individual case safety report
1. Member States and marketing authorisation holders shall (f) relevant medical history and concurrent conditions;
ensure that individual case safety reports are as complete as
possible and shall communicate the updates of those reports (g) the name, as defined in Article 1(20) of Directive
to the Eudravigilance database in an accurate and reliable 2001/83/EC, of the medicinal product(s) suspected to be
manner. 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
In the case of expedited reporting, the individual case safety
that allow for the identification of the medicinal product(s),
report shall include at least an identifiable reporter, an iden­
including the name of the marketing authorisation holder,
tifiable patient, one suspected adverse reaction and the
marketing authorisation number, country of marketing
medicinal product(s) concerned.
authorisation, pharmaceutical form and (parent) route(s)
of administration, indication(s) for use in the case, dose
2. Member States and marketing authorisation holders shall administered, start date and end date of administration,
record the details necessary for obtaining follow-up information actions taken with the medicinal product(s), effect of the
on individual case safety reports. The follow-up of reports shall dechallenge and rechallenge for suspect medicinal products;
be adequately documented.
(h) for biological medicinal product(s), the batch number(s);
3. When reporting suspected adverse reactions, Member
States and marketing authorisation holders shall provide all (i) concomitant medicinal products, identified in accordance
available information on each individual case, including the with point (g), which are not suspected to be related to
following: the occurrence of the adverse reaction and past-medical
drug therapy for the patient (and for the parent), where
applicable;
(a) administrative information: report type, date and a
worldwide unique case identification number as well as
unique sender identification and sender type; the date on (j) information on the suspected adverse reaction(s): start date
which the report was first received from the source and the and end date of the suspected adverse reaction(s) or
date of receipt of the most recent information, using a duration, seriousness, outcome of the suspected adverse
precise date; other case identifiers and their sources, as reaction(s) at the time of last observation, time intervals
well as references to additional available documents held between suspect medicinal product administration and
by the sender of the individual case safety report, where start of adverse reaction, the original reporter’s words or
applicable; short phrases used to describe the reaction(s) and Member
State or third-country of occurrence of the suspected
adverse reaction;
(b) literature reference in accordance with the ‘Vancouver style’
as developed by the International Committee of Medical (k) results of tests and procedures relevant to the investigation
Journal Editors (1) for adverse reactions reported in the of the patient;
worldwide literature, including a comprehensive English
summary of the article;
(l) date and reported cause of death, including autopsy-
determined causes, in the event of death of the patient;
(c) study type, study name and the sponsor’s study number or
study registration number for reports from studies not (m) a case narrative, where possible, providing all relevant
covered by Directive 2001/20/EC of the European information for individual cases with the exception of
Parliament and of the Council of 4 April 2001 on the non-serious adverse reactions;
approximation of the laws, regulations and administrative
provisions of the Member States relating to the implemen­
(n) reasons for nullifying or amending an individual case safety
report.
(1) International Committee of Medical Journal Editors. Uniform
requirements for manuscripts submitted to biomedical journals. N
Engl J Med 1997; 336:309-15. (2) OJ L 121, 1.5.2001, p. 34.
L 159/16 EN Official Journal of the European Union 20.6.2012

For the purposes of point (b), upon request of the Agency, the initiated, managed or financed by the marketing authorisation
marketing authorisation holder that transmitted the initial holder voluntarily or pursuant to obligations imposed by the
report shall provide a copy of the relevant article taking into national competent authorities, the Agency or the Commission.
account copyright restrictions, and a full translation of that All post-authorisation obligations shall be listed in the summary
article into English. of the risk management plan together with a timeframe.

For the purposes of point (h), a follow-up procedure shall be in Article 31

place to obtain the batch number where it is not indicated in
the initial report. Summary of the risk management plan

For the purposes of point (m), the information shall be 1. The summary of the risk management plan to be made
presented in a logical time sequence, in the chronology of the publicly available in accordance with point (c) of Article 106 of
patient’s experience including clinical course, therapeutic Directive 2001/83/EC and Article 26(1)(c) of Regulation (EC)
measures, outcome and follow-up information obtained; any No 726/2004 shall include key elements of the risk
relevant autopsy or post-mortem findings shall also be management plan with a specific focus on risk minimisation
summarised in the narrative. activities and, with regard to the safety specification of the
medicinal product concerned, important information on
4. Where suspected adverse reactions are reported in potential and identified risks as well as missing information.
narrative and textual descriptions in an official language of
the Union other than English, the original verbatim text and 2. Where a risk management plan concerns more than one
a summary thereof in English shall be provided by the medicinal product, a separate summary of the risk management
marketing authorisation holder. plan shall be provided for each medicinal product.
Member States may report case narratives in their official
Article 32
language(s). For those reports, case translations shall be
provided where requested by the Agency or other Member Updates of the risk management plan
States for the evaluation of potential signals.
1. Where the marketing authorisation holder updates a risk
English shall be used for the reporting of suspected adverse management plan, it shall submit the updated risk management
reactions originating outside the Union. plan to the national competent authorities or the Agency as
appropriate. After agreement with the national competent auth­
Article 29 orities or the Agency as appropriate, the marketing authori­
sation holder may submit only the modules concerned by the
Format of electronic transmission of suspected adverse update. If necessary, the marketing authorisation holder shall
reactions provide the competent authorities or the Agency with an
Member States and marketing authorisation holders shall use updated summary of the risk management plan.
the formats provided for in Article 26 and the terminology
provided for in Article 25 for the electronic transmission of 2. Each submission of the risk management plan shall have a
suspected adverse reactions. distinct version number and shall be dated.

CHAPTER VI
Article 33
Risk management plans Format of the risk management plan
Article 30 The risk management plan shall be in the format set out in
Content of the risk management plan Annex I.

1. The risk management plan established by the marketing CHAPTER VII

authorisation holder shall contain the following elements:
Periodic safety update reports
(a) an identification or characterisation of the safety profile of
the medicinal product(s) concerned; Article 34
Content of periodic safety update reports
(b) an indication of how to characterise further the safety
profile of the medicinal product(s) concerned; 1. The periodic safety update report shall be based on all
available data and shall focus on new information which has
(c) a documentation of measures to prevent or minimise the emerged since the data lock point of the last periodic safety
risks associated with the medicinal product, including an update report.
assessment of the effectiveness of those interventions;

(d) a documentation of post-authorisation obligations that have 2. The periodic safety update report shall provide an accurate
been imposed as a condition of the marketing authorisation. estimate of the population exposed to the medicinal product,
including all data relating to the volume of sales and volume of
2. Products containing the same active substance and prescriptions. This estimate of exposure shall be accompanied
belonging to the same marketing authorisation holder may be by a qualitative and quantitative analysis of actual use, which
subject, where appropriate, to the same risk management plan. shall indicate, where appropriate, how actual use differs from
the indicated use based on all data available to the marketing
3. Where a risk management plan refers to post-authori­ authorisation holder, including the results of observational or
sation studies, it shall indicate whether those studies are drug utilisation studies.
20.6.2012 EN Official Journal of the European Union L 159/17

3. The periodic safety update report shall contain the results CHAPTER VIII
of assessments of the effectiveness of risk minimisation activities
relevant to the risk–benefit assessment. Post-authorisation safety studies
Article 36
Scope
4. Marketing authorisation holders shall not be required to
include systematically detailed listings of individual cases, 1. This chapter applies to non-interventional post-authori­
including case narratives, in the periodic safety update report. sation safety studies initiated, managed or financed by a
However, they shall provide case narratives in the relevant risk marketing authorisation holder under obligations imposed by
evaluation section of the periodic safety update report where a national competent authority, the Agency or the Commission
integral to the scientific analysis of a signal or safety concern in in accordance with Articles 21a and 22a of Directive
the relevant risk evaluation section. 2001/83/EC and Articles 10 and 10a of Regulation (EC) No
726/2004.

5. Based on the evaluation of the cumulative safety data and 2. The marketing authorisation holder shall submit the study
the risk-benefit analysis, the marketing authorisation holder protocol, the abstract of the final study report and the final
shall draw conclusions in the periodic safety update report as study report which have been provided in accordance with
to the need for changes and/or actions, including implications Articles 107n and 107p of Directive 2001/83/EC in English
for the approved summary of product characteristics for the except for studies to be conducted in only one Member State
product(s) for which the periodic safety update report is that requests the study according to Article 22a of Directive
submitted. 2001/83/EC. For the latter studies the marketing authorisation
holder shall provide an English translation of the title and
abstract of the study protocol as well as an English translation
of the abstract of the final study report.
6. Unless otherwise specified in the list of Union reference
dates and frequency of submission referred to in Article 107c of
Directive 2001/83/EC or agreed with the national competent
3. The marketing authorisation holder shall ensure that all
authorities or the Agency, as appropriate, a single periodic
study information is handled and stored so as to allow for
safety update report shall be prepared for all medicinal
accurate reporting, interpretation and verification of that
products containing the same active substance and authorised
information and shall ensure that the confidentiality of the
for one marketing authorisation holder. The periodic safety
records of the study subjects remains protected. The
update report shall cover all indications, routes of adminis­
marketing authorisation holder shall ensure that the analytical
tration, dosage forms and dosing regimens, irrespective of
dataset and statistical programmes used for generating the data
whether authorised under different names and through
included in the final study report are kept in electronic format
separate procedures. Where relevant, data relating to a particular
and are available for auditing and inspection.
indication, dosage form, route of administration or dosing
regimen shall be presented in a separate section of the
periodic safety update report and any safety concerns shall be
4. The Agency may publish appropriate templates for the
addressed accordingly.
protocol, abstract and final study report.

7. Unless otherwise specified in the list of Union reference Article 37

dates and frequency of submission referred to in Article 107c of
Definitions
Directive 2001/83/EC, if the substance that is the subject of the
periodic safety update report is also authorised as a component For the purposes of this chapter, the following definitions shall
of a fixed combination medicinal product, the marketing auth­ apply:
orisation holder shall either submit a separate periodic safety
update report for the combination of active substances auth­
orised for the same marketing authorisation holder, with cross- (1) ‘Start of data collection’ means the date from which
references to the single-substance periodic safety update information on the first study subject is first recorded in
report(s), or provide the combination data within one of the the study dataset or, in the case of the secondary use of
single-substance periodic safety update reports. data, the date from which data extraction starts;

Article 35 (2) ‘End of data collection’ means the date from which the
analytical dataset is completely available.
Format of periodic safety update reports
1. Electronic periodic safety update reports shall be
Article 38
submitted in the format set out in Annex II.
Format of post-authorisation safety studies
Protocols, abstracts and final study reports for non-interven­
2. The Agency may publish templates for the modules set tional post-authorisation safety studies shall be submitted in
out in Annex II. the format set out in Annex III.
L 159/18 EN Official Journal of the European Union 20.6.2012

CHAPTER IX the terminology provided for in points (c) to (g) of Article 25

shall apply from 1 July 2016.
Final provisions
Article 39 2. Article 26(2) shall apply from 1 July 2016.
Data protection
3. The obligation on the part of the marketing authorisation
This Regulation shall apply without prejudice to the obligations holder to comply with the format and content as provided for
of national competent authorities and marketing authorisation in Articles 29 to 38 shall apply from 10 January 2013.
holders relating to their processing of personal data under
Directive 95/46/EC or the obligations of the Agency relating Article 41
to its processing of personal data under Regulation (EC) No
45/2001. Entry into force and application
Article 40 This Regulation shall enter into force on the twentieth day
following that of its publication in the Official Journal of the
Transitional provisions European Union.
1. The obligation on the part of marketing authorisation
holders, national competent authorities and the Agency to use It shall apply from 10 July 2012.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Brussels, 19 June 2012.

For the Commission

The President
José Manuel BARROSO
20.6.2012 EN Official Journal of the European Union L 159/19

ANNEX I

Risk management plans

Format of the risk management plan

The risk management plan shall consist of the following modules:

Part I: Product(s) overview

Part II: Safety specification

Module SI: Epidemiology of the indication(s) and target population(s)

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 requirements for the safety specification

Module SVII: Identified and potential risks

Module SVIII: Summary of the safety concerns

Part III: Pharmacovigilance plan (including post-authorisation safety studies)

Part IV: Plans for post-authorisation efficacy studies

Part V: Risk minimisation measures (including evaluation of the effectiveness of risk minimisation activities)

Part VI: Summary of the risk management plan

Part VII: Annexes

L 159/20 EN Official Journal of the European Union 20.6.2012

ANNEX II

Format of the electronic periodic safety update reports

The periodic safety update report shall consist of the following modules:

Part I Title page including signature

Part II Executive Summary

Part III Table of contents

1. Introduction

2. Worldwide marketing authorisation 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 exposure 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 serious adverse events from clinical trials

6.3. Cumulative and interval summary tabulations from post-marketing data sources

7. Summaries of significant findings 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 use 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

10. Non-clinical data

11. Literature

12. Other periodic reports

13. Lack of efficacy in controlled clinical trials

14. Late-breaking information

20.6.2012 EN Official Journal of the European Union L 159/21

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 analysis 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 periodic safety update report

L 159/22 EN Official Journal of the European Union 20.6.2012

ANNEX III

Protocols, abstracts and final study 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 concerned, and a sub-title with a version identifier and the date of the last version.

2. Marketing authorisation holder.

3. Responsible parties including a list of all collaborating institutions and other relevant study sites.

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;
20.6.2012 EN Official Journal of the European Union L 159/23

(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 investi­
gators 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;

L 159/24 EN Official Journal of the European Union 20.6.2012

(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.
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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.