REPORT FROM THE COMMISSION 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  COM(2016) 498 final   REPORT FROM THE COMMISSION Pharmacovigilance related activities of Member States and the European Medicines Agency concerning medicinal products for human use  (2012 – 2014) {SWD(2016) 284 final}  
 
 
REPORT FROM THE COMMISSION 

Pharmacovigilance related activities of Member States and 
the European Medicines Agency concerning medicinal products for human use 
 (2012 – 2014) 

2 

 
 
1. 

INTRODUCTION 

In the European Union (EU) medicinal products for human use are subject to strict testing and 
assessment of their quality, efficacy and safety before being authorised either at Member State 
or  EU  level.  Once  placed  on  the  market  they  continue  to  be  monitored  through 
pharmacovigilance activities. 

Pharmacovigilance, as defined by the World Health Organisation (WHO), is ‘the science and 
activities  relating  to  the  detection,  assessment,  understanding  and  prevention  of  adverse 
effects or any other drug-related problem’. 

Some side effects or ‘adverse reactions’ may not be seen until a large number of people have 
in  real-life use  received  the  medicine.  It is  therefore  vital  that  the safety  of  all  medicines  is 
monitored throughout their use in healthcare practice. 

The  EU  legal  framework  of  pharmacovigilance  for  medicinal  products  for  human  use  is 
provided  for  in  Regulation  (EC)  No 726/20041  and  Directive  2001/83/EC2.  The  legislation 
was amended in 20103 and 20124. 

Article 29 of Regulation (EC) No 726/2004 and Article 108b of Directive 2001/83/EC require 
regular reporting on the performance of pharmacovigilance tasks by the European Medicines 
Agency (EMA) and the Member States respectively. 

This  report  and  the  accompanying  Staff  Working  Document5  describe  the  activities  of  the 
EU’s networked and collaborative system for monitoring and controlling the safety of human 
medicines and is focused on activities since the start of operation of new legislation in 2012 
until the end of 2014, but also includes information on some tasks and processes initiated up 
to July 2015. 

1  

2  

3  

4  

5  

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. 
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. 
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 and  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. 
Regulation  (EU)  No  1027/2012  of  the  European  Parliament  and  of  the  Council  of  25  October  2012 
amending  Regulation  (EC)  No  726/2004  as  regards  pharmacovigilance,  OJ  L  316,  14.11.2012,  p.  38 
and  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. 
SWD (2016) 284 final 

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2. 

STRONG COLLABORATION BETWEEN EUROPEAN REGULATORY AUTHORITIES 

Ensuring  that  regulators  can  respond  to  emerging  or  urgent  health  issues  in  a  timely  and 
efficient way is a key deliverable of the new pharmacovigilance legislation. For that purpose 
the  medicines  regulatory  authorities  in  31  European  Economic  Area  (EEA)  countries,  the 
EMA and the European Commission closely collaborate and work in partnership as a network 
to  discuss  and  deal  swiftly  with  any  emerging  problem  in  the  interest  of  patients'  access  to 
safe  and  efficacious  medicines6.  The  ability  to  take  quick  and  robust  regulatory  action  was 
enhanced through the legislation by: the creation of the Pharmacovigilance Risk Assessment 
Committee;  strengthening  of 
the  Co-ordination  group  for  Mutual  recognition  and 
Decentralised  procedures  –  human  and  the  introduction  of  new  procedures  to  fast-track 
decision-making when public health is at risk. 

2.1. 

The role of Member States 

The individual Member States of the EEA power the entire pharmacovigilance system. They 
provide much of the resource and knowledge for assessing signals of possible emerging side 
effects and take the lead in evaluating and analysing data when a safety issue is assessed at a 
European  level.  They  maintain  the  inspectorates  that  ensure  that  medicines  marketed  in  the 
EU are manufactured appropriately and are of suitable quality, and that the pharmacovigilance 
systems of industry are working as they should. 

The  legislation  gives  the  Co-ordination  group  for  Mutual  recognition  and  Decentralised 
procedures  –  human  (CMDh)7,  a  body  representing  the  national  regulators  of  the  EEA,  the 
mandate to lead on decision-making when no centrally authorised medicines are involved.  

2.2. 

The role of the European Medicines Agency 

The  EMA  has  a  central  role  in  the  EU  system  co-ordinating  its  activities  and  providing 
technical, regulatory and scientific support to the Member States and industry.  

The new scientific committee, the Pharmacovigilance Risk Assessment Committee (PRAC), 
came into existence in July 2012. PRAC’s mandate covers all aspects of risk management of 
medicinal products for human use. PRAC members include experts in pharmacovigilance and 
regulation  from  EU  Member  States  as  well  as  scientific  experts  and  representatives  of 
healthcare  professionals  and  patient  organisations  appointed  by  the  European  Commission. 
Figure 1 in the annex presents the relative frequency of the main pharmacovigilance-related 
activities on the PRAC agenda between July 2012 and December 2014.  

2.3. 

The role of the Commission 

The European Commission is the competent authority for centrally authorised medicines and 
supplies the legal authority that underpins the EU pharmacovigilance system. 

6  

7  

European  Medicines  Agency,  The  European  regulatory  system  for  medicines  and  the  European 
Medicines Agency, EMA/437313/2014. 
Further  information  on  the  role  and  activities  of  CMDh  is  available  on  the  following  webpage: 
http://www.hma.eu/cmdh.html.  

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3. 

MAIN PHARMACOVIGILANCE RELATED TASKS AND ACTIVITIES 

The  entire  pharmacovigilance  process—from  systems  that  monitor  for  and  detect  possible 
adverse  effects  through to  regulatory  action  to  mitigate  risks—is  highly  co-ordinated  across 
the regulatory network, the pharmaceutical industry and health systems. The system receives 
a wide range of input including that from non-EU regulators, academia, health professionals 
and patients. 

The pharmacovigilance process can be broken down into the following key tasks: 

  Risk  management  planning  -  assessing  the  risks  of  each  new  medicine  and 
developing  plans  to  collect  data  and  minimise  those  risks.  PRAC  reviewed  48  risk 
management plans (RMPs) in July–December 2012, 637 in 2013 and 597 in 2014. The 
Member  States,  collectively,  received  around  3 500  (2012),  7 500  (2013),  and  9 000 
(2014) RMPs for nationally authorised medicines. 

  Collecting and managing case reports of possible side effects (adverse drug reactions 
(ADR)). Figure 2 in the annex presents the reports of serious adverse events between 
2011 and 2014. 

  Signal  detection  and  management  -  analysing  reports  of  suspected  side  effects  to 
identify  signals.  Some  193  unique  signals  were  evaluated  by  PRAC  between 
September  2012  and  December  2014.  Figure  3  in  the  annex  presents  the  number  of 
discussions  in  PRAC  concerning  either  new  signals  or  follow  up  discussions  and 
Figure 4 gives an overview of the regulatory action following signal assessment. 

  Routine  benefit-risk  monitoring  of  medicines  via  periodic  safety  update  reports 
(PSURs) and maintaining the list (EURD list) of schedules for submitting PSURs. The 
number of PSURs reviewed by PRAC was 20 (July-December 2012), 436 (2013) and 
471 (2014). Figure 5 in the annex gives an overview of the regulatory action following 
PSUR assessment. In addition, the number of PSURs submitted to national competent 
authorities in the Member States for purely national assessments were around 5 000 in 
2012,  3 500  in  2013  and  3 000  in  2014  with  an  additional  62,  151  and  116  PSUR 
worksharing  procedures  for  purely  nationally  authorised  medicines  during  the  same 
periods. 

  Referrals - Europe-wide reviews of important safety and benefit-risk issues. Between 
July  2012  and  December  2014,  31  safety  referrals  were  sent  to  the  PRAC.  Nine  of 
these referrals involved centrally authorised medicines, the remainder dealt solely with 
nationally authorised products. (See Figure 6 in the annex). Some additional concerns 
at  a  national  level  were  also  discussed  by  the  CMDh  to  decide  on  whether  an 
assessment  at  EU  level  was  required  but  did  not  ultimately  trigger  a  referral.  Such 
CMDh discussions were held on 2 occasions in 2013 and 6 in 2014. 

  Managing  information  on  products  subject  to  additional  monitoring,  and  products 
that have been withdrawn. At the end of 2014, the list of medicines under additional 
monitoring  included  193  centrally  authorised  medicines  and  8  substances  in  1 269 

5 

 
 
nationally  authorised  products.  During  2014  EMA  received  132  notifications  of 
withdrawal of products. 

  Assessing  and  co-ordinating  studies  after  marketing  through  post-authorisation 
safety  studies  and  post-authorisation  efficacy  studies.  Between  July  2012  and 
December  2014,  PRAC  reviewed  protocols  for  38  imposed  non-interventional  post-
authorisation safety studies (PASSs). Member States evaluated an additional 17 PASS 
protocols for nationally authorised medicines. 

  Carrying out inspections to ensure company pharmacovigilance systems comply with 
good  pharmacovigilance  practice.  The  number  of  inspections  undertaken  was  207 
(2012),  195  (2013)  and  167  (2014)  with  26,  37  and  48  respectively  for  centrally 
authorised medicines. 

  Communicating about safety-related issues, and interacting with and engaging with 
relevant stakeholders. The agendas, highlights and minutes of the PRAC meetings are 
published as well as public safety communications on relevant issues. There were 14 
public safety communications issued in the second half of 2012, 78 in 2013 and 57 in 
2014. 

  Development of systems and guidelines, and promotion of research to address gaps 

in knowledge. 

  Monitoring performance of the system, including compliance with legal obligations 

and standards. 

  Training and capacity building. 

4. 

SYSTEMS AND SERVICES IMPROVEMENT 

The role of 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 developments have included: 

  The  Article  57  database8  of  all  authorised  medicines  (both  centrally  and  nationally 
authorised) in the EU with information on over 580 000 medicines from nearly 4 300 
marketing authorisation holders. 

  Literature  monitoring  service  -  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  individual  case  safety  reports.  The  service 
was launched in June 2015. 

  The PSUR repository was developed and made available during the reporting period 

with its functionality successfully audited in 2015. 

8 Article 57(1)(l) of Regulation (EC) No 726/2004. 

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  The  legislation  requires  enhancement  of  EudraVigilance  database  to  support 
simplified reporting, better search, analysis and tracking functions, and improved data 
quality.  Progress  has  been  made  on  enhancements  during  the  reporting  period 
including  the  launch  of  the  ADR  website  and  support  to  signal  detection  activities. 
The final audit of the updated system is expected to be completed in early 20189. 

5. 

COOPERATION AND COORDINATION  

As  well  as  co-ordination  among  the  network  of  over  30  national  competent  authorities,  the 
Commission and the EMA work closely with other  international regulators through bilateral 
arrangements  and  through  multilateral  fora  such  as  the  Association  of  the  International 
Council  for  Harmonisation  of  Technical  Requirements  for  Pharmaceuticals  for  Human  Use 
(ICH) to promote common approaches and standardised requirements for the authorisation of 
medicines. 

Good  pharmacovigilance  relies  on  co-operation  among  the  stakeholders  and  this  has  been 
encouraged by the legislation. The input of patients and healthcare professionals throughout 
the authorisation of medicines and pharmacovigilance is vital. This is provided through civil 
society representatives being members of PRAC and specifically consulted for certain types 
of referrals. 

6. 

CONTINUING AND FUTURE DEVELOPMENT OF THE NETWORK 

Over  the  period  of  the  report  and  beyond,  the  pharmacovigilance  network  is  focusing  on 
training  to  develop  understanding  of  pharmacovigilance  and  regulatory  science  to  enable 
sharing  of  best  practice,  improving  the  efficiency  and  effectiveness  of  the  processes,  and 
building capacity. 

The  Member  States  and  EMA  offer  extensive  training  for  regulatory  staff  and  for  relevant 
external stakeholders. The efficiency and effectiveness of pharmacovigilance processes have 
the  science  and  practice  of 
improved.  Projects  have  been 
to 
for  Operating 
pharmacovigilance 
Pharmacovigilance  in  Europe  (SCOPE)  Joint  Action;  the  European  Network  of  Centres  for 
Pharmacoepidemiology  and  Pharmacovigilance  (ENCePP);  and,  the  PROTECT  project10. 
Outcomes  from  these  initiatives  are  already  starting  to  inform  further  process  development 
and updates to guidelines. 

Strengthening  Collaboration 

initiated 
the 

including: 

improve 

7. 

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 participants 
to  share  in  the  best  available  expertise  and  evidence  and  co-ordinate  the  regulatory  actions, 
producing more efficient and consistent outcomes for everybody. The regulatory tools made 

9  

10  

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). 
Pharmacoepidemiological  Research  on  Outcomes  of  Therapeutics  by  a  European  Consortium,  an 
Innovative Medicines Initiative public-private funded project. 

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available  under  the  revised  legislation,  including  risk  management  plans,  post-authorisation 
studies,  signal  detection  and  management  at  EU  level,  periodic  safety  update  reports 
assessment  and  reviews  of  medicines  through  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. Mechanisms have been put in place to ensure that accurate safety information reaches 
the  EU  public  in  a  timely  manner.  Engagement  of  key  stakeholders  such  as  patients  and 
healthcare  professionals  is  embedded  in  the  system  including  through  patient  reporting  of 
suspected  side  effects.  For  the  future,  deepening  involvement  is  foreseen,  including  the 
holding of public hearings for critical safety issues. 

Work  is  proceeding  on  the  infrastructure  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, of the PSUR repository and full use of 
the  Article  57  EU  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,  such  as  the  research  supported  through  the  EU 
Research Framework Programmes, will also support future improvements. 

8 

 
 
Abbreviations 

ADR 

adverse drug reaction 

CHMP 

Committee for Medicinal Products for Human Use 

CMDh 

EEA 

EMA 

EU 

EURD 

ICSR 

PASS 

Co-ordination Group for Mutual Recognition and Decentralised procedures—
human 

European Economic Area 

European Medicines Agency 

European Union 

list of European Union reference dates and frequency of submission of periodic 
safety update reports 

individual case safety report 

post-authorisation safety study 

PRAC 

Pharmacovigilance Risk Assessment Committee 

PSUR 

periodic safety update report 

RMP 

risk management plan 

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ANNEX — Figures and Tables 

Figure 1: Number of items on the Pharmacovigilance Risk Assessment Committee (PRAC) 
agenda July–December 2012, January–December 2013 and January–December 2014 

Number of items on PRAC agenda 

1800

1600

1400

1200

1000

800

600

400

200

0

Jul-Dec 2012

2013

2014

Other safety issues - MS

Other safety issues - CHMP (including
CHMP requests to PRAC for Art.5.3
referrals)
Pharmacovigilance Inspections

Renewals, Conditional Renewals and
Annual Reassessments

PASS Results

PASS Protocols

PSURs

RMPs

Signals

Referrals

10 

 
 
 
 
Figure  2  Reporting  of  individual  case  safety  reports  to  the  EudraVigilance  database  from 
European Economic Area countries or non-European Economic Area countries 2011–2014 

Individual Case Safety Reporting to 
EudraVigilance (EEA) 

350000

300000

250000

200000

150000

100000

50000

0
2011

2012

2013

2014

Patients and HCPs

Patients

Healthcare professionals

11 

 
 
 
Individual Case Safety reporting to 
EudraVigilance (non-EEA) 

900000

800000

700000

600000

500000

400000

300000

200000

100000

0
2011

2012

2013

2014

Patients and HCPs

Patients

Healthcare professionals

HCPs - Healthcare professionals 

12 

 
 
 
 
 
 
 
Figure  3:  Number  of  signal  related  discussions, 
the 
Pharmacovigilance Risk Assessment Committee (PRAC) September 2012 to December 2014 

initial  and  follow  up, 

in 

13 

 
 
 
Figure  4:  Type  of  regulatory  action  following  signal  assessment  by  the  Pharmacovigilance 
Risk Assessment Committee (PRAC) September 2012 to December 2014 

PRAC signals assessment Sep 2012 - Dec 2014, 
total=193 

Update of RMP; 
2; 1% 

PASS; 1; 0% 

Referral ; 11; 
6% 

Assessment 
on-going; 33; 
17% 

Routine 
pharmaco-
vigilance, 46, 
24% 

Update of 
product 
information; 
100; 52% 

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Figure  5:  Outcome  of  the  periodic  safety  update  report  (PSUR)  assessment  by  the 
Pharmacovigilance Risk Assessment Committee (PRAC) September 2012 to December 2014 

Outcomes of PSUR assessments and PSUSAs 

0%

20%

40%

60%

80% 100%

Jul-Dec 2012

17 

3 

2013

360 

76 

2014

383 

88 

Maintenance

CHMP variation

Suspension

Revocation

PSUSA – Periodic safety update report – Single assessment 

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Figure 6: Pharmacovigilance related referral started in 2012, 2013 and 2014 

Procedure 

2012 

Codeine 

Diclofenac 

SABA (Short Acting Beta Agonists) 

HES (Hydroxyethyl starch solutions) 

Almitrine 

Diacerein 

2013 

Tredaptive, Trevaclyn, Pelzont (nicotinic 
acid/laropiprant) 

Tetrazepam 

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

Combined hormonal contraceptives 

Flupirtine 

Domperidone 

Nicotinic acid and related substances - acipimox, 
xantinol nicotinate 

Kogenate Bayer/Helixate NexGen (octocog alfa) 

Renin-angiotensin system (RAS)-acting agents 

Protelos/Osseor (strontium ranelate) 

NUMETA G13%E, NUMETA G16%E emulsion for 
infusion and associated names (glucose, lipids, amino-
acids and electrolytes) 

Zolpidem-containing medicinal products 

Hydroxyethyl starch (HES) - containing medicinal 
products 

Bromocriptine-containing medicines  

Valproate related substances  

Iclusig (ponatinib) 

16 

Article 

Started  Outcome 

31 

31 

31 

31 

31 

31 

Oct-12 

Oct-12 

Nov-12 

Nov-12 

Nov-12 

Nov-12 

20 

Jan-13 

107i 

107i 

Jan-13 

Feb-13 

31 

Feb-13 

107i 

Mar-13 

31 

31 

20 

31 

20 

Mar-13 

Mar-13 

Mar-13 

May-13 

May-13 

V 

V 

V,R 

V 

R 

V 

S 

S 

V 

V 

V 

V,R 

V 

V 

V 

V 

107i 

Jun-13 

V,S 

31 

Jul-13 

107i 

Jul-13 

31 

31 

20 

Sep-13 

Oct-13 

Dec-13 

V 

V 

V 

V 

V 

 
 
 
 
 
 
 
 
 
 
2014 

Testosterone 

Codeine for cough in paediatric population 

Ambroxol/Bromhexine 

Methadone 

Hydroxyzine 

Corlentor and Procoralan (ivabradine) 

Ibuprofen and dexibuprofen 

Key: 

31 

31 

31 

Apr-14 

Apr-14 

Apr-14 

107i 

Apr-14 

31 

20 

31 

May-14 

May-14 

Jun-14 

V 

V,R 

V 

V,S 

V 

V 

V 

Article 20 referrals – only centrally authorised medicines are concerned 
Article 107 referrals – urgent Union interest referrals 
Article 31 referrals – Union interest referrals 

V – variation of the marketing authorisation 
R – revocation of the marketing authorisation 
S – suspension of the marketing authorisation 

17