COMMISSION STAFF WORKING DOCUMENT Accompanying the document Commission Report Pharmacovigilance related activities of Member States and the European Medicines Agency concerning medicinal products for human use (2012 – 2014)
Date: 2016-08-08
Institutions: Directorate-General for Health and Food Safety, European Commission
Subjects: European Medicines Agency, European cooperation, consumer protection, drug surveillance, market approval, marketing standard, medicinal product, public health, withdrawal from the market

EN 

   EN 

   EUROPEAN COMMISSION  Brussels, 8.8.2016  SWD(2016) 284 final   COMMISSION STAFF WORKING DOCUMENT Accompanying the document Commission Report Pharmacovigilance related activities of Member States and the European Medicines Agency concerning medicinal products for human use  (2012 – 2014) {COM(2016) 498 final}  
 
 
 
 
EXECUTIVE SUMMARY  

  The European Union (EU) Member States, the European Medicines Agency (EMA), and the 
European  Commission  work  together  in  a  network  to  support  safe  and  effective  use  of 
medicines  by  patients  and  healthcare  professionals.  Safety  of  medicines  is  monitored  and 
assessed continuously after marketing. 

  New European legislation which came into operation in mid-2012 has been designed to build 
on  and  enhance  pharmacovigilance  in  the  EU.  The  new  legislation  has  built  on  existing 
activities  and  structures  and  brought  new  tools  which  allow  regulators  better  ways  to 
proactively optimise safe and efficacious use of medicines for the benefit of EU citizens. 

  A  new  EU-level  expert  committee,  the  Pharmacovigilance  Risk  Assessment  Committee 
(PRAC),  brings  together  Member  State  and  other  experts  and  patient  and  healthcare 
professional  representatives,  to  share  effort  and  best  available  expertise  in  many  key 
pharmacovigilance tasks. 

  This  report  describes  the  development  of  the  system  over  the  period  from  July  2012  (when 
the  new  legislation  came  into  operation)  to  June  2015,  with  data  collected  to  the  end  of 
December 2014. Some of its key findings are: 

 
Side-effect reporting has improved, with reporting of suspected adverse reactions 
from  the  European  Economic  Area  (EEA)  increasing  from  around  240,000  in  2012  to 
nearly 290,000 in 2014. 

 
all Member States have implemented measures to allow and encourage patients to 
report  side  effects  as  well  as  healthcare  professionals;  this  strengthened  patient 
involvement is shown by an increase of around 50% in individual patient reports. 

 
Member States and the EMA are contributing collaboratively to the detection and 
validation of signals (information about new or changing safety issues potentially caused 
by a medicine); nearly 200 such signals were assessed by the PRAC during the period of 
the report. About half of confirmed signals led to updates of the product information, and 
a further quarter to other regulatory measures. 

 
The  safety  of  medicines  is  increasingly  being  managed  proactively  through  risk 
management plans. These identify known and potential risks of marketed medicines and 
the measures planned to manage them, as well as detailing binding commitments on how 
they will be monitored for safety and actions to be taken to provide evidence where it is 
lacking. 

 
The  PRAC  is  now  assessing  around  600  risk  management  plans  each  year  for 
centrally  authorised  medicines,  while  over  the  period  of  the  report  some  20,000  risk 
management  plans  have  been  submitted  to  the  Member  States  for  nationally  authorised 
medicines;  and  publication  of  public  summaries  of  risk  management  plans  has  been 
trialled. 

  During  the  reporting  period  discussion  of  the  protocols  (study  designs)  for  post-
authorisation safety studies were included in the PRAC agenda on over 230 occasions, 
and results of such studies were discussed on around 60 occasions. In addition, since the 
introduction of the relevant legislation some 14 post-authorisation efficacy studies have 
been  imposed  by  the  regulator.  Member  States  assessed  a  further  17  safety  studies  and 
one efficacy study. 

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  Regular re-assessment of the benefit-risk balance of marketed medicines is being carried 
out  via  submission  of  periodic  safety  update  reports  (PSURs)  for  assessment  by 
regulators. Member States evaluated over 12,000 PSURs for purely nationally authorised 
medicines.  In  addition,  the  PRAC  reviewed  and  finalised  over  900  assessments  for 
centrally  authorised  medicines,  or  for  active  substances  used  in  both  centrally  and 
nationally  authorised  medicines.  From  the  last  quarter  of  2014  all  nationally  authorised 
medicines containing substances listed in the EU Reference Date (EURD) list will have a 
periodic safety update report single assessment (PSUSA) reviewed by the PRAC and the 
number  of  procedures  through  the  PRAC  for  substances  only  included  in  nationally 
authorised medicines increased significantly in 2015. 

  There  were  31  safety-related  referrals  to  the  PRAC  during  the  period.  The  revised 
legislation has improved the efficiency of the referral procedure, with greater involvement 
of  patients  and  other  key  stakeholders  in  the  process,  and  improvement  in  the 
identification  of  key  evidence  for  assessment,  with  outcomes  communicated  clearly and 
appropriately. 

  Around 200 pharmacovigilance inspections have been carried out yearly (167 in 2014) 
and  the  proportion  of  these  related  to  centrally  authorised  medicines  increased  over  the 
period  from  26  in  2012  to  48  in  2014.  It  is  routine  practice  for  a  copy  of  the 
pharmacovigilance  master  file  and  logbook  to  be  requested  in  all  inspections  by  the 
regulatory authorities. 

  A clearer focus on medication errors is expected to help reduce associated harms. Side-
effect  reports  related  to  medication  errors  increased  from  around  4,500  in  2012  to  over 
7,000 in 2014, in part because of increased awareness and a clearer legal basis. Member 
States  and  the  EMA  have  used  various  channels  to  communicate  about  the  risks  of 
medication errors, and in 2013 were involved with key stakeholders in a major workshop 
to develop an EU action plan to complement the various national activities already being 
carried out. 

  The  activity  and  performance  measures  relating  to  the  EU  pharmacovigilance  system, 
particularly  for  signals,  PSURs  and  referrals  suggest  that  the  new  system  delivers  faster 
detection  of  safety  issues  and  faster  advice  and  warnings  to  users  of  medicines.  Through 
faster warnings, patients and healthcare professionals are empowered to use medicines more 
safely. 

  The  EU  pharmacovigilance  system  now  provides  an  unprecedented  level  of  transparency, 
with prompt communication to the public on safety concerns regarding medicines as they are 
investigated and managed. There is public access to the agendas and minutes of the PRAC, 
outcomes  of  signals  and  PSURs,  and  aggregated  data  on  suspected  side  effects.  An  early-
notification  system  (ENS)  and  circulation  of  agreed  lines-to-take  help  ensure  that  messages 
are co-ordinated and consistent across the EU regulatory network. 

  The  focus  on  engaging  patients  and  healthcare  professionals  is  a  key  pillar  of  the  new 
legislation.  Patients  and  healthcare  professionals  report  suspected  side  effects,  contribute  to 
the  decision-making  process  and  add  the  invaluable  perspective  of  those  most  affected  by 
diseases and their treatment. 

  The EU pharmacovigilance system has improved co-ordination and collaboration between 
regulators  and  other  stakeholders,  including  academia  and  industry,  and  has  developed  an 
enhanced infrastructure to support its new tasks. 

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  The  extensive  work  over  the  reporting  period  and  the  experience  gained  gives  a  solid 

foundation to further develop and streamline the system in coming years. 

This  document  builds  on  the  one-year  report  on  the  European  Medicines  Agency  human 
medicines pharmacovigilance tasks published in May 20141, which covered the reporting period 
July 2012 to July 2013 and described the initial implementation of the revised pharmacovigilance 
legislation with a particular focus on the tasks of the EMA.  

This  report  provides  data  on  key  pharmacovigilance  tasks  over  a  three-year  period  (including 
quantitative  data  from  July  2012  to  December  2014)  and  importantly,  given  their  major 
contribution,  includes  Member  State  tasks.  In  addition  the  report  provides  evidence  of  the 
continuing  development  and  improvement  of  the  system  as  regulators  and  other  stakeholders 
have  gained  experience  in  the  use  of  the  tools  the  legislation  provides.  It  also  includes  some 
information on ongoing developments and anticipated future elaborations of the system. 

While certain impacts of the tasks of pharmacovigilance are highlighted in this report, it does not 
attempt to provide a comprehensive impact assessment. 

1 European Medicines Agency. One-year report on human pharmacovigilance tasks by the European Medicines 
Agency: http://ec.europa.eu/health/files/pharmacovigilance/2014_ema_oneyear_pharmacov_en.pdf. 

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INTRODUCTION 

This report describes the activities of the networked and collaborative system for monitoring and 
controlling the safety of human medicines in the EU over a period covering three years following 
the start of operation of new European legislation designed to improve that system.  

While the legislation foresees different timelines for reports on tasks of the Member State and of 
the EMA, reporting on the EMA tasks has been brought forward for this report in order to allow a 
joined-up overview of the tasks of the EU network. 

This  report  specifically  includes  quantitative  data  gathered  over  the  period  from  July  2012  to 
December  2014  (the  data  lock  point),  but  includes  information  on  some  relevant  tasks  and 
processes over the whole 3-year period up to July 2015. The body of the report gives a summary 
of  the  activities  with  technical  data  provided  in  full  in  annexes.  It  contains  a  high-level 
description of the EU pharmacovigilance system (the system for monitoring and maintaining the 
safety  of  medicines  in  Europe),  the  roles  of  various  parties  within  that  system,  key  activities 
undertaken  by  the  system  during  the  reporting  period,  discussion  of  the  co-operation  between 
various stakeholders and interested parties, and consideration of the ways in which the system is 
being developed and adapted for future improvement. 

PHARMACOVIGILANCE IN THE EUROPEAN UNION (EU) 

What is pharmacovigilance? 

Pharmacovigilance  is  planned  monitoring  of  the  safety  of  medicines  so  that 
anything  that  affects  their  safety  profile  can  be  swiftly  detected,  assessed,  and 
understood and  appropriate  measures  can  be taken  to  manage  the  issue  and  assure 
public health.  

Before a medicine is authorised for use, evidence of its safety and efficacy is usually limited to 
the results from clinical trials.  This means that at the time of a medicine’s authorisation, it will 
only have been tested in a relatively small number of patients for a limited length of time. 

Some  side  effects  or  'adverse  reactions'  may  only  be  seen  in  patients  with  particular 
characteristics or may be so rare that they are not seen until a very large number of people have 
received the medicine and used it over longer time periods. This can only happen once healthcare 
professionals begin prescribing. It is therefore vital that the safety of all medicines is monitored 
throughout  their  use  in  healthcare  practice.  This  monitoring  applies  both  to  the  hundreds  of 
centrally authorised medicines (CAPs, those with a single marketing authorisation adopted by 
the Commission which is valid across the EU on the basis of an evaluation by the EMA) and to 
the many thousands of nationally authorised medicines (NAPs, authorised in particular Member 
States  following  national  evaluation  procedures 
the  mutual  recognition  and 
decentralised procedures). 

including 

The EU network 

Over  the  years  the  EU  Member  States  have  developed  systems  for  monitoring  the  safety  of 
medicines  on their markets. EU legislation has gradually built  on their best practice to  create a 
networked  system  that  joins  the  knowledge  and  resources  of  the  Member  States  together,  co-
ordinated  and  supported  by  the  EMA,  with  the  European  Commission  providing  the  legal 
authority and legislative tools that the system requires.  

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Regulatory context 

The legislation 

The legal framework of pharmacovigilance for medicines for human use marketed within the EU 
is  provided  for  in  Regulation  (EC)  No  726/20042 and  in  Directive  2001/83/EC3,  as  amended. 
These were updated by the new pharmacovigilance legislation contained in Regulation (EU) No 
1235/20104 and Directive 2010/84/EU5, which entered into force from July 2012 and were further 
refined  by  Regulation  (EU)  No 1027/2012 6  and  Directive  2012/26/EU 7  which  provided 
strengthened measures  for monitoring medicines  safety and carrying out  reviews at a European 
level.  
In addition in 2012 the Commission Implementing Regulation (EU) No 520/20128 laid down the 
rules concerning the roles and responsibilities regarding certain aspects of pharmacovigilance for 
marketing authorisation holders, national competent authorities and the EMA.  

Member  States  and  the  EMA  have  also  produced,  in  consultation  with  relevant  stakeholders, 
in  detail  how 
good  pharmacovigilance  practice  guidelines 
pharmacovigilance activities should be carried out.  

(GVP) 9  which  explain 

The role of the Member States 

The  individual  Member  States  of  the  EU  power  the  entire  system.  The  national  medicines 
regulators (national competent authorities) supervise the collection of information on suspected 
side-effects  of  medicines,  particularly  spontaneous  reports  from  patients  and  healthcare 
professionals. Equally, they provide much of the resource base and knowledge needed to assess 
signals  of  possible  emerging  side  effects.  Member  State  experts  also  take  the  lead  (as  the  so-
called rapporteur and co-rapporteur teams) in evaluating and analysing data when a safety issue is 
assessed  at  the  European  level  (a  referral).  They  play  a  critical  role  in  tailoring  and 
communicating safety messages to healthcare professionals, patients and the public at a national 
level. 

Member States also maintain the inspectorates that carry out the work of ensuring that medicines 
marketed  in  the  EU  are  manufactured  appropriately  and  are  of  suitable  quality,  that  the 
pharmacovigilance  systems  of  industry  are  working  as  they  should,  and  which  check  that  the 

2 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 and veterinary use and 
establishing a European Medicines Agency, OJ L 136, 30.4.2004, p. 1.  
3 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code 
relating to medicinal products for human use, OJ L 311, 28.11.2001, p. 67.  
4 Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010 amending, as 
regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and 
establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal 
products, OJ L 348, 31.12.2010, p.1.  
5 Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards 
pharmacovigilance, Directive 2001/83/EC of the European Parliament and of the Council on the Community code 
relating to medicinal products for human use, OJ L 348, 31.12.2010, p. 74.  
6 Regulation (EU) No 1027/2012 of the European Parliament and of the Council of 25 October 2012 amending 
Directive 2001/83/EC as regards pharmacovigilance, OJ L 316, 14.11.2012, p. 38.  
7 Directive 2012/26/EU of the European Parliament and of the Council of 25 October 2012 amending, as regards 
pharmacovigilance, Directive 2001/83/EC, OJ L 299, 27.10.2012, p.1.  
8 Commission Implementing Regulation (EU) No 520/2012 of 19 June 2012 on the performance of 
pharmacovigilance activities provided for in Regulation (EC) No 726/2004 of the European Parliament and of the 
Council and Directive 2001/83/EC of the European Parliament and of the Council, OJ L 159, 20.6.2012, 0.5.  
9 http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp 

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clinical  studies  that  provide  the  evidence  of  the  safety  and  effectiveness  of  medicines  are 
performed in line with appropriate standards. 

The role of the European Medicines Agency (EMA) 

The EMA has a central role the EU system, co-ordinating its activities and providing technical, 
regulatory  and  scientific  support  to  the  Member  States  and  industry.  It  also  provides  essential 
infrastructure  required  by  the  system  and  has  specific  tasks  laid  down  in  the  legislation  in  the 
conduct of pharmacovigilance including signal detection for centrally authorised products. 

The  new  EU  pharmacovigilance  legislation  established  an  additional  scientific  committee,  the 
Pharmacovigilance  Risk Assessment Committee (PRAC), whose members include experts in 
pharmacovigilance  and  regulation  working  within  the  national  competent  authorities  of  the 
Member  States  (plus  Iceland  and  Norway),  representatives  of  patients  and  healthcare 
professionals,  and  scientific  experts  in  areas  such  as  epidemiology,  signal  detection,  biological 
medicines  and  risk  communication  nominated  by  the  European  Commission.  The  PRAC  meets 
monthly and is responsible for the assessment of safety issues at EU level. It also monitors many 
of  the  pharmacovigilance  activities  foreseen  in  the  legislation.  It  works  closely  with  other 
scientific committees, especially the Committee for Medicinal Products for Human Use (CHMP) 
which leads on centrally authorised medicines, and also with the Co-ordination Group for Mutual 
Recognition  and  Decentralised  Procedures  –  Human  (CMDh),  a  body  representing  the  national 
regulators of the EEA, which leads on many issues relating to nationally authorised medicines. 

The staff of EMA develop and maintain various essential databases and information technology 
(IT) functions that support the system, in particular a database called EudraVigilance that is used 
to  collate  worldwide  reports  of  suspected  side  effects  (adverse  reactions)  and  underpins  the 
detection  of  potential  signals  regarding  side  effects  and  their  analysis.  The  EMA  also  supplies 
specialist scientific, legal and regulatory knowledge to support activities such as safety reviews, 
and  helps  ensure  that  communications  about  safety  issues  are  provided  in  a  timely,  transparent 
and co-ordinated fashion across the EU. 

The role of the Commission 

The  European  Commission  is  the  competent  authority  for  centrally  authorised  products  and 
supplies  the  legal  authority  that  underpins  the  EU  pharmacovigilance  system.  It  provides  the 
legislative framework needed to carry out its functions in the most efficient way.  

Tasks and procedures 

Key tasks carried out by the network for the purpose of pharmacovigilance include: 

 

 

 

 

assessing  the  known  and  potential  risks  of  each  medicine  before  marketing  and  developing 
plans to collect data and minimise those risks (risk management planning); 

collecting and managing case reports of possible side effects (adverse drug reactions); 

analysing reports of side effects to identify signals (signal management); 

routine benefit-risk monitoring of medicines via periodic safety update reports (PSURs) and 
maintaining the EU Reference Date (EURD) list of when they should be submitted; 

  managing information on products which are subject to additional monitoring, and products 

that have been withdrawn; 

  Europe-wide reviews of important safety and benefit-risk issues (referrals); 

 

assessing  and  co-ordinating  studies  after  marketing  (post-authorisation  safety  studies,  post-
authorisation efficacy studies); 

7 

 
 
 

 

 

 

carrying  out  inspections  to  ensure  company  pharmacovigilance  systems  comply  with  good 
pharmacovigilance practice; 

communicating in a clear, effective and timely manner about safety-related issues to relevant 
stakeholders; 

continuous development and improvement of systems (including IT infrastructure), guidelines 
and standards for the system, and promotion of research to address gaps in knowledge; 

interacting with and engaging key stakeholders, including patients, healthcare professionals, 
the  pharmaceutical  industry,  other  parts  of  the  regulatory  system  (including  international 
regulators), academia, the media, global standards bodies, and wider civil society; 

  monitoring  the  performance  of  the  system  and  its  components,  including  compliance  with 

legal obligations and standards; 

 

training and capacity building. 

SOURCES OF DATA 

Information  regarding  Member  State  activities  has  been  supplied  by  the  national  competent 
authorities of the different countries (see Annex 10), and includes data from the SCOPE project10, 
funded  as  a  Joint  Action  by  the  European  Commission  and  co-ordinated  by  the  UK  Medicines 
and Healthcare products Regulatory Agency (MHRA). Data on centralised activities, particularly 
those  carried  out  by  the  PRAC  and  some  other  areas  such  as  side-effect  reporting,  has  been 
collected by the EMA in its co-ordinating role within the EU network. 

Qualitative information, including some descriptive case studies, is included in the report in order 
to illustrate the way the legislation works at the level of individual issues and to demonstrate the 
experiences of stakeholders. 

How was it measured/analysed? 

The quantitative data for the report covers the period from July 2012 to December 2014 (the data 
lock point). Measures of relevant tasks are provided using a variety of indicators. Some represent 
basic activity measurements, e.g. simple counts of numbers of procedures or submissions. Others 
have been used as part of the pharmacovigilance system governance by the EMA, including key 
performance  indicators,  which  have  been  specifically  developed  to  measure  how  well  it  is 
carrying out its tasks and to reflect specific outputs required by the new legislation.  

10 Strengthening Collaboration for Operating Pharmacovigilance in Europe, an EU-funded Joint Action project 
involving regulators from 23 EU Member States plus Norway and Iceland.  

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OVERVIEW OF KEY ACTIVITIES 

A number of key pharmacovigilance activities over the period from July 2012 to December 2014 
(the data lock point), or in some cases over the whole 3-year period up to July 2015, are described 
in more detail in the following sections.  

Since  establishment  of  the  PRAC  by  the  new  legislation,  the  EU  pharmacovigilance  network 
carries  out  many  of  these  activities  in  this  forum,  allowing  broad  access  to  expertise  and  a 
consistent  and  resource-efficient  approach  to  medicines  safety  across  the  EU.  The  relative 
frequency  with  which  various  pharmacovigilance  activities  appear  on  the  PRAC  agenda  is 
indicated by the figures below (see also Annex 9).  

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Side effect reporting 

see also Annex 1 

Reports  of  suspected  side  effects  (adverse  reactions)  submitted  by  patients  and 
healthcare  professionals  are  collected  by  the  national  competent  authorities  of  the 
Member  States  or  by  industry.  EU  law  requires  all  serious  adverse  reactions  
occurring in the EEA to be included in the EudraVigilance database by the Member 
States  and  marketing  authorisation  holders.  The  latter  are  also  required  to  include 
serious reports gathered outside the EEA in EudraVigilance. An ICSR (individual 
case  safety  report)  is  the  standardised  format  used  by  regulators  for  reports  of 
suspected adverse reactions (side effects) or problems with the safety and quality of 
medicines.  

The number of serious adverse reactions (SARs) received by EudraVigilance (EV) has been used 
as  the  measure  of  adverse  drug  reaction  (ADR)  reporting.  Reports  of  ADRs  following  the 
authorisation of medicines (i.e. postmarketing) from the EEA have increased steadily following 
the  implementation  of  the  new  legislation,  from  around  240 000  in  2012  to  nearly  290 000  in 
2014. There has also been an increase in similar reports from outside the EEA. 

One  of  the  aims  of  the  legislation  was  to  strengthen  patient  involvement  in  the  safety 
monitoring of medicines. All 28 Member States have patient reporting systems in place, with the 
majority introducing them in 2012/13 (although the first of them to introduce this process did so 
in 1968 and the second in 1996). Overall, the number of individual patient reports from the EEA 
has increased over the two and a half years of the reporting period by around 50%. This includes 
ADR  reports  not  notified  by  other  reporters  such  as  healthcare  professionals,  which  represent 
information that would not otherwise be captured 

Data  on  national  activities  in  this  area  has  been  obtained  from  a  survey  of  the  Member  States 
carried out via the SCOPE Joint Action. In 24 Member States patients can report via mail, in 21 
via  e-mail,  20  through  fax  and  web-based  forms,  and  in  19  via  telephone.  One  also  specified 
mobile reporting, and 2 others that patients can report in person. Most (22) Member States have 
more  than  one  type  of  reporting  form,  with  the  majority  having  2  different  types  of  forms  for 
different users (such as patients and healthcare professionals).  

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The Member States make patient reporting forms available through a variety of sources; the most 
common  source,  aside  from  national  competent  authorities,  are  regional  centres  (8  Member 
States), patient organisations (7), marketing authorisation holders (7) and healthcare websites (6). 
In addition paper forms are made available via pharmacies in 7 Member States.  

The  single  most  important  tool  for  encouraging  side-effect  reporting  is  institutional  webpages. 
However, 23 Member States also use educational material and letters for healthcare professionals, 
and 20 Member States make information publicly available in annual reports. 

In addition, nearly a third (28%) of Member States engage with the media (through advertising 
hoardings,  radio, 
in  side-effect  reporting  campaigns. 
Engagement  via  regional  centres,  e-learning  platforms,  and  social  media  like  Facebook  and 
Twitter (in 4 Member States) is less frequent. 

internet,  newspapers) 

television, 

The majority (64%) of Member States have a strategy in place to raise awareness about reporting, 
although only a third of the countries have a specific budget dedicated to raising awareness. 

About  40%  of  Member  States  have  organised  a  public  campaign  about  reporting  side  effects, 
with 62 campaigns in total across all the countries. During campaigns, Member States primarily 
collaborate  with  healthcare  professional  organisations,  and  to  a  lesser  extent  with  patient 
organisations.  Campaigns  have  focussed  on  a  number  of  areas,  the  top  three  being:  the 
importance of reporting; content of reports; and, highlighting the schemes in place for reporting.  

Some  Member  States  work  with  patient  organisations  to  facilitate  side  effect  reporting.  The 
number of patient organisations involved per Member State varies from 1 to 20. For example, in 
Denmark the regulator holds meetings with all major patient organisations. 

The  Member  States,  the  EMA  and  marketing  authorisation  holders  work  collaboratively  to 
improve  the  quality of suspected ADR reports. This includes the use of technology to support 
reporting  (e.g.  web  forms),  training,  quality  review  and  feedback,  follow-up  with  reporters  and 
detection and amalgamation of duplicate reports. During 2013 and 2014, over 250 000 potential 
duplicate  couples  of  case  reports  were  assessed  and  approximately  110 000  merged  ‘master’ 
ICSRs were created. 

11 

 
 
 
 
 
Suspected side effects due to biological medicinal products 

EU legislation requires Member States to clearly identify so-called biological medicinal products 
(medicines  that  contain  one  or  more  active  substances  made  by  or  derived  from  a  biological 
source) that  are  associated  with  suspected  adverse  reactions.  These  active  substances  are larger 
and more complex than those of nonbiological medicines, and their complexity and the way they 
are produced may result in small variations in the molecule, especially between different brands 
and also between batches of the same brand.  

The  numbers  of  ICSRs  received  for  biological  centrally  authorised  products  over  the  period 
increased  slightly  from  around  34 500  in  July-December  2012,  73 000  in  2013  and  77 500  in 
2014.  Most  Member  States  require  the  batch/brand  in  reporting  forms,  and  if  not  present,  will 
generally follow up with the reporter. 

Signals 

see also Annex 2 

A safety signal is information on a new or known adverse event that is potentially 
caused  by  a  medicine  and  that  warrants  further  investigation.  Signals  may  be 
generated from any information source but most come from ICSRs, clinical studies 
or  the  scientific  literature.  This  information  undergoes  an  initial  examination  to 
determine  that  it  can  be  considered  a  possible  signal  (validation),  before  being 
confirmed as a possible signal for evaluation by the PRAC and regulatory action if 
necessary. 

The  work  of  detecting  signals  is  shared  between  the  Member  States  and  the  EMA.  Since  July 
2012,  revised  signal  detection  processes  have  been  put  in  place  for  all  centrally  authorised 
medicines. For active substances in nationally authorised medicines, Member States have shared 
between them the task of monitoring new data and validating and confirming signals on behalf of 

12 

 
 
 
the  rest  of  the  EU  system,  with  EMA  supporting  them  in  applying  the  new  signal  detection 
processes. Each  country  may be Lead Member State (LMS) for a number of  active substances. 
This  allows  the  different  Member  States  to  contribute  according  to  their  resources  and  permits 
more  efficient  use  of 
those  resources  by  avoiding  duplication  and  clearly  defining 
responsibilities. 

Some 193 unique signals were evaluated by the PRAC over the period of this report. The work of 
validation was shared more or less evenly between the Member States and the EMA. 

Over  two-thirds  of  signals  are  for  substances  found  in  centrally  authorised  products,  or  in  both 
centrally  and  nationally  authorised  products,  which  would  include  the  great  majority  of  new 
active substances entering the EU market.  

Validated by NCAs as LMS = reviewed by the lead Member State (the Member State taking the 
lead  on  a  given  active  substance);  validated  by  NCAs  =  reviewed  by  another  Member  State; 
validated by EMA = reviewed by the European Medicines Agency 

13 

 
 
 
 
 
 
After a signal is evaluated by the PRAC, it may result in an update of the product information for 
the medicine(s)  concerned  – for example,  to  add a warning or  mention  a new side effect, or  to 
update information on the frequency of a known one – or the regulatory authorities may require 
the manufacturer to carry out further study, or put in place additional measures to minimise any 
risk. A list of signal recommendations is published after each meeting of the PRAC11.  

Over  the  reporting  period  and  up  to  the  start  of  2015,  about  half  of  all  confirmed  signals 
evaluated by the PRAC resulted in recommendations to update the product information (PI) used 
by doctors and patients, and a further quarter to other routine pharmacovigilance measures such 
as changes to frequency or content of periodic safety update reports, while about 1 in 20 led to 
more intensive action in the form of a European-level safety review or ‘referral’.  

The functioning of the signal assessment process under the legislation can be illustrated by two 
case  studies,  one  representing  a  signal  picked  up  by  routine  signal  monitoring  activities  at  the 
EMA and one a signal first identified by a Member State. 

Case study: Filgrastim and pegfilgrastim (Neulasta and other products) – signal of systemic 
capillary leak syndrome and cytokine release syndrome 

What was the signal and what evidence supported it? 

Filgrastim, or its modified, longer-acting version pegfilgrastim, are substances similar to a natural 
protein called granulocyte colony-stimulating factor (G-CSF) which encourages the bone marrow 
to  produce  more  white  blood  cells.  They  are  used  under  various  names,  representing  both 
centrally  and  nationally  authorised  products,  to  help  reverse  a  shortage  of  white  blood  cells 
(neutropenia) that can be caused by cancer chemotherapy and which leaves patients vulnerable to 
infection. 

11 

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000375.jsp&mi
d=WC0b01ac0580727d1c 

14 

 
 
 
 
                                               
In  2012, routine signal monitoring activities by the EMA identified 15 cases of two potentially 
life-threatening conditions, systemic capillary leak syndrome and cytokine release syndrome, in 
patients  treated  with  these  medicines.  After  discussion  with  the  rapporteur  for  the  centrally 
authorised pegfilgrastim product Neulasta, the PRAC was requested in December 2012 to assess 
the signal.  

How was it evaluated? 

The PRAC agreed the signal needed further investigation and noted that the two conditions might 
be hard to distinguish. It asked the company holding the marketing authorisation to systematically 
review  the  scientific  literature  and  provide  within  60  days  an  analysis  of  all  reports  of  either 
condition in patients receiving filgrastim or pegfilgrastim for assessment by the rapporteur (UK). 

On  the  basis  of  this  assessment  and  the  PRAC  discussion  the  Committee  considered  that  there 
was fairly strong evidence that systemic capillary leak syndrome was associated with treatment 
with  filgrastim  or  pegfilgrastim,  and  that  given  the  potential  seriousness  of  the  condition  there 
was  a  need  to  inform  prescribers  of  the  risk.  The  evidence  for  a  link  with  cytokine  release 
syndrome was more limited, but needed to be kept under review.  

What action was taken? 
As a result of its evaluation, in March 2013 the PRAC recommended12: 

 

 

 

the  update  of  the  product  information  (for  both  centrally  and  nationally  authorised 
products) within 30 days to include a warning of the potential risks; 
the  preparation  of  a  letter  for  healthcare  professionals  explaining  the  changes  to  the 
product information and the possible risks of the condition; 
the update of the risk management plan to include systemic capillary leak syndrome as an 
important  identified  risk  and  cytokine  release  syndrome  as  a  potential  risk,  with 
appropriate ongoing monitoring. 

Conclusions 

The system enables effective detection of new side effects and rapid action to manage them. 

Case  study:  Basiliximab  (Simulect)  –  signal  of  cardiovascular  instability  resulting  in  fatal 
outcome associated with off-label use in cardiac transplantation 

What was the signal and what evidence supported it? 

Basiliximab (Simulect) is a centrally authorised medicine approved for use as part of combination 
treatment  to  prevent  rejection  of  a  transplanted  kidney.  It  contains  the  active  substance 
basiliximab,  an  antibody  that  reduces  proliferation  of  activated  T-lymphocytes,  a  type  of  white 
blood cells that play a major role in rejection of a transplanted organ. 

In  2013  the  Swedish  Medicines  Agency  identified  3  cases  of  patients  who  had  died  when 
basiliximab  was  used  outside  its  approved  uses  (off-label)  to  help  prevent  rejection  of  a 
transplanted heart rather than a kidney. A search in EudraVigilance also identified cases of heart 
failure and cardiac arrest in patients who had been given basiliximab for its approved indication. 
Sweden requested that the PRAC assess the signal. 

12 Pharmacovigilance Risk Assessment Committee. Minutes of 4-7 March 2013 meeting. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2013/04/WC500142504.pdf. 

15 

 
 
 
 
                                               
How was it evaluated? 

The PRAC agreed that the signal needed further investigation. It asked the company holding the 
marketing  authorisation  for  an  initial  analysis  of  all  cases  describing  events  due  to  clots 
obstructing  blood  vessels  (thromboembolic  events),  disorders  of  heart  rhythm  (arrhythmia, 
bradycardia),  or  heart  failure.  Subsequently  it  requested  further  analysis  of  effects  on  the  heart 
and data from studies in heart transplantation. 

The  PRAC  found  that  data  from  studies  in  renal  transplantation  and  from  the  literature  were 
reassuring  when  the  medicine  was  used  for  its  authorised  indication.  However,  although  the 
evidence  did  not  show  a  strong  signal  of  increased  heart  risk  in  patients  undergoing  heart 
transplantation, data from 6 clinical trials which were examined did not indicate benefit in these 
patients. 

What action was taken? 
As a result of its evaluation, the PRAC recommended that13: 

 

the  product  information  be  updated  within  60  days,  to  include  a  warning  about  use  in 
heart  transplantation,  advising  healthcare  professionals  that  benefit  had  not  been 
demonstrated and that serious effects on the heart had been reported more often than with 
other anti-rejection medicines; 

  a letter be sent to remind heart surgeons and doctors in heart transplant centres in the EU 

 

that basiliximab is only approved for use in kidney transplantation; 
the risks of effects on the heart be included in the risk management plan for the product 
and to be included in regular ongoing safety monitoring (PSURs). 

Conclusions 

Signal evaluation by the PRAC offers a new instrument for early interventions on safety issues, 
increasing the flexibility present in the system and improving its response time. 

Risk management plans 

see also Annex 3 

Every medicine approved for marketing in the EU is now required to include a Risk 
Management  Plan  (RMP)  as  part  of  the  dossier  submitted  by  the  company.  The 
plan  identifies  known  and  potential  safety  issues  with  the  medicine,  and  includes 
binding commitments on how the medicine will be monitored for safety during its 
lifetime.  It  also  identifies  the  actions  that  will  be  taken  to  minimise  the  risks  and 
provide evidence where it is lacking, so as to ensure the most favourable balance of 
risks against the medicine’s benefits.  

Risk  management  plans  for  centrally  authorised  medicines  are  reviewed  by  the 
PRAC, with initial detailed evaluation by assessors in the Member States who take 
the  lead  in  evaluating  the  medicine,  and  approved  by  the  CHMP.  RMPs  for 
nationally  authorised  medicines  are  evaluated  at  Member  State  level  with 
consultation of the PRAC only at the request of a Member State. 

13 Pharmacovigilance Risk Assessment Committee. Minutes of 3-6 February 2014 meeting. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2014/03/WC500163384.pdf. 

16 

 
 
 
                                               
Risk management plans represent an important part of the move to proactive pharmacovigilance. 
Every new medicine and significant extension of indication approved during the reporting period 
has a risk management plan, meaning that a binding plan for risk minimisation and further study, 
as envisaged by the legislation, is in place for these products.  

There were 48 RMP assessments handled by the PRAC during June-December 2012, 637 in 2013 
and  597  in  2014,  representing  about  20%  of  the  discussion  time  in  the  meetings  of  the  PRAC. 
During the same period, around 3 500, 7 500, and 9 000 RMPs respectively were submitted to the 
Member States for nationally authorised medicines. 

RMPs submitted to NCAs 

10 000

8 000

6 000

4 000

2 000

 0

2012 Jul-Dec

2013

2014

17 

 
 
 
 
 
The complete risk management plan is a very lengthy technical document, and is not published in 
full.  However,  public  assessment  reports  are  required  to  be  published  for  all  marketing 
authorisations for new medicines and significant extensions of indication for existing medicines, 
and  these  include  discussion  of  the  safety  and  relevant  risk  management  aspects.  To  further 
increase  transparency  and,  as  required  by  the  updated  legislation,  to  provide  information  on 
RMPs to the public, a pilot of the publication of summaries of the RMP plan was carried out in 
2014. For further details, see the section on Communications and Transparency, below. 

Periodic safety update reports 

see also Annex 4 

European legislation requires marketing authorisation holders to submit regular reports 
providing  an  evaluation  of  the  benefit-risk  balance  of  a  medicine.  These  periodic 
benefit-risk  evaluation  reports  (PBRERs),  known  as  periodic  safety  update  reports 
(PSURs),  must be submitted for both  centrally and nationally  authorised  medicines at 
defined  time  points  following  a  medicine’s  authorisation.  They  include  the  results  of 
studies carried out with the medicine, as well as any other new information on safety or 
benefits, and cover both authorised and unauthorised uses.  

The information is reviewed by the PRAC to determine if there are new risks identified 
for a medicine or whether the balance of benefits and risks of a medicine has changed. 
If it has not, then the marketing authorisation can be maintained, but the PRAC can also 
decide if further investigations need to be carried out or can take action to protect the 
public  from  any  new  risks  identified,  such  as  updating  the  information  provided  for 
healthcare professionals and patients through a variation, or potentially even suspending 

18 

 
 
 
 
 
or revoking the authorisation. A list of dates for submission of PSURs (the EURD list) 
is made available on the EMA website14.  

A single assessment of related PSURs (known as a PSUSA) is carried out for medicines 
that contain the same active substance or combination of active substances and whose 
assessment  period  has  been  synchronised.  This  allows  for  more  efficient  use  of 
resources  and  also  ensures  that  these  related  medicines  are  evaluated  in  a  consistent 
way. 

The  regular  re-assessment  of  benefit-risk  represented  by  the  PSURs  is  a  fundamental  part  of 
ensuring  the  safe  use  of  medicines  for  EU  citizens;  it  ensures  that  the  benefit-risk  balance  is 
regularly monitored, with appropriate action where needed, but also allows the regulatory burden 
to  be  proportionate  to  the  risks,  with  more  frequent  assessments  where  the  PRAC  deems 
necessary, for example for newer medicines.  

The  number  of  PSURs  reviewed  by  the  PRAC  was  20  during  the  starting  period  of  July-
December  2012  relating  to  active  substances  that  were  contained  in  only  centrally  authorised 
medicines, but increased to 436 in 2013 and 471 in 2014 as the scope of the PRAC’s assessments 
was  broadened  to  PSUR  single  assessments  (PSUSA)  for  active  substances  contained  in  both 
centrally  and  nationally  authorised  medicines.  In  most  cases  the  marketing  authorisations  were 
maintained unchanged, but  around 1 in  5 of the PSUR assessments during the reporting  period 
resulted in variations to the terms of the authorisation resulting in changes such as updates of the 
product  information  to  improve  information  on  side  effects  or  precautions  when  using  the 
medicine.  

The  number  of  PSURs  additionally  submitted  to  national  competent  authorities  in  the  Member 
States for purely national assessments were around 5 000, 3 700 and 3 300 for the same periods. 

500

400

300

200

100

0

PSUR assessments and PSUSA 
finalised per year 

6 

45 

430 

426 

20 

Jul-Dec 2012

2013

2014

CAPs only

14 http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/10/WC500133159.xls 

19 

 
 
 
 
 
                                               
PSURs submitted to NCAs 

6 000

5 000

4 000

3 000

2 000

1 000

 0

2012 Jul-Dec

2013

2014

There  were  62,  151  and  116  PSUR  worksharing  procedures  for  purely  nationally  authorised 
medicines  during  the  same  periods  (where  one  country  acted  as  ‘reference  Member  State’, 
carrying out the review on behalf of other countries). Since the last quarter of 2014 all nationally 
authorised medicines containing substances listed in the EURD list will have a PSUSA reviewed 
by  the  PRAC,  which  should  increase  the  consistency  of  the  review  and  allow  Member  States 
access to a shared pool of expertise. 

An example of the way in which the PSUR can lead to further action to ensure safety, as well as 
of the checks and balances built into the system, is the strontium ranelate containing medicines 
Protelos and Osseor: 

Case study: Protelos/Osseor and risk of cardiovascular (heart and circulatory) events 

What is Protelos/Osseor 

Protelos  (strontium  ranelate)  is  a  medicine  approved  for  the  treatment  of  osteoporosis  (a  bone 
disorder associated with weakness of the bones and an increased risk of fractures). This medicine 
(also  marketed  as  Osseor)  was  approved  in  the  EU  in  2004  for  use  in  preventing  fractures  in 
women who have been through the menopause, and extended for use in men in 2012. In March 
2012, the product information of the medicine was amended to warn against use in patients who 
were immobile or at risk of blood clots, following an EU level review of the risks of blood clots 
in the veins (venous thromboembolism (VTE)) and severe allergic skin reactions15. 

What were the PSUR findings? 

PSURs  for  strontium  ranelate  are  submitted  on  a  three-year  cycle.  In  April  2013,  the  PRAC 
completed a routine PSUR of the medicine, which included key data from studies in around 7 500 
post-menopausal women, which showed an increased risk of heart attack (myocardial infarction) 
and  VTE  in  women  taking  the  medicine  who  had  uncontrolled  high  blood  pressure  or  a  past 

15 See Community register: http://ec.europa.eu/health/documents/community-register/html/h288.htm and the EMA 
assessment report: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-
_Variation/human/000560/WC500131789.pdf. 

20 

 
 
 
 
                                               
history of circulatory or heart problems. As a result, the PRAC recommended further restriction 
of  the  product’s  use  as  an  interim  risk-minimisation  measure,  and  considered  further  in-depth 
analysis of the data was needed.  

What happened next? 

In May 2013, the European Commission requested a further in-depth review by the PRAC (a so-
called Article 20 referral). This was carried out in a matter of months, and initially led (in January 
2014) to a recommendation that the medicine’s marketing authorisation should be suspended.  

The PRAC recommendations were forwarded to the CHMP. While in overall agreement with the 
PRAC analysis of the risks, the CHMP considered that the medicine might still have a place for 
patients  with  no  alternative  treatment,  provided  they  were  carefully  monitored  for  the 
development of cardiovascular problems. After further discussion, it therefore agreed to restrict 
the use of the medicine to patients who could not be treated with other medicines approved for 
osteoporosis  and  that  treatment  should  be  stopped  if  patients  developed  heart  or  circulatory 
problems. As previously recommended, use should be avoided in patients with a history of such 
problems. 

Conclusions 

The case16 illustrates the value of routine reassessment of benefits and risks in delivering timely 
and  risk-proportionate  regulation.  The  two  committees  working  together,  with  complementary 
knowledge  and  expertise,  allowed  the  best  balance  to  be  achieved  between  the  acknowledged 
risks of the medicine on the one hand and the unmet medical need of those with few treatment 
alternatives on the other. 

Additional monitoring 

In 2013, the EU introduced a new system to label medicines that are being monitored particularly 
closely  by  regulatory  authorities17.  These  medicines  are  described  as  being  under  'additional 
monitoring' and are monitored more intensively than other medicines. This is generally because 
there  is  less  information  available,  for  example  because  a  medicine  contains  a  new  active 
substance,  is  a  biological  product,  or  it  has  been  approved  in  circumstances  where  there  are 
limited  data  on  its  long-term  use.  Additional  monitoring  does  not  mean  that  the  medicines  are 
unsafe.  

Medicines under additional monitoring have a black inverted triangle displayed in their package 
leaflet  and  in  the  information  for  healthcare  professionals  called  the  summary  of  product 
characteristics, together with a short explanation that the symbol means the product is subject to 
additional monitoring and particularly encouraging users to report suspected side effects. There 
was  a  consultation  of  the  Member  States  and  other  stakeholders,  especially  patients  and 
healthcare professionals, on the choice of symbol and its implementation. 

The  black  triangle  is  now  being  used  in  all  EU  Member  States  to  identify  medicines  under 
additional  monitoring.  It  started  appearing  in  the  package  leaflets  of  the  medicines  concerned 
from  the  autumn  of  2013,  and  was  accompanied  by  a  communications  campaign  to  the  public, 

16 European Medicines Agency. Protelos/Osseor to remain available but with further restrictions (published 
18/09/2014). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Protelos_and_Osseor/human_referr
al_prac_000025.jsp&mid=WC0b01ac05805c516f. 
17 Defined by Article 23 of Regulation (EC) No 726/200 and Article 11 of Directive 2001/83/EC; the implementing 
regulation for the black symbol is Commission Implementing Regulation (EU) No 198/2013 of 7 March 2013 on the 
selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional 
monitoring, OJ L 65, 8.3.2013, p. 17. 

21 

 
 
                                               
developed by Member States, the EMA and the European Commission with the aid of relevant 
stakeholders18. In addition, a European list of medicines under additional monitoring is published 
and is updated monthly to include new medicines and any changes in monitoring status of those 
on  the  list19.  At  the  end  of  2014  the  list  included  193  centrally  authorised  and  8  nationally 
authorised medicines. The annexes related to medicines that had certain conditions imposed, for 
example as an outcome of referrals, included a further 1 269 nationally authorised medicines. 

Referrals 

see also Annex 5 

A pharmacovigilance referral is a procedure used to resolve issues such as concerns 
over the safety or the benefit-risk balance of a medicine or a class of medicines. The 
matter  is  ‘referred’  to  the  European  Medicines  Agency,  so  that  it  can  make  a 
scientific assessment leading to a recommendation for a harmonised position across 
the European Union. 

Pharmacovigilance  referrals  follow  a  defined  procedure.  The  PRAC  appoints 
members as  rapporteurs and co-rapporteurs, and their expert teams  in  the Member 
States  perform  an  initial  assessment  of  the  data  on  the  PRAC’s  behalf  to  help  it 
reach  its  recommendations.  An  opinion  is  then  provided  either  by  the  CHMP  (for 
referrals  including  centrally  authorised  medicines)  or  CMDh  (for  nationally 
authorised  medicines).  This  is  passed  to  the  European  Commission  for  a  final, 
legally  binding  decision  (except  for  consensus  decisions  of  CMDh,  which  can  be 
implemented directly at national level). 

Pharmacovigilance  referrals  can  be  governed  by  several  articles  of  the  legislation. 
Procedures  triggered  when  it  is  considered  that  urgent  action  for  nationally 
authorised medicine(s) is necessary because of a safety issue are covered by Article 
107(i) of Directive 2001/83/EC. Concerns relating to the safety or benefit-risk of a 
medicine  or  a  class  of  medicines  that  include  nationally  authorised  products  are 
assessed by procedures triggered under Article 31 of Directive 2001/83/EC. Safety 
or  benefit-risk  issues  with  medicines  that  have  been  authorised  via  the  centralised 
procedure only are covered by Article 20 of Regulation (EC) No 726/2004.  

A  total  of  31  safety  referrals  were  dealt  with  by  the  PRAC  over  the  reporting  period.  Nine  of 
these referrals involved centrally authorised medicines, the remainder dealt solely with nationally 
authorised products.  

18 European Medicines Agency. Medicines under additional monitoring. Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000365.jsp
&mid=WC0b01ac058067bfff. 
19 http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp  

22 

 
 
                                               
The  outcomes  of  these  referrals  included  variations  of  marketing  authorisation  in  24  cases, 
suspensions of marketing authorisation in 6 cases (reversible if the marketing authorisation holder 
can provide new evidence to justify the lifting of the suspension), and permanent revocations of 
marketing  authorisation  in  4  cases.  (When  a  referral  concerns  a  group  of  medicines,  combined 
outcomes,  such  as  variations  of  certain  indications  within  the  marketing  authorisations  and 
revocation of others, are possible.) 

The  revised  legislation has  improved  the  efficiency  of  the referral  procedure,  providing  a  more 
flexible and more transparent mechanism for reviewing safety and resulting in more effective and 
co-ordinated action to protect public health across the EU when needed. 

The increased flexibility available with the new legislative tools, the greater transparency and the 
involvement of patient and healthcare professional representatives have had important impacts on 
safety referrals during this period, as illustrated by the below case study. 

Case  study:  Combined  hormonal  contraceptives  (CHCs),  Article  31  referral  on  risk  of 
thromboembolism 

What was the reason for the referral? 

Current combined hormonal contraceptives (CHCs) contain two types of hormone, a low dose of 
an  oestrogen  together  with  one  of  a  number  of  different  progestogens.  They  have  long  been 
known  to  be  associated  with  a  rare  but  serious  increased  risk  of  clots  forming  within  blood 
vessels  (thromboembolism)  and  the  type  of  progestogen  chosen  can  influence  this  risk,  as  can 
risk factors affecting the woman taking the medicine. 

Although  reviews  of  this  risk  have  previously  taken  place  at  both  national  and  European  level, 
with  consequent  changes  to  their  product  information,  in  February  2013  the  French  medicines 
regulator, ANSM, asked for a referral under Article 31 to further review the benefit-risk of CHCs, 
focusing particularly on information about the risk of thromboembolism and advice on reducing 
it.  This  was  because  of  further  data  about  the  risk  of  thromboembolism  and  consequent 
complications such as pulmonary embolism, in CHCs containing newer progestogens rather than 
the older progestogens levonorgestrel or norethisterone. 

What evidence was reviewed? 

The  PRAC  reviewed  the  available  data  from  clinical  trials,  pharmacoepidemiological  studies, 
published  literature  and  spontaneous  reports  of  suspected  adverse  drug  reactions  as  well  as  the 

23 

 
 
 
 
 
 
views of an ad-hoc expert meeting. This represented a large amount of high quality evidence and 
provided information from many millions of woman-years of use. 

What were the recommendations of the scientific review? 

In October 2013 the PRAC confirmed that CHCs provide highly effective contraception and their 
benefits  continue to  outweigh their risks  as  the risk of thromboembolism in  the veins (VTE) is 
small.  It  confirmed  that  there  were  differences  in  this  small  risk  depending  on  the  progestogen 
chosen,  with  the  lowest  risk  attached  to  the  progestogens  levonorgestrel,  norethisterone  or 
norgestimate. A table of relative risks was adopted by the PRAC following input from patient and 
healthcare professional representatives. 

Risk of developing a blood clot (VTE) in a year 

Women not using a combined hormonal 
pill/patch/ring and are not pregnant 

About 2 out of 10 000 women 

Women using a CHC containing 
levonorgestrel, norethisterone or norgestimate 

About 5 to 7 out of 10 000 women 

Women using a CHC containing etonogestrel 
or norelgestromin 

About 6 to 12 out of 10 000 women 

Women using a CHC containing 
drospirenone, gestodene or desogestrel 

Women using a CHC containing 
chlormadinone, dienogest or nomegestrol 

About 9 to 12 out of 10 000 women 

Not known at time of review so studies 
were expected or recommended to allow 
estimation of the risk 

The  PRAC  recommended  modifying  the  product  information  of  CHCs  to  give  up-to-date 
information  to  women  and  prescribers  on  the  risks  and  how  to  minimise  them,  and 
communicating  the  outcome  of  the  review  through  educational  materials  including  a  letter  to 
healthcare professionals. 

What was the outcome? 

The PRAC’s recommendations were supported by the CHMP, which gave a positive opinion on 
the  recommendations  in  November  2013,  and  the  European  Commission  adopted  a  legally 
binding decision in January 2014 modifying the product information of all CHCs throughout the 
EU20. 

Conclusions 

Previous experience has shown that concerns about side effects of CHCs can, if mishandled, lead 
to undesirable consequences including increases in the rate of unintended pregnancy (which itself 
can increase the risk of VTE) and abortion. The 2013 referral was a good example of the way that 
the tools and expertise now available to the EU network allowed for a rapid, collaborative review 
of  the  available  evidence,  with  unprecedented  levels  of  transparency  and  communication  co-
ordinated  across  the  network,  without  triggering  excessive  public  concern.  The  involvement  of 

20 European Medicines Agency. Benefits of combined hormonal contraceptives (CHCs) continue to outweigh risks 
(published 31/01/2014). Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Combined_hormonal_contraceptive
s/human_referral_prac_000016.jsp&mid=WC0b01ac05805c516f. 

24 

 
 
                                               
patient and healthcare professional representatives was key to ensuring that the risks and benefits 
of  the  medicines  were  communicated  clearly  and  appropriately.  The  ultimate  outcome  is  that 
women and prescribers have the best available evidence to support making an informed decision 
about the choice of contraceptive. 

Another  case-study  of  a  referral,  illustrating  the  important  input  of  those  affected  by  adverse 
effects, is included under Cooperation and Coordination with Stakeholders, below. 

Issues that do not lead to referral 

Some additional concerns at a national level which could potentially have led to a referral under 
Article 107(i)  were  also  discussed  by  the  CMDh  to  decide  on  whether  an  EU  level  assessment 
was  required  but  did  not  ultimately  trigger  a  referral.  Such  discussions  were  held  on  two 
occasions in 2013 and six in 2014. 

Post-authorisation studies 

see also Annex 6 

A  post-authorisation  safety  study  (PASS)  is  a  study  that  is  carried  out  after  a 
medicine  has  been  authorised  to  obtain  further  information  on  its  safety,  or  to 
measure  the  effectiveness  of  risk-management  measures.  Under  EU  legislation, 
regulators  may  proactively  impose  a  requirement  for  a  PASS  on  a  marketing 
authorisation holder or may require one as part of the risk management plan because 
of an identified safety concern before or after marketing.  

The  protocol  for  imposed  non-interventional  PASSs  (i.e.  their  proposed  study 
design)  and their final  outcomes  are assessed by the PRAC. (A  non-interventional 
study  is  one  in  which  the  medicine  is  prescribed  in  accordance  with  the  approved 
indication,  and  patients  who  receive  it  do  so  in  accordance  with  normal  medical 
practice, with no special tests or monitoring.) All studies required by regulators are 
included in the risk management plan. 

In addition, companies may voluntarily carry out a PASS to identify or characterise 
a  safety  concern,  confirm  the  safety  profile  of  a  medicine,  or  measure  the 
effectiveness of risk minimisation measures. 

The protocols and abstracts of the final study reports of PASSs are published in the 
EU post-authorisation study (PAS) register on the European Network of Centres in 
Pharmacoepidemiology and Pharmacovigilance (ENCePP) website.  

Understanding  the  benefits  as  well  as  the  risks  of  a  medicine  is  important  in 
authorising  its  use.  Sometimes,  aspects  of  its  efficacy  may  only  be  able  to  be 
resolved  after  it  has  been  marketed.  In  addition,  changes  in  the  understanding  of 
diseases  or  their  study  and  treatment  may  mean  that  previous  efficacy  evaluations 
need  to  be  revised.  In  such  instances  post-authorisation  efficacy  studies  (PAES) 
may be required by regulators to complement available efficacy data. 

The  use  of  PASSs  and  PAESs  represents  a  commitment  from  both  regulators  and  marketing 
authorisation holders to address gaps in the evidence base in a more proactive and planned way.  

25 

 
 
 
 
Post-authorisation safety studies 

During  the  reporting  period,  the  PRAC  reviewed  protocols  for  38  imposed  non-interventional 
PASSs in order to approve them. In two cases the PRAC requested proposals for alternative study 
designs. The  review of PASS protocols and their  results by the PRAC  is  increasing, so  that  by 
2014 around 140 (nearly 10%) of the items on the Committee agenda related to PASS protocols 
(some of these represented repeated consideration of the same protocol) and protocol results had 
been discussed on some 50 occasions. Member States have also evaluated an additional 17 PASS 
protocols for nationally authorised medicines. 

No. of imposed non 
interventional PASS protocols 
for CAPs reviewed at PRAC 

23 

11 

4 

Jul-Dec 2012

2013

2014

25

20

15

10

5

0

Post-authorisation efficacy studies 

Post-authorisation  efficacy  studies    may  be  required  by  regulators  in  order  to  address  some 
efficacy aspects and complement the available data. Because both benefits and risks have to be 
regularly  assessed  in  order  to  be  sure  that  the  balance  between  them  remains  positive,  post-
authorisation  studies  of  efficacy  can  also  have  relevance  in  the  context  of  pharmacovigilance 
activities.  A  Commission  Delegated  Regulation  (EU)  No 357/201421 dealing  with  PAES  was 
adopted in February  2014, towards the end of the three-year  period covered by this report, and 
since  this  came  into  operation  and  up  to  July  2015,  14  PAES  had  been  imposed  by  CHMP 
(although many of these post-date the data-lock point). One additional PAES was required by a 
Member State for a nationally authorised medicine. 

Inspections 

see also Annex 7 

Rigorous programmes of inspection underpin the pharmacovigilance system, as they do also for 
the quality and manufacture of medicines. The ongoing work undertaken by inspectors helps to 
ensure that EU citizens receive the safe, high-quality medicines they deserve.  

The total number of inspections undertaken was 207 in 2012 (for the whole year), 195 in 2013 
and 167 in 2014. The proportion of these related to centrally authorised medicines increased in 

21 Commission Delegated Regulation (EU) No 357/2014 of 3 February 2014 supplementing Directive 2001/83/EC of 
the European Parliament and the Council as regards situations in which post-authorisation efficacy studies may be 
required, OJ L 107, 10.4.2014, p.1.  

26 

 
 
 
 
                                               
the same periods, being 26, 37 and 48 respectively. There were 9 inspections at the request of the 
CHMP  during  2012  (7  taking  place  in  July-December),  6  in  2013  and  13  (of  which  3  were 
inspections of investigator sites related to conduct of a PASS) in 2014.  

In  5  cases,  penalties  were  imposed  on  marketing  authorisation  holders  (MAHs)  for  failure  to 
comply with obligations. 

Master files/logbook 

The pharmacovigilance system in place for each medicine that receives a marketing authorisation 
must  be  described  by  a  pharmacovigilance  system  master  file,  held  by  the  company,  which 
includes a description of the persons, places, and procedures put in place by them to monitor the 
safety of the medicine. Companies must keep this file up to date and available for inspection, and 
a logbook detailing the history of any changes to the file must also be maintained. 

It is routine practice for a copy of the master file and logbook to be requested during all safety 
inspections by the regulatory authorities.  

Medication errors 

see also Annex 8 

A medication  error can be defined as an unintended failure in the drug treatment 
process  that  leads  to,  or  has  the  potential  to  lead  to,  harm  to  the  patient.  This  can 
include a patient taking or being given the wrong medicine, using the wrong dose or 
route of administration, or a medicine being given to the wrong patient. Medication 
errors do not necessarily lead to harm, however the cost to patients and healthcare 
systems can be high, and many medication errors are preventable. 

27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In 2012 there were around 4 500 side effect reports received by EudraVigilance associated with 
medication errors, increasing to some 5 700 in 2013 and over 7 000 in 2014. It is likely that at 
least  some  of  the  apparent  increase  may  be  due  to  increased  awareness  and  better  reporting,  in 
itself a positive outcome from the new legislation. 

In  the  EU,  national  competent  authorities  and  the  EMA  play  a  key  role  in  identifying  and 
reducing  the  risk  of  medication  errors  before  and  after  the  authorisation  of  a  medicine.  Direct 
patient reporting of side effects, including those caused by medication errors, as brought in by the 
revised  pharmacovigilance  legislation  assists  regulatory  authorities  in  implementing  risk 
minimisation measures at an early stage and avoiding further harm due to these errors. 

Communication  about medication errors is an important tool  in reducing the risk. The Member 
States  play  a  major  role  in  such  communication,  along  with  other  channels  such  as  direct 
healthcare  professional  communications  (DHPCs),  educational  material  and  communications 
from  national  patient  safety  organisations.  Going  forward,  the  EMA  has  prepared  proposals  to 
streamline its current ‘safety communications’ to consistently capture key information related to 
medication  errors  which  are  assessed 
by  its  scientific  committees  as  a 
complement  to  information  issued  at 
a  national  level  and  a  dedicated  area 
on  the  its  website  will  provide  links 
to such communications22. 

Individual Case Safety Reporting to 
EudraVigilance - medication errors 
(EEA) 

8 000

7 000

6 000

5 000

4 000

3 000

2 000

1 000

 0

2011

2012

2013

2014

CAPs NAPs

A  workshop  took  place  in  2013 
involving  Member  States  and  the 
EMA with stakeholders from all areas 
of  healthcare  to  develop  and  share 
best  practices  for  the  prevention  of 
medication errors. It helped develop a 
subsequent 
for 
action 
implementation  during  2014  to  2015 
on  how 
the  EU  system  could 
complement  and  facilitate  (within 
existing  frameworks)  the  extensive 
and  national  programmes 
local 
carried out in the Member States23. 

plan 

The  clearer  focus  on  medication  errors  as  part  of  the  pharmacovigilance  process  and  the 
availability of new tools  in  the legislation that can  be used to  address them  is  expected to  help 
reduce the harm that results from them. 

COMMUNICATIONS AND TRANSPARENCY 

In order for the EU regulatory network to function, good communication between its constituent 
members, and between the network and the wider public it ultimately serves, is vital. The system 
operates  with  a  high  level  of  transparency,  as  foreseen  and  guaranteed  by  legislation,  and 

22 http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000398.jsp 
&mid=WC0b01ac058098f1c0  
23 See European Medicines Agency. Medication errors: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000570.jsp&mid=WC
0b01ac0580659655. 

28 

 
 
                                               
 
 
communicates synchronously to the public about safety concerns of medicines at different stages 
of the regulatory process. 

As  mentioned  above  under  Side-effect  reporting,  Member  States  engage  extensively  with  the 
media  and  relevant  stakeholders  to  communicate  relevant  safety  messages  and  promote  public 
understanding  of  issues  of  medicines  safety.  A  survey  conducted  though  the  SCOPE  project24 
showed  that  all  25  Member  States  who  responded  also  provide  safety-related  information  on  a 
website,  which  may  include  information  for  healthcare  professionals,  industry  and  patients  on 
different ways to report side effects. The survey found that 11 Member States have national/local 
guidelines stating what information should be presented on the website. At the time of the survey, 
some  Member  States  were  in  the  process  of  introducing  changes  to  their  web-pages  including 
tailoring the information to audience type. 

The  increased  work  being  done  to  assure  the  safety  of  medicines  under  the  revised  EU 
pharmacovigilance system has been complemented with greater public availability of information 
on the interim steps and outcomes of that work. The agendas and minutes of the monthly formal 
PRAC  meetings  are  made  available  on  the  EMA  website,  and  highlights  of  the  outcomes  are 
published the next working day after the conclusion of the meeting. 

The system produces public safety communications on relevant issues, including announcements 
of  the  start  of  referrals,  communication  of  the  recommendations  issued  by  the  PRAC,  and 
detailed  public  health  communication  of  the  final  outcome  (including  elements  tailored 
specifically  to  patients  and  healthcare  professionals,  which  are  produced  with  input  from 
representatives of the relevant stakeholder groups). There were 14 such communications issued in 
the second half of 2012, 78 in 2013 and 57 in 2014.  

In  addition,  a  pilot  project  to  produce  public  summaries  of  the  RMP  has  been  carried  out.  A 
summary was prepared for each new medicine approved centrally in 2014, resulting in a total of 
54 such summaries being published. A survey of stakeholder responses to this pilot will inform 
the content and nature of future RMP summary publication. 

The  EMA  helps  co-ordinate  communications  within  the  EU  network,  providing  an  Early 
Notification System (ENS) to the national competent authorities, the European Commission and 
other network partners, which provides early warning of safety issues on the PRAC, the CMDh 
or the CHMP agendas. Lines-to-take for press and communication officers in the Member States 
to  reply  to  enquiries  from  the  media  or  other  stakeholders  are  co-ordinated  by  the  EMA  with 
input from internal and scientific experts from national medicines regulators. Such lines-to-take 
were distributed within the network on 46 occasions from June-December 2012, 75 in 2013, and 
47 in 2014. 

In  addition  to  the  detailed  communication  on  referrals  already  mentioned,  public  access  to 
aggregated  data  from  reports  of  suspected  side  effects  contained  in  EudraVigilance  has  been 
ensured through the European  database  of  suspected  adverse  drug  reaction  reports25 which 
was launched in 2012 at the start of the period covered by this report. Initially providing access to 
suspected side effects for centrally authorised medicines, and subsequently extended in October 
2014  to  provide  information  on  common  active  substances  included  in  nationally  authorised 
medicines. It now covers over 500 active substances for centrally authorised products and more 
than 1 500 for nationally authorised medicines. More detailed information can be made available 
to selected stakeholders on application, in accordance with the EudraVigilance access policy and 
data protection laws. 

24 http://www.scopejointaction.eu/ 
25 http://www.adrreports.eu 

29 

 
 
                                               
Details of recommendations made by the PRAC about signals are published monthly. When there 
is  a  recommendation  for  a  change  to  product  information  the  changes  are  translated  into  all 
official EU languages and published by the EMA as a service the Member States and to industry. 
The outcomes of imposed PASS studies are available in the register on the ENCePP website26. 
Full  RMPs  are  not  published  (although  they  can  be  made  available  via  EMA’s  access  to 
documents  policy),  but  as  already  mentioned  summaries  in  public-friendly  language  are  being 
published for new medicines approved since 2014. 

Work has also taken place to allow for greater transparency on the outcomes of single-assessment 
PSURs (PSURs for a group of medicines all containing the same active substance or combination 
are  considered  together).  The  outcomes  of  PSURs  for  centrally  authorised  medicines  which 
recommend changes to the marketing authorisation are published on the EMA website as part of 
each  medicine’s  European  Public  Assessment  Report  (EPAR).  The  outcome  for  nationally 
authorised medicinal products included in 'mixed' procedures where centrally authorised products 
were also involved can be found on the Community register27 . As of mid-2015, conclusions of 
PSUR  single  assessments  related  to  only  nationally  authorised  medicines  are  also  being 
published28.  

Transparency as an underlying principle of communications 

The high degree of transparency about pharmacovigilance issues, in which not only outcomes but 
processes  are  communicated,  carries  some  risks  of  causing  alarm  amongst  medicines  users  and 
wider civil society. It is acknowledged that this could have unintended  consequences for public 
health  (e.g.  patients  discontinuing  beneficial  medicines).  Interaction  with  stakeholders  is 
therefore crucial in ensuring that risks are communicated clearly, accurately and proportionately 
and in the context of the potential benefit.  

In  the  long-run  trust  in  the  regulatory  system  requires  this  transparency,  which  forms  part  of  a 
wider transparency agenda in which European legislators and regulators are playing a leading 
role;  ever  more  of  the  clinical  evidence  on  which  decisions  about  medicines  are  made  is 
becoming publicly available. The greater transparency and communication brought about by the 
new  legislation  in  terms  of  pharmacovigilance  fosters  an  environment  in  which  transparency  is 
seen as a norm. This encourages openness and communication about other regulatory processes.  

SYSTEMS AND SERVICES IMPROVEMENT 

The role of the EMA includes the provision of some of the systems and services needed for the 
pharmacovigilance  network  to  function.  The  new  legislation  has  required  the  development  of 
some new systems and services and enhancement or simplification of others. Member States and 
key stakeholders including the pharmaceutical industry have had an important input to the design 
and development of these systems. 

The  revised  legislation  foresees  that  pharmacovigilance  activities  conducted  at  EU  level  for 
human medicinal products should be financed by fees paid by marketing authorisation holders29. 

26 http://www.encepp.eu/encepp_studies/indexRegister.shtml 
27 http://ec.europa.eu/health/documents/community-register/html/index_en.htm 
28 

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000620.jsp&mid=WC0b01
ac0580902b8d 
29 Regulation (EU) No 658/2014 of the European Parliament and of the Council of 15 May 2014 on fees payable to 
the European Medicines Agency for the conduct of pharmacovigilance activities in respect of medicinal products for 
human use, OJ 189, 27.6.2014, p.112.  

30 

 
 
                                               
These  additional resources will be used  to  remunerate the national competent authorities  of the 
Member  States  for  the  pharmacovigilance  assessments  they  carry  out  as  rapporteurs  for  the 
PRAC and to contribute to the pharmacovigilance-related costs of the EMA, including the system 
improvements described in this section of the report. The Article 57 database referred to below 
the  collection  of 
supports  routine  pharmacovigilance  business  processes,  as  well  as 
pharmacovigilance fees. 

Article 57 database 

A database of all authorised medicines (both centrally and nationally authorised) in 
the  EU  has  been  developed  over  the  reporting  period,  as  originally  envisaged  in 
Article  57  of  Regulation  (EC)  No  726/2004  and  developed  in  the  updated 
pharmacovigilance  legislation.  Maintaining  this  information  in  a  single  location  is 
intended  to  reduce  duplication  of  effort  and  costs,  and  improve  the  efficiency  of 
database  and  systems  communication  within  the  network,  with  international 
partners,  and  with  the  industry.  It  will  allow  identification  of  products  and 
substances  in  reports  of  suspected  side  effects,  in  referral  procedures  and  PSURs, 
and is used to support collection of pharmacovigilance fees from the industry.  

It is envisaged that this database will eventually support the provision of information 
to patients and the public via a medicines web-portal. 

The development of the Article 57 database and collecting and maintaining the medicinal product 
entries received from the marketing authorisation holders, has been a considerable undertaking, 
requiring  close  co-operation  between  the  EMA  and  the  industry.  The  database  represents 
information on over 580 000 medicines from nearly 4 300 marketing authorisation holders. The 
information  was  updated  by  submissions  from  the  companies  during  2014,  and  the  database 
started to enter routine use and maintenance in 2015. 

EudraVigilance enhancements30 

The  legislation  requires  enhancement  of  EudraVigilance  to  support  simplified  reporting,  better 
search, analysis and tracking functions, and improved data quality. The database needs to support 
the Member States in their requirement to monitor reports of suspected side effects and to support 
industry in monitoring the safety of its products. The enhancements will include compliance with 
various international data standards, which will facilitate data exchange. Significant progress on 
enhancing the EudraVigilance database has been made during the reporting period including the 
launch  of  the  ADR  website,  the  support  to  signal  detection  activities  through  production  and 
distribution  to  the  Member  States  of  data  outputs  from  the  system,  and  in  the  planning  and 
building of the enhanced system with its new functionalities and new data structure. At the time 
of reporting the development of the system is on track to undergo in early 2018 the audit foreseen 
in the legislation.  

Literature monitoring service 

The EMA is required to monitor selected medical literature for reports of suspected side effects to 
certain  active  substances,  and  enter  them  into  the  EudraVigilance  database  as  ICSRs 31.  This 

30 Further information on the EudraVigilance database is available in the annual report foreseen under Article 24(2) 
of Regulation (EC) No 726/2004  
(http://www.ema.europa.eu/docs/en_GB/document_library/Report/2016/03/WC500203705.pdf) 
31 Article 27 of Regulation (EC) No 726/2004. 

31 

 
 
                                               
should  enhance  the  quality  of  the  safety  information  available,  and  it  is  hoped  will  reduce  the 
administrative burden on the industry for reporting for the relevant substances. Preparation of the 
EudraVigilance  system  to  perform  this  service  was  completed  in  2014  and  the  service  was 
launched in June 2015. 

PSUR repository 

The  legislation  creates  a  legal  requirement  to  set  up  a  repository  for  all  PSURs 32 and  their 
assessment reports. This will considerably simplify the submission process for the pharmaceutical 
industry  and  provide  ready  access  by  regulators  via  a  user  interface  that  will  allow  search  and 
retrieval of documents. 

The repository has been developed during the reporting period, with system feedback supplied by 
Member  State  and  industry  users,  and  the  repository  was  made  available  and  audited  for 
functionality  during  2015.  Use  of  the  repository  for  the  submission  of  PSURs  will  become 
compulsory in mid-2016. 

COOPERATION AND COORDINATION WITH REGULATORS 

Within the EU network 

The  EU  regulatory  network  requires  close  co-operation  and  co-ordination  between  over  30 
national competent authorities, the EMA and the European Commission. The updated legislation 
has  aimed  to  facilitate  this  by  strengthening  the  network,  reducing  duplication,  and  clarifying 
roles and responsibilities.  

The  PRAC  is  an  important  pillar  of  this  improved  system,  with  its  members  working  at  the 
European  level  but  supplying  knowledge  and  perspectives  developed  within  their  national 
agencies.  

Improved and co-ordinated communication, including the Early Notification System and the use 
of lines-to-take, has helped to ensure that the system speaks coherently to external stakeholders, 
so patients and the public receive consistent messages about the safety of their medicines across 
the  EU,  and  that  Member  States  are  made  aware  of  developing  issues  in  one  country  that  may 
lead  to  media  interest  in  another.  The  development  of  improved  systems  and  services  over  the 
reporting  period,  in  which  Member  State  input  has  been  crucial,  should  allow  further 
improvement. 

International regulators and ICH 

The EU pharmacovigilance system exists in the context of global safety monitoring and as part of 
a tradition of long-standing cooperation between regulators and harmonisation of guidelines and 
practices. The EMA acts as a central point of contact with other major regulators, in particular the 
US  Food  and  Drug  Administration  (FDA),  Health  Canada  and  the  Japanese  regulatory 
authorities.  Confidentiality  arrangements  between  regulators  permit  sharing  of  critical  data  and 
expertise  related  to  safety  issues  and  product  assessments,  and  assist  timely  and  co-ordinated 
communication  about  relevant  issues  (for  example,  by  giving  early  warning  of  safety-related 
communications that may generate public concern or media enquiries). Based on the successful 
product-related  collaboration,  the  system  has  also  concluded  on  strengthened  strategic 
collaboration with the FDA, via the so-called international pharmacovigilance cluster33. The EU 

32 Article 25a of Regulation (EC) No 726/2004. 
33 European Medicines Agency/FDA/ Guiding principles for the international pharmacovigilance cluster, 
22 May 2015. Available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/12/WC500179390.pdf. 

32 

 
 
                                               
network’s  best  practice  have  been  shared  with  external  regulators  via  training  courses  and 
workshops. 

The members of the EU regulatory network play a key role in developing harmonised guidelines 
for  human  medicines  regulators  through  the  Association  of  the  International  Council  for 
Harmonisation  of  Technical  Requirements  for  Pharmaceuticals  for  Human  Use  (ICH).  ICH 
brings  together  the  regulatory  authorities  of  Europe,  Japan,  the  United  States,  Canada  and 
Switzerland,  and  experts  from  the  pharmaceutical  industry,  with  the  aim  of  agreeing  common 
approaches and requirements where possible for the authorisation of medicines. The membership 
in the ICH Association is expected to increase further. 

An important outcome during the reporting period was the adoption by ICH of a new guideline 
on the format and content of periodic benefit-risk evaluation reports34, based on the approach for 
PSURs brought in by the new EU pharmacovigilance legislation.  

COOPERATION AND COORDINATION WITH STAKEHOLDERS 

Patients and healthcare professionals 

Patients  and  healthcare  professionals  are  key  stakeholders 
the  revised  European 
pharmacovigilance  system,  since  they  are the  people  actually  prescribing,  dispensing  and  using 
medicines. The PRAC membership therefore includes representatives of these groups, who have 
input to all the activities of the Committee, and supply relevant perspectives to all aspects of its 
work. Broader consultations with patient and healthcare professional organisations may form part 
of referrals and a patient representative is included in scientific advisory groups (SAGs), expert 
groups  convened  to  supply  specialist  input.  Patient  and  healthcare  professional  representatives 
also  review  relevant  safety  communications.  Work  has  also  been  undertaken  in  preparing  for 
future public hearings in the context of referral procedures. 

in 

The importance of involving these critical stakeholders is illustrated by the review of valproate 
and related substances in pregnant women, an Article 31 referral which began in October 2013. 

Case study: Valproate and related substances, Article 31 referral 

What was the reason for the referral? 

Valproate  and  related  medicines  are  nationally  authorised  medicines  that  have  been  used  for 
many years to treat epilepsy and bipolar disorder, and in some Member States are also authorised 
to prevent migraine. It has been known for many years that use in pregnant women increases the 
risk of certain birth defects in children, and evidence has also built up that they may result in a 
delay in the child’s development. In October 2013, the UK requested a review of these medicines 
following the publication of new studies suggesting that in some children effects on development, 
which could include autism, might be long-lasting. 

What evidence was reviewed? 

The PRAC reviewed available studies and reports providing the most recent evidence on harms, 
including  both  congenital  malformations  and  long-lasting  developmental  disorders,  and 
importantly, consulted representatives of patients and families who had been affected as well as a 
group  of  experts  and  specialists  in  fields  such  as  neurology,  child  development  and  obstetrics. 
Patient representatives were thus actively involved in the process and had significant input into 

34 ICH guideline E2C (R2) on periodic benefit-risk evaluation report. 

33 

 
 
 
                                               
the development of risk minimisation measures. 

What were the recommendations of the scientific review? 

The PRAC recommended a strengthening of warnings in the product information to ensure that 
healthcare  professionals  and  patients  were  aware  of  the  risks  and  that  patients  were  prescribed 
valproate only when clearly necessary. Educational materials were recommended so that women 
and  healthcare  professionals  were  better  informed  about  the  risks  of  valproate  exposure  in  the 
womb and of the need for effective contraception while using it, and it was advised that treatment 
should  be  regularly  reviewed  by  doctors,  including  at  puberty  and  when  a  woman  wished  to 
become pregnant. 

What was the outcome? 

Since  these  medicines  were  all  authorised  nationally,  the  recommendations  were  sent  to  the 
CMDh which endorsed them by consensus in November 2014, and they were implemented by the 
Member States according to an agreed timetable. 

Conclusions 

The referral shows the way in which the regulatory system can incorporate the experiences and 
concerns  of  patients  and  sufferers  from  adverse  reactions  into  a  rigorous  and  timely  review 
process, resulting in better information for users of the medicines and more appropriate use of a 
valuable but potentially problematic treatment for these serious conditions. 

The  EMA  interactions  with  patient  and  healthcare  professional  representatives  are  managed  in 
line with an agreed framework for interaction designed to minimise conflicts of interest.  

At  the  Member  State  level  many  interactions  also  take  place  between  the  various  national 
medicines regulators and national patient and healthcare professional organisations. A survey of 
national  competent  authorities  carried  out  in  January  2015  by  the  Working  Group  of 
Communication Professionals (representing the Member States) and the EMA found that 85% of 
respondents had formal or semi-formal interactions with patient groups and representatives. This 
has  been  particularly  true  in  the  area  of  side  effect  reporting  where  some  Member  States  work 
directly  with  patient  organisations  to  facilitate  side  effect  reporting,  and  13  of  them  work  with 
patients or patient representatives to user-test side effect reporting forms. 

Following  the  establishment  of  the  PRAC  and  the  bedding  in  of  the  new  legislation,  improved 
procedures  for  drafting  and  reviewing  safety  communications  to  healthcare  professionals 
(DHPCs) were also developed, to ensure that these were appropriately reviewed by members of 
the relevant committees and their content was clear.  

Academia 

Academia  plays  a  significant  role  in  generating  the  evidence  on  which  regulators  rely  to  make 
judgements about the benefits and risks of medicines. In pharmacovigilance, the EU network has 
engaged  actively  with  academia,  most  notably  through  the  European  Network  of  Centres  for 
Pharmacoepidemiology  and  Pharmacovigilance  (ENCePP).  Engagement  has  also  occurred 
through regulatory science projects, particularly the Innovative Medicines Initiative (IMI) funded 
EU PROTECT35 project on pharmacovigilance methods.  

35 Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium. 

34 

 
 
 
                                               
The industry 

The  pharmaceutical  industry  is  a  key  actor  in  pharmacovigilance.  Individual  marketing 
authorisation  holders  have  specific  responsibilities  under  the  legislation  in  terms  of  running  a 
system of pharmacovigilance, monitoring and reporting for their products. The EU network has 
strengthened its communication and consultation with industry on draft guidance and through a 
regular  ‘Industry  Platform’  where  representatives  of  EU  industry  associations  meet  with 
regulators.  

The media 

Press  and  communication  departments  of  the  national  competent  authorities  and  of  the  EMA 
interact  regularly  with  local  and  international  media  to  encourage  side-effect  reporting  and 
disseminate important safety-related messages and outcomes of regulatory processes as described 
under Communications, above.  

The national regulators, with their close understanding of the healthcare and media environment 
within  their  own  countries,  play  a  key  role  in  ensuring  safety-related  messages  are  clearly 
understood  and  disseminated  in  each  Member  State  in  appropriate  ways.  Timely  provision  of 
lines-to-take  and  safety  communications  to  the  Member  States  is  important  in  supporting  this 
work. 

Press releases and communications strategies are developed for areas of particular public interest, 
including  referrals  such  as  those  related  to  hormonal  contraceptives  or  the  medicine  Diane  35 
(cyproterone and ethinyloestradiol, a hormonal combination approved for the treatment of women 
with severe acne). The network works to ensure that strategic messages and important issues are 
communicated appropriately to the media. 

PHARMACOVIGILANCE AND PUBLIC HEALTH 

While  medicines  save  lives  and  prevent  suffering,  the  burden  of  adverse  drug  reactions  is 
considerable: some 5% of hospital admissions in the EU and around 197 000 deaths per year have 
been thought to be due to adverse reactions to medicines36.  

Experience to date suggests that the revised pharmacovigilance system now in place in the EU is 
resulting  in  more  timely  and  consistent  outcomes  to  optimise  the  safe  and  effective  use  of 
medicines. This is based on risk-proportionate scientific decisions made on the basis of the best 
available  evidence.  Fast  and  robust  detection  of  issues,  decision-making  and  communication  to 
users of medicines allows those users to make informed decisions and reduces risks from the use 
of the medicines, thus benefiting public health. Furthermore, efficiencies gained by working in a 
network can make more efficient use of resources.  

The  existence  of  reliable  systems  for  monitoring  drug  safety  and  pro-active  planning  of  data 
collection and ways to minimise those risks in the form of RMPs and post-authorisation studies is 
important in supporting authorisation of new and innovative medicines.  

Work is ongoing to develop better measurements for the impacts of pharmacovigilance including 
health outcomes and the PRAC strategy on health impact measurement was published in 201637. 
It  is  expected  that  the  strategy  will  support  the  collection  of  more  data  relevant  to  the  health 
impact of the EU pharmacovigilance system which can be relevant for subsequent reports. 

36 Annex 2 of the Report on the impact assessment of strengthening and rationalising EU Pharmacovigilance,  
Commission of the European Communities, Sept 2008. 
37 European Medicines Agency, PRAC strategy on health impact measurement, EMA/790863/2015, 11 January 
2016. 

35 

 
 
                                               
CONTINUING AND FUTURE DEVELOPMENT OF THE NETWORK 

Training 

the 

training  on 

infrastructure  and  procedures 

The  national  competent  authorities  of  the  Member  States  and  the  EMA  offer  programmes  of 
for 
internal  and  external 
pharmacovigilance.  This  has  included  training  to  familiarise  regulators,  industry  and  other 
stakeholders with the details of the revised legislation, the guidelines on good pharmacovigilance 
practices,  and  the  updated  processes  for  data  submission  and  analysis.  For  example,  in  2014 
alone,  24  training  sessions  on  EudraVigilance  data  submission,  11  training  sessions  on  the 
medicinal product dictionary used by EudraVigilance (xEVMPD) and two introductory sessions 
to  EudraVigilance  took  place,  along  with  access  to  the  xEVMPD  e-learning  platform  by  250 
users. 

required 

Measures  have  been  put  in  place  during  the  period  covered  by  the  report  to  improve  training 
within the network, in the form of a joint initiative between the EMA and the Member States to 
develop an EU Network Training Centre (EU NTC). The initiative was agreed in 2014, and is 
intended to ensure that the best scientific and regulatory practices are spread across the network, 
through the provision of high quality and relevant training materials shared through the EU NTC 
platform. In addition to ensuring harmonised standards and providing professional development 
for regulatory staff, it should reduce duplication of effort and thus ensure that resources available 
for training are used most effectively. 

Process improvement 

Based  on  the  experience  of  the  first  years  of  operation  of  the  new  EU  pharmacovigilance 
legislation  and  in  dialogue  with  stakeholders,  the  EU  network  is  putting  effort  into  increasing 
both the efficiency and effectiveness of pharmacovigilance processes. This can be seen through 
revised  processes,  revisions  to  guidelines  on  good  pharmacovigilance  practice  and  through  the 
development  of  systems  and  services  such  as  medical  literature  monitoring  and  the  PSUR 
repository.  Further  processes  improvement  will  be  a  focus  for  the  next  period,  based  both  on 
experience and the results of regulatory sciences. 

Building capacity and improving regulatory science 

A number of projects have been initiated during the reporting period to improve the science and 
practice of pharmacovigilance, and so enable future improvements in the system.  

The  Strengthening  Collaboration  for  Operating  Pharmacovigilance  in  Europe  (SCOPE)  Joint 
Action will run from 2013 until 2016. It is an EU-funded ‘Joint Action’ with contributions from 
the  involved  Member  States,  designed  to  understand  how  regulators  in  EU  countries  run  their 
national  pharmacovigilance  systems.  Using  this  information,  SCOPE  will  develop  and  deliver 
guidance  and  training  in  key  aspects  of  pharmacovigilance,  along  with  tools  and  templates  to 
support  best  practice38.  Survey  data  from  the  Member  States  obtained  under  the  auspices  of 
SCOPE has been used in the preparation of this report. 

Work  to  encourage  the  conduct  of  high  quality,  multi-centre,  independent  post-authorisation 
studies  is  also  ongoing  within  the  context  of  the  European  Network  of  Centres  in 
Pharmacoepidemiology  and  Pharmacovigilance39.  This  is  a  partnership  involving  147  centres 
across  Europe  that  brings  together  expertise  and  resources  in  pharmacoepidemiology  and 
pharmacovigilance. The EU register of these studies is available from its website. It also develops 
methodological standards and governance principles for such studies. 

38 Progress in the various work packages that constitute the project is reported on a dedicated website: 
http://www.scopejointaction.eu/. 
39 http://www.encepp.eu/index.shtml 

36 

 
 
                                               
The PROTECT project (Pharmacoepidemiological Research on Outcomes of Therapeutics by a 
European Consortium)40 was a public-private partnership co-ordinated by the EMA which looked 
at ways to strengthen safety surveillance and the monitoring of the benefit-risk of medicines in 
Europe.  This  was  to  be  achieved  by  developing  new  tools and  methods  for  early  detection and 
assessment of adverse drug reactions, and finding improved ways to present data on benefits and 
risks. These methods were tested in real-life situations in order to provide all stakeholders with 
accurate  and  useful  information  supporting  risk  management  and  continuous  benefit-risk 
assessment.  The  project  finished  in  2015  and  assessment  of  outputs  for  implementation  into 
routine  practice  is  now  underway,  with  new  tools  already  being  implemented  in  guidance  and 
systems (e.g. EudraVigilance). 
Other regulatory science projects initiated during this period include WebRADR41 which aims to 
investigate  apps  for  side-effect  reporting  and  the  role  of  social  media  data  in  this  area  of 
pharmacovigilance  and  ADVANCE 
(Accelerated  development  of  vaccine  benefit-risk 
collaboration in Europe)42 which aims to establish a blueprint for a sustainable system for vaccine 
benefit-risk  monitoring  in  the  EU.  The  EU  invested  31.7  million  euros  into  pharmacovigilance 
research under the 7th Research Framework Programme, which ended in 2013.  

CONCLUSIONS  

The  European  pharmacovigilance  network  represents  an  example  of  successful  co-operation  at 
the European level, to the benefit of EU citizens. The networked system allows all participants to 
share in the best available expertise and evidence and co-ordinate the regulatory actions required, 
producing  more  efficient  and  consistent  outcomes  for  everybody.  The  regulatory  tools  made 
available  under  the  revised  legislation,  including  risk  management  plans,  post-authorisation 
studies, signal detection and management at EU level, PSUR assessment and referrals, represent 
an  increasingly  proactive  approach  to  medicines  safety,  complemented  by  improvements  in 
regulatory action and communication when safety concerns are identified. 

The  system  operates  with  high  transparency,  necessary  to  develop  the  trust  of  the  society  it 
serves.  Engagement  of  key  stakeholders  such  as  patients  and  healthcare  professionals  is 
embedded  in  the  system,  and  the  perspectives  they  provide  contribute  significantly  to  the 
decision-making  process.  For  the  future,  deepening  involvement  is  foreseen,  including  the 
holding of public hearings for critical safety issues. 

Work is proceeding on the infrastructure and procedures needed to support further development 
of  the  system,  and  to  simplify  and  streamline  existing  processes  where  possible  so  that  the 
regulatory burden is minimised for all stakeholders. Delivery of the medical literature monitoring 
service, of the new EudraVigilance system and of the PSUR repository and full use of the Article 
57  EU  medicinal  product  database  will  increase  efficiency  and  deliver  simplification  for 
stakeholders. Work continues to complete the development and implementation of other systems 
such as centralised ADR reporting through the EudraVigilance database. Ongoing research in the 
field of regulatory science, will also support future improvements. 

The  work  to  implement  the  revised  legislation  and  the  increased  level  of  transparency  and 
communication it brings has been challenging for all parties, but is now well established and has 
opened new ways of communicating on medicines which are helping to set the tone for increased 
communication and transparency in medicines regulation in general. 

40 http://www.imi-protect.eu/ 
41 http://web-radr.eu/ 
42 http://www.advance-vaccines.eu/ 

37 

 
 
 
                                               
ADR 

ADVANCE 

Art. 107i 

Art. 20 

Art. 31 

ANSM 

CAP 

CHC 

CHMP 

CMDh 

DHPC 

EC 

EEA 

EMA 

ENCePP 

ABBREVIATIONS  

adverse drug reaction (side effect) 

Accelerated  Development  of  VAccine  beNefit-risk  Collaboration  in 
Europe,  a  project  to  improve  assessment  of  benefits  and  risks  of 
vaccines 

from 

resulting 

the  evaluation  of  data 

Article 107(i) of Directive 2001/83/EC. It applies when, on the basis 
from 
of  concerns 
pharmacovigilance  activities,  a  Member  State  or  the  European 
Commission considers: 
  suspending or revoking a marketing authorisation (MA);  
  prohibiting the supply of a medicinal product;  
 
 

refusing the renewal of a MA;  
is  informed  by  the  marketing  authorisation  holder  that,  on  the 
basis  of  safety  concerns,  he  has  interrupted  the  placing  on  the 
market of a medicinal product or has taken action to have a MA 
withdrawn,  or  intends  to  take  such  action  or  has  not  applied  for 
the renewal of a MA. 

Article  20  of  Regulation  (EC)  726/2004.  It  applies  when  a  referral 
procedure is initiated as a result of the  evaluation of data relating to 
the 
pharmacovigilance  of  medicinal  product(s)  authorised  via 
centralised procedure only. 

Article 31 of Directive 2001/83/EC. It applies where the interests of 
the  Union  are  involved.  When  a  referral  procedure  is  initiated  as  a 
result  of  the  evaluation  of  data  relating  to  pharmacovigilance  of  an 
authorised  medicinal  product(s) 
the 
Pharmacovigilance Risk Assessment Committee. 

is  referred 

issue 

the 

to 

Agence  Nationale  de  Sécurité  du  Médicament  et  des  Produits  de 
Santé, the French medicines regulator  

centrally authorised product, a medicine for human use authorised by 
the European Commission based on an evaluation by EMA  

combined hormonal contraceptive 

Committee for Medical Products for Human Use 

Co-ordination  Group  for  Mutual  recognition  and  Decentralised 
procedures – human 

direct healthcare professional communication 

European Commission 

European Economic Area 

European Medicines Agency 

European  Network  of  Centres 
in  Pharmacoepidemiology  and 
Pharmacovigilance,  a  partnership  involving  147  centres  across 
Europe 

38 

 
 
ENS 

EPAR 

EU 

EURD 

EV 

G-CSF 

GVP 

HCP 

ICH 

ICSR 

IMI 

IT 

LMS 

MAH 

MHRA 

NAP 

NCA 

NTC 

PAES 

PAS 

PASS 

PhV 

PRAC 

early notification system 

European  public  assessment  report,  a  dossier  of  public  information 
relating to the approval of a medicine 

European Union 

List of European Union reference dates and frequency of submission 
of periodic safety update reports (a list of active substances for which 
PSURs must be submitted and the dates and frequencies at which this 
should occur) 

EudraVigilance,  the  database  for  collating  suspected  side-effect 
reports that is maintained by EMA 

granulocyte colony stimulating factor, a protein that stimulates white 
blood cell production 

good 
pharmacovigilance activities should be carried out 

pharmacovigilance 

practice, 

guidelines 

on 

how 

healthcare professional 

Association  of  the  International  Council  for  Harmonisation  of 
Technical Requirements for Pharmaceuticals for Human Use 

individual case safety report, a standardised report of a suspected side 
effect 

Innovative  Medicines  Initiative,  a  public-private  initiative  aiming  to 
speed up the development of better and safer medicines for patients 

information technology 

lead  Member  State,  a  Member  State  who  acts  on  behalf  of  the 
network  in  assessing  pharmacovigilance  data  for  a  particular  active 
substance 

marketing authorisation holder, the company marketing a medicine 

Medicines  and  Healthcare  products  Regulatory  Agency,  the  UK 
medicines regulator 

nationally authorised product, a medicine evaluated and approved by 
national regulators 

National Competent Authority, a national medicines regulator 

Network Training Centre 

post-authorisation efficacy study 

post-authorisation study 

post-authorisation safety study 

pharmacovigilance 

Pharmacovigilance Risk Assessment Committee 

PROTECT 

Pharmacoepidemiological Research on Outcomes of Therapeutics by 
a European Consortium, a public-private partnership to examine ways 

39 

 
 
PSUR 

PSUSA 

RMP 

SAG 

SAR 

SCOPE 

VTE 

WebRADR 

to  strengthen  safety  surveillance  and  the  monitoring  of  the  benefit-
risk of medicines in Europe 

periodic safety update report 

periodic safety update – single assessment 

risk management plan 

Scientific Advisory Group 

serious adverse reaction 

Strengthening  Collaboration  for  Operating  Pharmacovigilance  in 
Europe, an EU-funded Joint Action project involving regulators from 
many EU Member States plus Norway and Iceland 

venous thromboembolism (a blood clot obstructing a vein) 

a  consortium  developing  a  mobile  app  to  report  suspected  adverse 
drug  reactions,  and  investigating  the  potential  for  publicly  available 
social media data for identifying drug safety issues 

xEVMPD 

eXtended EudraVigilance Medicinal Product Dictionary 

40 

 
 
 
 
ANNEXES – technical data 

The following annexes present the detailed numerical data which supports the text and figures in 
the report. It has  been  collected by the Member States  and the EMA, as  detailed in the section 
Sources  of  data  at  the  start  of  the  report.  The  data  should  be  read  in  conjunction  with  the 
explanations and clarifications in the text of the report. 

41 

 
 
 
 
ANNEX 1 

1.  

1a. 

SIDE EFFECT REPORTING 

Number of individual case-safety reports (ICSRs) European Economic Area (EEA) 

Postmarketing ADR 
reporting (EEA) 

Healthcare 
professionals (HCP) 

Patients 

Patients and HCPs 

Other sources*  

Total no. of ICSRs 
received (EEA) 

No. ICSR reported 
which have been 
identified as subject 
to medication error 
(EEA) 

CAPs 

Non 
CAPs 

Total 

CAPs 

Non 
CAPs 

Total 

CAPs 

Non 
CAPs 

Total 

CAPs 

Non 
CAPs 

Total 

CAPs 

Non 
CAPs 

Total 

CAPs 

NAPs  

Total 

2011 

2012 

2013 

2014 

January-
December 

January-
December 

January-
December 

January-
December 

115 130 

121 219 

140 729 

148 579 

83 582 

82 337 

89 519 

87 694 

198 712 

203 556 

230 248 

236 273 

7 302 

5 373 

12 675 

10 637 

5 223 

10 103 

8 326 

18 429 

11 976 

5 587 

16 227 

15 783 

32 010 

12 766 

4 708 

17 697 

15 595 

33 292 

14 208 

4 672 

15 860 

17 563 

17 474 

18 880 

467 

737 

403 

793 

1 204 

1 196 

342 

383 

725 

514 

483 

997 

133 536 

143 701 

94 915 

97 043 

170 064 

110 393 

180 998 

108 444 

228 451 

240 744 

280 457 

289 442 

1 723 

2 353 

4 076 

1 928 

2 593 

4 521 

2 636 

3 121 

5 757 

3 429 

3 649 

7 078 

*Please  note  that  ‘Other  sources’  were  combined  with  ‘Healthcare  professionals’  for 
charts on p. 10 - 11 

42 

 
 
 
 
1b.  

Number of individual case-safety reports (ICSRs) non European Economic Area 

ADR reporting  

2011 

2012 

2013 

2014 

(non EEA) 

Healthcare professionals  
Patients 
Other sources* 
Patients and HCPs 

258 879 
46 502 
11 555 
100 980 

324 089 
143 257 
11 714 
134 532 

332 291 
212 777 
11 935 
156 794 

363 704 
210 179 
17 310 
174 361 

*Please  note  that  ‘Other  sources’  were  combined  with  ‘Healthcare  professionals’  for 
charts on p. 10 - 11 

2.  

2a.  

SIGNALS 

Worksharing in signal management 

ANNEX 2 

43 

 
 
 
 
 
2b.  

Numbers of signals 

Signal reference data 

2012 

2013 

2014 

July-December 

January-
December 

January-
December 

No. of signal 
validated (total) 

No. of signal 
validated by 
NCA 

No. of signal 
validated by 
EMA 

CAPs 

Non CAPs 

Total 

CAPs 

Non CAPs 

Total 

CAPs 

Non CAPs 

Total 

CAPs 

No. of signal 
confirmed (total) 

Non CAPs 

Total 

CAPs 

No. of EMA 
signal confirmed  

Non CAPs 

Total 

CAPs 

No. of NCA 
signal confirmed  

Non CAPs 

Total 

CAPs 

No. of signal not 
confirmed (total) 

Non CAPs 

No. of EMA 
signal not 
confirmed  

No. of NCA 
signal not 
confirmed  

Total 

CAPs 

Non CAPs 

Total 

CAPs 

Non CAPs 

Total 

63 

29 

92 

22 

28 

50 

41 

1 

42 

54 

27 

81 

34 

1 

35 

20 

26 

46 

9 

2 

11 

7 

0 

7 

2 

2 

4 

55 

16 

71 

23 

16 

39 

32 

0 

32 

47 

15 

62 

27 

0 

27 

20 

15 

35 

8 

1 

9 

5 

0 

5 

3 

1 

4 

43 

19 

62 

15 

18 

33 

28 

1 

29 

33 

18 

51 

24 

1 

25 

9 

17 

26 

10 

1 

11 

4 

0 

4 

6 

1 

7 

44 

 
 
 
2c.  

Signal detection by lead Member State 

Member 
State 

Number of substances for signal 
detection (lead Member State – LMS) 

Germany (DE) 

United Kingdom (UK) 

Denmark (DK) 

Sweden (SE) 

Ireland (IE) 

Netherlands (NL) 

Finland (FI) 

France (FR) 

Hungary (HU) 

Italy (IT) 

Czech Republic (CZ) 

Spain (ES) 

Austria (AT) 

Portugal (PT) 

Romania (RO) 

Belgium (BE) 

Slovakia (SK) 

Norway (NO) 

Poland (PL) 

Estonia (EE) 

Latvia (LV) 

Croatia (HR) 

Bulgaria (BG) 

Lithuania (LT) 

Slovenia (SI) 

Cyprus (CY) 

Malta (MT) 

TOTAL 

2012 

2013 

2014 

152 

114 

111 

152 

114 

111 

168 

115 

102 

54 

60 

52 

51 

48 

42 

34 

79 

35 

27 

18 

24 

19 

19 

13 

13 

10 

15 

0 

5 

4 

5 

1 

1 

54 

60 

52 

51 

48 

42 

34 

79 

35 

27 

18 

24 

19 

19 

13 

13 

10 

15 

0 

5 

4 

5 

1 

1 

72 

58 

53 

48 

46 

42 

42 

36 

35 

32 

28 

20 

18 

18 

13 

13 

10 

10 

6 

5 

4 

4 

1 

1 

1 006 

1 006 

1 000 

45 

 
 
  
 
ANNEX 3 

3.  

3a.  

RISK MANAGEMENT PLANS 

Number of Risk Management Plans 

No. of Risk 
Management 
Plans submitted 

2012 

June-December 

2013 

January-
December 

2014 

January-
December 

PRAC (CAPs) 

National 
competent 
authorities 
(NAPs) 

48 

637 

597 

3 553 

7 356 

8 992 

For distribution of the RMPs for the NAPs authorised by Member State, see Annex 10. 

3b.  

Public Assessment reports as a measure of new approvals 

No. of Public 
Assessment 
Reports 
published on 
EMA's web-
portal for CAPs 

New applications 

Extension of 
indications 
RMP summaries 
(from Apr 2014) 

2012 

2013 

2014 

81 

50 

N/A 

94 

50 

N/A 

89 

51 

54 

46 

 
 
 
 
 
 
4.  

4a.  

ROUTINE BENEFIT RISK MONITORING (PERIODIC SAFETY UPDATE REPORTS) 

Number of PSURs 

2012 

2013 

2014 

July-December 

January-December 

January-December 

ANNEX 4 

PSURs reviewed at 
PRAC for CAPs only 

PSURs reviewed at 
PRAC for CAPS and 
NAPS 

Total number of 
PSUR reviewed at 
PRAC (CAP/NAP) 

PSURs submitted to 
an NCA for 
assessment at national 
level only (NAP) 

20 

0 

20 

430 

6 

436 

426 

45 

471 

5 093 

3 726 

3 310 

For distribution of the PSURs for the NAPs authorised by individual Member State,  see Annex 
10. 

4b.  

PSUR worksharing 

No. of PSURs in 
which one NCA acted 
as lead Member State 

2012 

2013 

2014 

July-December 

January-December 

January-December 

62 

151 

116 

4c.  

Medicines under additional monitoring as of December 2014 

List 

Annexes 

List + Annexes 

CAPs 

NAPs 

Total 

No. annexes 

NAPs 

Total 
CAPs 

Total 
NAPs 

Total - 
All 

193 

8 

201 

12 

1 269 

193 

1 277 

1 470 

47 

 
 
 
 
 
 
 
 
 
UK 

UK 

HU 

DE 

FR 

FR 

EC 

EC 

EC 

FR 

FR 

V 

V 

V,R 

V 

R 

V 

S 

S 

S 

S 

V 

5.  

5a.  

REFERRALS 

Table of referral procedures, 2012-2014 

Procedure name 

INN (for overview) 

Art. 

Started 

Triggered 
by 

Outcome 

ANNEX 5 

2012 

Codeine 

Diclofenac 

codeine 

diclofenac 

SABA (Short Acting Beta 
Agonists) 

terbutaline, salbutamol, hexoprenaline, 
ritodrine, fenoterol 

31 

31 

31 

Oct-12 

Oct-12 

Nov-12 

HES (Hydroxyethyl starch 
solutions) 

hydroxyethyl starch 

31 

Nov-12 

almitrine 

diacerein 

nicotinic acid/laropiprant 

nicotinic acid/laropiprant 

nicotinic acid/laropiprant 

tetrazepam 

cyproterone/ethinylestradiol 

31 

31 

20 

20 

20 

107i 

107i 

Nov-12 

Nov-12 

Jan-13 

Jan-13 

Jan-13 

Jan-13 

Feb-13 

2013 

Almitrine 

Diacerein 

Tredaptive 

Trevaclyn 

Pelzont 

Tetrazepam 

Cyproterone, ethinylestradiol 
- DIANE 35 & other 
medicines containing 
cyproterone acetate 2mg and 
ethinylestradiol 35 
micrograms 

Combined hormonal 
contraceptives 

Flupirtine 

flupirtine 

Domperidone 

domperidone 

Nicotinic acid and related 
substances - acipimox, 
xantinol nicotinate 

Kogenate Bayer/Helixate 
NexGen 

nicotinic acid, acipimox, xantinol 
nicotinate 

desogestrel, gestodene, norgestimate, 
etonogestrel, drospirenone, dienogest, 
chlormadinone, norgestimate, 
nomegestrol acetate/estradiol, 
norelgestromin/ethinylestradiol 

31 

Feb-13 

FR 

V 

107i 

Mar-13 

31 

31 

Mar-13 

Mar-13 

DE 

BE 

DK 

V 

V,R 

V 

octocog alfa 

20 

Mar-13 

EC 

V 

48 

 
 
 
 
 
 
 
 
 
 
 
 
Procedure name 

INN (for overview) 

Art. 

Started 

Triggered 
by 

Outcome 

31 

May-13 

IT 

V 

Renin-angiotensin system 
(RAS)-acting agents 

captopril, imidapril, zofenopril, 
candesartan, delapril, telmisartan, 
aliskiren, moexipril, enalapril, 
valsartan, fosinopril, irbesartan, 
perindopril, quinapril, ramipril, 
eprosartan, olmesartan, trandolapril, 
losartan, azilsartan, lisinopril, spirapril, 
benazepril, cilazapril 

Protelos/Osseor 

strontium ranelate 

NUMETA G13%E, 
NUMETA G16%E emulsion 
for infusion and associated 
names 

Zolpidem-containing 
medicinal products 

Hydroxyethyl starch (HES) - 
containing medicinal 
products 

Bromocriptine-containing 
medicines  

glucose, lipids, amino-acids and 
electrolytes 

20 

May-13 

107i 

Jun-13 

zolpidem 

31 

Jul-13 

hydroxyethyl starch 

107i 

Jul-13 

bromocriptine 

31 

Sep-13 

Valproate related substances  

valproate 

Iclusig 

ponatinib 

2014 

Testosterone 

Codeine for cough in 
paediatric population 

testosterone 

codeine 

31 

20 

31 

31 

Oct-13 

Dec-13 

Apr-14 

Apr-14 

Ambroxol/Bromhexine 

ambroxol/bromhexine 

31 

Apr-14 

methadone 

107i 

Apr-14 

hydroxyzine hydrochloride 

Corlentor and Procoralan 

ivabradine 

Ibuprofen and dexibuprofen 

ibuprofen and dexibuprofen 

31 

20 

31 

May-14 

May-14 

Jun-14 

Methadone 

Hydroxyzine 

EC 

SE 

IT 

UK 

FR 

UK 

EC 

ET 

DE 

BE 

NO 

HU 

EC 

UK 

V 

V,S 

V 

V 

V 

V 

V 

V 

V,R 

V 

V,S 

V 

V 

V 

to  outcomes:  V=variation  of  marketing  authorisation;  S=suspension  of  marketing 
Key 
authorisation  (can  be  lifted  if  new  evidence  is  presented  by  marketing  authorisation  holder); 
R=revocation  of  marketing  authorisation  (permanent).  A  referral  of  a  group  of  medicines  may 
result in differing outcomes for different medicines. 

49 

 
 
 
 
 
 
 
5b.  

Distribution of rapporteurships for referrals by Member State 

6.  

6a.  

POST-AUTHORISATION STUDIES 

Post-authorisation safety studies 

2012 

2013 

2014 

July-December 

January-December 

January-December 

ANNEX 6 

11 

6 

23 

6 

No. of imposed non 
interventional PASS 
protocols for CAPs 
reviewed at PRAC 

Nationally imposed 
PASS 

6b.  

Post-authorisation efficacy studies 

2014 

CHMP imposed 

National 

4 

5 

14 

1 

50 

 
 
 
 
 
 
 
 
ANNEX 7 

2012 

2013 

2014 

9* 

26 

6 

37 

207 

195 

13** 

48 

167 

7.  

7a.  

INSPECTIONS 

Number of inspections 

No. of 
pharmacovigilance 
inspections performed 
(CHMP mandated) 
No. of 
pharmacovigilance 
inspections performed 
(CAP programme) 
No. of 
pharmacovigilance 
inspections performed 
(EU total) 

*7 from July-December 2012 

**including 3 sites inspected for conduct of a PASS 

7b.  

Master file and logbook 

No. of occasions when 
the MAH to submit a 
copy of the PhV 
system master file 

2012 

2013 

2014 

9  

6 

10 

7c.  

Imposed penalties on marketing authorisation holders 

2012 

2013 

2014 

July-December 

January-December 

January-December 

0 

4* 

1 

No. penalties to 
MAHs regarding 
noncompliance with 
their PhV obligations 

*includes one local infringement notice issued  

51 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.  

8a.  

MEDICATION ERRORS 

Individual case safety reports (ICSRs) related to medication errors 

2012 

July-December 

2013 

January-
December 

2014 

January-
December 

ANNEX 8 

No. ICSR 
reported which 
have been 
identified as 
subject to 
medication error 
(EEA) 

Total no. of 
ICSRs received 
(EEA) 

CAPs 

NAPs 

Total 

CAPS 

Non-CAPs 

Total 

1 173 

1 374 

2 547 

76 833 

51 669 

128 502 

2 636 

3 121 

5 757 

170 064 

110 393 

280 457 

3 429 

3 649 

7 078 

180 998 

108 444 

289 442 

ANNEX 9 

9.  

9.  

PHARMACOVIGILANCE ACTIVITIES BY THE PRAC 

Items on PRAC Agenda 

Workload 

2012 

2013 

2014 

(Jul-Dec ) 

Art.31 referrals 
Art.107i referrals 
Art.5(3) referrals 
Signals 
RMPs 
PSURs 
PASS Protocols 
PASS Results 
Renewals, Conditional Renewals and Annual 
Reassessments 
Pharmacovigilance Inspections 
Other safety issues - CHMP 
Other safety issues – Member State 
Total items 

7 

51 
48 
20 
5 

11 
12 
5 
159 

54 
16 
3 
127 
637 
438 
91 
13 
104 

14 
29 
8 
1 534 

34 
5 
1 
118 
597 
470 
137 
51 
56 

10 
19 
23 
1 521 

52 

 
 
 
  
  
  
  
 
10.  

PHARMACOVIGILANCE ACTIVITIES BY MEMBER STATES AT NATIONAL LEVEL 

ANNEX 10 

Table shows entries for activity at purely national level for each EEA country participating in the pharmacovigilance network, except for 
Luxembourg, Iceland and Liechtenstein for which no data were available. 

Two sets of figures are shown for Germany, which has two NCAs (BfArm – the Federal Agency for Medicines and Health Products and 
PEI – the Paul-Ehrlich-Institute, Federal Institute for Vaccines and Biomedicines).  

Where the data were not available this is indicated by n/a. 

53 

Question\MS-->ATBEBGCYCZDE-BfarmDE-PEIDKEEESFIFRGRHRHUIEITLTLVMTNLNOPLPTROSESISKUKTotals1. RMPs213139200196528054563042635797000349564147132719224737108542166155715392504921026791199012012 Jul-Dec271443614651512n/a717934n/an/a7681242433982152376522862483975203n/a35532013105447473808015824n/a138118734n/an/a12724669503712159392146162562410515243729673562014818181843914938227n/a217159932n/an/a1462375458181230134562106364666710626538649589922. PSURs14921080519120428271573664587243250026504324035455310941232827743260822113072012 Jul-Dec48132016421820744723242132521n/an/a132349713218n/a414684n/a11565n/a3414752201343638028134649175861334013109n/an/a2712716421230n/a4122148521650n/a19535312014575380746402623548283195120n/a26107114220105n/a2684962241111n/a28630243. PASS212111172012 Jul-Dec0000n/an/a0n/a00n/a400000100n/a0000n/a000520131000n/an/a0n/a00n/a500000000n/a0000n/a000620141000n/an/a0n/a00n/a301100000n/a0000n/a00064. PAES112014 May-Dec0000n/a00n/a0n/an/an/a0000100000000000015. Penalties4152012 Jul-Dec0000n/a000000000000000n/a00000000020130000n/a000000000003000n/a00000001320140000n/a000000000001000n/a000000001 
 
 
 
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