Proposal for a Regulation of the European Parliament and of the Council 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 {SEC(2008) 2670} {SEC(2008) 2671}
Date: 2008-12-10
Institutions: European Commission
Subjects: European Medicines Agency, drug surveillance, marketing, medicinal product

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COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels, 10.12.2008 
COM(2008) 664 final 

2008/0257 (COD) 

Proposal for a 

REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 

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 

{SEC(2008) 2670} 
{SEC(2008) 2671} 

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EXPLANATORY MEMORANDUM 

1. 

CONTEXT OF THE PROPOSAL 

1.1. 

Grounds for and objectives of the proposal 

Medicinal  products  contribute  considerably  to  the  health  of  EU  citizens.  The  discovery, 
development  and  effective  use  of  medicinal  products  improve  quality  of  life,  reduce  the 
length  of  time  spent  in  hospital  and  save  lives.  Medicinal  products  can,  however,  also  have 
adverse  effects  and  adverse  drug  reactions  present  an  important  public  health  burden  in  the 
Community.  It  is  estimated  that  5%  of  all  hospital  admissions  are  due  to  an  adverse  drug 
reaction, 5% of all hospital patients suffer an adverse drug reaction and adverse drug reactions 
are the fifth most common cause of hospital death. 

Some adverse reactions will only be detected after a medicine has been authorised and the full 
safety  profile  of  medicinal  products  can  only  be  known  once  they  have  entered  the  market. 
Pharmacovigilance rules are therefore necessary for the protection of public health in order to 
prevent, detect and assess adverse effects of medicinal products. 

Community  rules  so  far  adopted  have  made  a  major  contribution  to  the  achievement  of  the 
objective  that  medicinal  products  authorised  to  be  placed  on  the  Community  market  are 
continuously  monitored  as  regards  their  safety.  However,  in  the  light  of  the  experience 
acquired  and  following  an  assessment  by  the  Commission  of  the  Community  system  of 
pharmacovigilance,  it  has  become  clear  that  new  measures  are  necessary  to  improve  the 
operation of the Community rules on the pharmacovigilance of medicinal products for human 
use.  

Therefore,  the  proposals  aim  at  the  strengthening  and  rationalizing  the  Community 
pharmacovigilance  system  of  medicinal  products  for  human  use  through  the  amendment  of 
the two legal acts governing this field, with the overall objectives of better protecting public 
health,  ensuring  proper  functioning  of  the  internal  market.  and  simplifying  the  current  rules 
and procedures. The specific objectives are: 

•  Providing  for  clear  roles  and  responsibilities  for  the  key  responsible  parties  and 

clear obligations against which they perform their roles; 

•  Rationalising  EU  decision-making  on  drug  safety  issues  in  order  to  deliver 
measures  that  are  equally  and  fully  implemented  for  all  relevant  products  and 
across the Community with a view to preventing unnecessary patient exposure to 
risks; 

•  Strengthening  medicines  safety  transparency  and  communication  to  increase  the 
understanding  and  trust  of  patients  and  health  professionals  in  the  safety  of 
medicines and improve the penetration of key warnings; 

•  Strengthening  companies'  pharmacovigilance  systems,  allowing  companies  to 

improve their systems constantly while reducing administrative burden; 

•  Ensuring the proactive and proportionate collection of high quality data relevant 
to the safety of medicines through risk management and structured data collection 
in  the  form  of  post  authorisation  safety  studies,  together  with  rationalised  single 
case and periodic reporting of suspected adverse reactions; 

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•  Involving  stakeholders  in  pharmacovigilance  including  through  direct  patient 
reporting of suspected adverse reactions and inclusion of patients and heath-care 
professionals in decision-making. 

•  Simplification  of  the  current  Community  pharmacovigilance  procedures  with 
consequent  efficiency  gains  for  both  the  pharmaceutical  industry  and  medicines 
regulators. 

1.2. 

General context 

Pharmacovigilance  is  defined  as  the  science  and  activities  relating  to  the  detection, 
assessment, understanding and prevention of adverse effects of medicinal products. 

The Community has had legislation on medicinal products on pharmacovigilance since 1965. 
Until  now  there  has  been  no  systematic  review  of  the  Community  pharmacovigilance 
legislation,  its  operation  and  its  effect  on  protecting  public  health.  Therefore,  in  2004  the 
Commission services launched an independent study into the functioning of the Community 
pharmacovigilance  system.  The  independent  report  together  with  a  subsequent  broad  public 
consultation revealed several shortcomings. 

1.3. 

Existing provisions in the area of the proposal 

Harmonised Community rules on the pharmacovigilance of medicinal products for human use 
are laid down in: 

•  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 
Agency1, as regards medicinal products authorized by the Commission in accordance with 
the procedure of that Regulation (the so-called "centralised procedure"); and 

•  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 use2, as regards general 
rules  on  medicinal  products  for  human  use  and  specific  rules  for  medicinal  products 
authorised by the Member States. 

While the rules are broadly the same in substance, there are certain divergences and various 
provisions  are  duplicated  in  the  two  legal  texts.  It  is  appropriate  to  rationalise  and  simplify 
this by laying down all general rules in the Community code on medicinal products for human 
use  (Directive  2001/83/EC),  and  cross-referring  to  them  in  the  regulation  governing  the 
centralised procedure (Regulation (EC) No 726/2004), with specific provisions  for  centrally 
authorised products only when justified. 

1.4. 

Consistency with the other policies and objectives of the Union 

The  proposals  are  consistent  with  the  overall  objective  of  the  Community  legislation  on 
medicinal products for human use, which is to remove disparities between national provisions 
in order to ensure the proper functioning of the internal market for such products, while at the 
same time safeguarding a high level of protection of public and human health. They are also 

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OJ L 136, 30.4.2004, p. 1.  
OJ L 311, 28.11.2001, p. 67.  

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consistent  with  Article  152(1)  of  the  Treaty  establishing  the  European  Community,  which 
provides  that  a  high  level  of  human  health  protection  shall  be  ensured  in  the  definition  and 
implementation of all Community policies and activities. 

The  proposal  is  equally  consistent  with  the  Commission  patient  safety  initiative3  and  the 
Commission  work  to  stimulate  innovation  in  the  pharmaceutical  sector,  through  the  7th 
Framework programme in general and the Innovative Medicines Initiative4 in particular. The 
proposal  is  also  consistent  with  Community  projects  which  aim  to  develop  and  validate  the 
use of innovative information technology tools to identify medicines adverse events5. 

2. 

CONSULTATION OF INTERESTED PARTIES AND IMPACT ASSESSMENT 

2.1. 

Consultation of interested parties 

All  interested  parties,  in  particular  patient  and  healthcare  professionals,  Member  States 
competent  authorities  and  industry,  have  been  widely  consulted  on  this  proposal.  Various 
means  of  consultation  have  been  used,  namely  two  internet-based  public  consultations, 
dedicated workshops, questionnaires and bilateral meetings.  

Additional information on the consultations conducted can be found in the Impact Assessment 
attached to this proposal. The detailed results of both parts of the consultation, including the 
individual consultation responses can be found at:   
http://ec.europa.eu/enterprise/pharmaceuticals/pharmacovigilance/pharmacovigilance_key.htm 

2.2. 

Impact assessment 

The  details  of  the  impact  assessment  are  provided  in  the  Commission  Staff  Working 
Document 'Impact Assessment' attached to this proposal. 

In  conclusion,  the  impact  assessment  suggests  that  increasing  the  clarity,  efficiency  and 
quality  of  the  EU  system  of  pharmacovigilance,  through  amendments  to  the  existing 
Community  legal  framework,  leads  to  major  public  health  improvements  and  overall  cost 
savings to the EU industry sector. 

3. 

LEGAL ELEMENTS OF THE PROPOSAL 

3.1. 

Summary of the proposed action 

The key elements of the proposals can be summarised as follows:  

Clear roles and responsibilities 

Current legislation contains some instances of overlapping or ambiguous responsibilities for 
pharmacovigilance.  

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See: http://ec.europa.eu/health/ph_overview/patient_safety/consultation_en.htm 
See: http://imi.europa.eu/documents_en.html 
A  number  of  Community  projects  aim  at  providing  insights  to  improve  pharmacovigilance  by 
analysing,  using  information  technology,  the  information  available  in  Electronic  Health  Records, 
including projects co-funded under the 7th Framework Research Programme.  

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The  tasks  and  responsibilities  of  involved  parties  in  the  legislation  (Member  State, 
Agency, marketing authorisation holders) are clarified and codified and the concept and scope 
of  Good  Vigilance  Practices  for  all  involved  in  pharmacovigilance  is  established.  The  key 
tasks  of  the  Agency  in  the  area  of  pharmacovigilance  laid  down  in  Regulation  (EC)  No 
726/2004  are  overall  maintained,  but  the  Agency's  coordinating  role  at  the  centre  of  the 
Community pharmacovigilance system is reinforced. The Member States should remain core 
to  the  operation  of  pharmacovigilance  in  the  Community,  with  increased  cooperation  and 
work-sharing mechanisms. The pharmacovigilance responsibilities of marketing authorisation 
holders  are  also  clarified,  in  particular  as  regards  the  scope  of  the  obligation  of  marketing 
authorisation  holders  to  continuously  monitor  the  safety  of  products  to  ensure  that  all 
information available is brought to the attention of the authorities. 

A  new  scientific  committee  responsible  for  pharmacovigilance  is  created  within  the 
Agency,  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee.  The  Committee  is 
intended  to  play  a  key  role  in  the  pharmacovigilance  assessments  in  the  Community,  by 
providing support both to the Committee for Medicinal Products for Human Use within the 
Agency (responsible for opinions on the quality, safety and efficacy of medicinal products for 
human  use  in  the  framework  of  Community  procedures),  and  the  coordination  group  of 
Member  States  established  by  Directive  2001/83/EC  (involved  in  the  national  authorisation 
procedures). 

The mandate of the coordination group composed of Member States representatives set up 
by Article 27 of Directive 2001/83/EC is enhanced for the sake of closer cooperation between 
the Member States in the area of pharmacovigilance and in order to increase work-sharing. 

The  Community  procedure  for  the  assessment  of  serious  safety  issues  for  nationally 
authorised  products  is  stream-lined  through  clear  and  binding  initiation  criteria  for  the 
Member  States,  rules  to  ensure  that  all  products  concerned  are  considered,  an  assessment 
procedure by the Pharmacovigilance Risk Assessment Advisory Committee, and rules for the 
subsequent follow-up as regards the terms of the marketing authorisations with a view to the 
adoption of harmonised measures across the Community. 

Transparency and communication 

Strengthened  medicines  safety  transparency  and  communication  should  increase  the 
understanding and trust of patients and health professionals in the safety of medicines and the 
regulatory  system.  Clear,  EU  coordinated  messages  about  specific  safety  risk  issues  will 
improve the safe use of medicines.  

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Strengthening  of  the  Eudravigilance  database  which  should  become  the  single  point  of 
receipt of pharmacovigilance information for medicinal products for human use authorised in 
the Community, therefore allowing all competent authorities to receive, access and share the 
information  at  the  same  time,  with  appropriate  access  to  the  Eudravigilance  database  data 
ensured. 

Community  coordination  of  communication  about  safety  issues  and  establishment  of  a 
European medicines safety web-portal: The principles of communications about major new 
or  changing  safety  issues  should  be  laid  down  in  the  legislation.  For  issues  affecting  active 
substances  authorised  in  more  than  one  Member  State,  the  Agency  should  coordinate  the 
communications of the Member States. Furthermore, the Agency should set-up and maintain 
an European medicines safety web-portal as the main platform for announcements related to 
medicines  safety  dealt  with  at  the  EU  level,  and  would  include  links  to  web-portals  of  the 
Member State competent authorities. 

Introduction  of  a  new  ‘key  information'  section  in  the  summary  of  the  product 
characteristics  and  the  package  leaflet  which  accompany  every  medicinal  product  placed 
on the Community market.  

Pharmacovigilance obligations by the marketing authorisation holder 

Currently legislation requires a ‘detailed description of the pharmacovigilance system’ to be 
submitted  in  marketing  authorisation  applications  and  kept  up  to  date  for  each  individual 
marketing authorisation. The proposals simplify the existing requirement. 

"Pharmacovigilance  system  master  file":  In  the  marketing  authorisation  application  only 
key elements of the pharmacovigilance system should be submitted, but this is balanced with 
a requirement for companies to maintain a detailed file on site. 

Risk management planning and non-interventional safety studies 

Rationalising of risk management planning should ensure that safety evaluation of products is 
prospective (i.e. based on risk management planning) and that high-quality, non-promotional 
safety studies are done when justified by safety concerns. 

In  the  provisions  currently  in  force,  applicants  for  a  marketing  authorisation  may  provide  a 
risk  management  system  for  specific  medicinal  products  if  considered  appropriate,  and 
there is no explicit legal basis for competent authorities to request it. The proposals require a 
risk management system for each medicinal product to be newly authorised in the Community 
(or for existing products on the basis of safety concerns), which should be proportionate to the 
identified  risks,  potential  risks,  and  the  need  for  additional  information  on  the  medicinal 
product.  

Harmonised  guiding  principles  and  a  procedure  for  the  supervision  of  non-
interventional  post-authorisation  safety  studies  (i.e.  safety  studies  of  authorised  products 
that  are  not  clinical  trials),  in  particular  to  ensure  that  they  are  non  promotional,  and  the 
follow-up of any safety data generated in such studies. 

Adverse drug reaction case reports 

Current  reporting  rules  apply  equally  to  all  medicinal  products,  irrespective  of  their  known 
risks,  are  submitted  to  several  authorities  where  a  product  is  authorised  in  more  than  one 

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Member  State,  and  lead  to  duplicative  assessments  as  there  is  no  provision  to  group 
assessments by products or substances. Besides, the notion of adverse reaction is linked to the 
side  effects  under  normal  conditions  of  use  of  medicinal  products,  and  other  side  effects 
(resulting e.g. from medication errors or overdose) are not necessarily reported. The proposals 
are intended to make reporting proportionate to risks, to empower patients to report their side 
effects, and to ensure that overdoses and medication errors are reported. 

Simplification  of  adverse  reaction  reporting.  It  is  proposed  to  considerably  simplify 
reporting  rules  by  providing  that  all  adverse  reaction  data  are  reported  by  marketing 
authorisation holders and Member States directly to the Eudravigilance database. As a result 
of this new reporting scheme, it will not be longer necessary to provide for different reporting 
rules  for  medicinal  products  authorised  in  accordance  with  the  centralised  procedure  and 
medicinal products authorised in the Member States.  

Monitoring of scientific literature by the Agency: The Agency is to take on a new task for 
the monitoring of selected scientific literature and for entering case reports of adverse effects 
onto the Eudravigilance database. 

Medication  errors  that  result  in  an  adverse  reaction  should  be  reported  to  the  competent 
authorities for medicines: The definition of adverse drug reaction should be clarified to make 
clear  that  companies  report  medication  errors  that  result  in  an  adverse  reaction  to  the 
competent authorities for medicines and ensure that all the relevant Member State authorities 
share  data  (including  between  the  authorities  for  medicines  and  any  authorities  for  patient 
safety).  

Make clear the legal basis for patients to report suspected adverse drug reactions. 

Periodic safety update reports and other safety related assessments 

Currently,  periodic  safety  update  reports  are  line  listings  of  adverse  reactions  and,  as  for 
adverse reactions reports, are submitted for all medicinal products. Since there is no provision 
to  group  submissions  and  assessments  by  products  or  substances,  this  leads  to  duplicative 
submissions  and  assessments.  The  update  of  product  information  as  a  result  of  these 
assessments is not governed in detail by the actual legislation. The proposals simplify periodic 
safety update report submission by industry and make it proportional to the knowledge about 
the safety/risk of the product, would introduce work-sharing mechanisms for the assessments, 
with  a  prominent  role  in  all  cases  by  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee,  and  faster  updating  of  product  information  through  the  establishment  of  clear 
procedures. 

As  a  result  of  the  submission  of  all  adverse  reaction  data  directly  to  the  Eudravigilance 
database, the scope of periodic safety update reports is amended to become an analysis of 
the  risk-benefit  balance  of  a  medicinal  product  rather  than  a  detailed  presentation  of 
individual  case  reports.  Besides,  the  requirements  for  periodic  safety  update  reports  are 
made  proportional  to  the  risks  posed  by  medicinal  products,  and  routine  reporting  is  no 
longer  necessary  for  products  considered  low  risk  or  where  reporting  would  be  duplicative 
(with the possibility for ad-hoc requests for such products).  

Explicit  provision  is  made  for  the  regulatory  follow-up  of  assessments  of  periodic  safety 
update reports, to ensure a clear link between pharmacovigilance evaluations and the review 
and updating of marketing authorisations authorised in the Community. 

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involvement  of 

The  proposals  create  the  framework  for  the  shared  use  of  resources  between  competent 
authorities  for  the  assessment  and  follow-up  of  periodic  safety  update  reports,  with  a 
strong 
the  Agency's  Pharmacovigilance  Risk  Assessment  Advisory 
Committee.  A  single  assessment  of  periodic  safety  update  reports  for  medicinal  products 
authorised  in  more  than  one  Member  State,  including  for  all  products  containing  the  same 
active  substance,  is  foreseen.  To  further  increase  the  efficiency  of  the  system,  a  single 
assessment would also be conducted in the case of pharmacovigilance issues which concern 
products authorised by the Member States and products authorised by the Commission.  

3.2. 

Legal basis 

The  proposal  is  based  on  Article  95  of  the  EC  Treaty.  Article  95,  which  prescribes  the 
codecision procedure described in Article 251, is the legal basis for achieving the aims set out 
in Article 14 of the Treaty, which includes the free movement of goods (Article 14(2)), in this 
case medicinal products for human use.  

While  taking  account  of  the  fact  that  any  regulation  on  medicinal  products  must  be 
fundamentally  aimed  at  safeguarding  public  health,  since  the  Amsterdam  Treaty  came  into 
force,  Article  95  is  the  legal  basis  of  the  Community  legislation  for  medicinal  products  for 
human  use,  including  Directive  2001/83/EC  and  Regulation  (EC)  No  726/20046,  since  the 
differences  between  the  national  legislative,  regulatory  and  administrative  provisions  on 
medicinal  products  tend  to  hinder  intra-Community  trade  and  therefore  directly  affect  the 
operation  of  the  internal  market.  Action  to  promote  the  development  and  authorisation  of 
medicinal  products  is  hence  justified  at  a  European  level,  with  a  view  to  preventing  or 
eliminating these obstacles.  

3.3. 

Subsidiarity principle 

Community rules in the area of pharmacovigilance allow the best protection of public health 
according  to  the  same  standards  across  the  Community.  Divergent  action  by  the  Member 
States  would  prevent  the  full  sharing  of  safety  data  and  would  increase  the  administrative 
burden on competent authorities and industry. A lack of coordination would deny the Member 
States access to the best scientific and medicinal expertise for the evaluation of the safety of 
medicines and for risk minimisation.  

The  impact  analysis  has  shown  that  the  ongoing  efforts  to  improve  the  Community 
pharmacovigilance  system  through  better  implementation  of  the  current  legal  framework, 
while  bringing  genuine  improvements  to  the  system,  would  be  insufficient  to  make  the  step 
change improvement needed to reduce the major public health burden of adverse reactions to 
medicinal products.  

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Regulation (EC) No 726/2004 is also based on Article 152(4)(b), as regards the regulation of veterinary 
medicinal products, outside the scope of the current proposals. 

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3.4. 

Proportionality principle 

The  proposal  has  been  carefully  designed  in  close  dialogue  with  stakeholders  particularly 
those stakeholders upon which direct obligations are placed by the legal provisions, in order to 
better protect public health without imposing an unnecessary regulatory burden. The proposal 
builds  on  existing  structures  (including  the  European  Medicines  Agency  and  Member  State 
competent  authorities),  procedures  (including the  existing  reporting  and referral  procedures), 
resources  (including  the  existing  Community  pharmacovigilance  database)  and  practices 
(including  work-sharing  by  the  Member  States).  The  proposal  strives  to  maximise  the 
efficiency of the processes  and maximise  the quality of the data collected and the quality of 
decisions taken thereby maximally benefiting public health. By increasing the efficiency of the 
Community pharmacovigilance system, the proposal will free up resource currently expended 
on meeting duplicative and complex administrative requirements and these resources can then 
be  channelled  into  activities  that  directly  promote  and  protect  public  health  including  better 
communications about the benefits and risks of medicines  

The  proposal  does  not  go  beyond  what  is  necessary  to  achieve  the  objective  pursued,  i.e.  to 
strengthen and rationalise Community pharmacovigilance system. The Impact Assessment has 
shown  cost  savings  for  the  industry  with  an  increase  in  costs  for  the  regulators  (national 
competent authorities and the Agency) that will be covered by industry fees. This increase in 
costs  is  modest  compared  to  the  projected  savings  to  society  including  from  reductions  in 
hospitalisations  and  prolonged  hospital  stays  caused  by  adverse  reactions  to  medicinal 
products. 

3.5. 

Choice of instruments 

The proposal aims at modifying the existing provisions on pharmacovigilance for medicinal 
products  for  human  use  contained  in  Regulation  (EC)  No  726/2004  and  in  Directive 
2001/83/EC, and an amending regulation and an amending directive are therefore considered 
the most appropriate legal instruments. 

4. 

BUDGETARY IMPLICATION 

The proposal has no implication for the Community budget. 

5. 

ADDITIONAL INFORMATION 

5.1. 

Simplification 

This initiative is referenced in the Commission Agenda Planning as 2008/ENTR/003. It is part 
of the Commission Legislative and Work Programme for 2008, under Annex 1 (Strategic and 
Priority initiatives)7. 

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http://ec.europa.eu/atwork/programmes/docs/clwp2008_en.pdf (see page 20). 

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The  proposals  contain  key  elements  for  the  simplification  of  the  Community  system  of 
pharmacovigilance,  including:  closer  collaboration  between  the  authorities  which  will 
maximise  the  expertise  available;  work-sharing  and  a  strengthened  role  for  the  coordination 
group  of  the  Member  States  to  increase  the  efficient  use  of  scarce  resources  and  reduce 
duplication of effort; simplified adverse reaction and periodic safety update reporting; and the 
Pharmacovigilance System Master File of marketing authorisation holder. 

5.2. 

European Economic Area 

The proposed act is of relevance to the EEA. 

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2008/0257 (COD) 

Proposal for a 

REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 

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 

(Text with EEA relevance) 

THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION, 

Having regard to the Treaty establishing the European Community, and in particular Article 
95 thereof, 

Having regard to the proposal from the Commission8, 

Having regard to the opinion of the European Economic and Social Committee9, 

Acting in accordance with the procedure laid down in Article 251 of the Treaty10, 

Whereas: 

(1) 

(2) 

(3) 

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  Agency11  creates  a  Community-wide  marketing  authorisation  procedure 
(the  so-called  ‘centralised  procedure’)  for  certain  categories  of  medicinal  products, 
lays  down  rules  for  the  pharmacovigilance  of  those  products  and  establishes  the 
European Medicines Agency (hereinafter referred to as the ‘Agency’). 

Pharmacovigilance  rules  are  necessary  for  the  protection  of  public  health  in  order  to 
detect, assess and prevent adverse effects of medicinal products placed on the market 
of the Community, as the full safety profile of medicinal products can only be known 
once they have entered the market.  

In  the  light  of  the  experience  acquired  and  following  an  assessment  by  the 
Commission of the Community system of pharmacovigilance, it has become clear that 
measures  are  necessary  to  improve  the  operation  of  the  Community  rules  on  the 
pharmacovigilance of medicinal products for human use.  

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OJ C , , p. . 
OJ C , , p. . 
OJ C , , p. . 
OJ L 136, 30.4.2004, p. 1. 

EN 

11 

   EN 

                                                 
(4) 

(5) 

(6) 

(7) 

(8) 

(9) 

The  main  tasks  of  the  Agency  in  the  area  of  pharmacovigilance  laid  down  in 
Regulation  (EC)  No  726/2004  should  be  maintained  and  further  developed,  in 
particular as regards the management of the Community pharmacovigilance database 
and data-processing network (hereinafter referred to as 'the Eudravigilance database') 
and the coordination of safety announcements by the Member States.  

In  order  to  allow  all  competent  authorities  to  receive  and  access,  at  the  same  time, 
pharmacovigilance information for medicinal products for human use authorised in the 
Community,  and  share  it,  the  Eudravigilance  database  should  be  maintained  and 
strengthened as the single point of receipt of such information. Member States should 
therefore  not  impose  on  marketing  authorisation  holders  any  additional  reporting 
requirements.  The  database  should  be  fully  accessible  to  the  Member  States,  the 
Agency  and  the  Commission,  and  accessible  to  an  appropriate  extent  to  marketing 
authorisation holders and the public. 

In  order  to  increase  transparency  as  regards  pharmacovigilance  issues,  a  European 
medicines safety web-portal should be created and maintained by the Agency.  

In  order  to  ensure  the  availability  of  the  necessary  expertise  and  resources  for 
pharmacovigilance assessments at Community level, it is appropriate to create a new 
scientific  committee  within  the  Agency,  the  Pharmacovigilance  Risk  Assessment 
Advisory  Committee.  That  committee  should  be  composed  of  independent  scientific 
experts  with  competence  in  the  safety  of  medicines  including  the  detection, 
assessment,  minimisation  and  communication  of  risk,  and  the  design  of  post-
authorisation safety studies and pharmacovigilance audit.  

The rules on scientific committees of the Agency, as laid down in Regulation (EC) No 
726/2004,  should  apply  to  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee. 

In  order  to  ensure  harmonised  responses  across  the  Community  to  safety  concerns 
regarding medicinal products for human use, the Pharmacovigilance Risk Assessment 
Advisory Committee should support the Committee for Medicinal Products for Human 
Use and the coordination group established by 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 use12 on any question relating to the pharmacovigilance 
of  medicinal  products  for  human  use.  However,  for  the  sake  of  consistency  and 
continuity of the assessments, the final responsibility for the risk-benefit assessment of 
medicinal  products  for  human  use  authorised  in  accordance  with  this  Regulation 
should  remain  with  the  Committee  for  Medicinal  Products  for  Human  Use  of  the 
Agency  and  with 
the  granting  of  marketing 
authorisations. 

the  authorities  competent  for 

(10) 

In  accordance  with  Directive  2001/83/EC  the  Agency  provides  the  secretariat  to  the 
coordination group . In view of the enlarged mandate of the coordination group in the 
area of pharmacovigilance, the technical and administrative support by the secretariat 
of  the  Agency  to  the  coordination  group  should  be  reinforced.  Provision  should  be 
made  for  the  Agency  to  ensure  appropriate  coordination  between  the  coordination 
group and the Agency's scientific committees. 

12 

OJ L 311, 28.11.2001, p. 67. 

EN 

12 

   EN 

                                                 
(11) 

In order to protect public health, there should be adequate funding of activities related 
to  pharmacovigilance  by  the  Agency.  Provision  should  be  made  to  allow  adequate 
funding  for  pharmacovigilance  activities  through  the  collection  of  fees  charged  to 
marketing authorisation holders. The management of those collected funds should be 
under  a  permanent  control  of  the  Management  Board  in  order  to  guarantee  the 
independence of the Agency. 

(12)  To ensure the highest levels of expertise and the functioning of the Pharmacovigilance 
Risk  Assessment  Advisory  Committee,  rapporteurs  providing  assessment  for 
Community  pharmacovigilance  procedures,  periodic  safety  update  reports,  post-
authorisation  safety  study  protocols  and  risk  management  systems  should  receive 
payment through the Agency. 

(13)  Provision should be made for the Agency to collect fees as regards the activities of the 
coordination group within the Community system of pharmacovigilance, as provided 
for in Directive 2001/83/EC, and for rapporteurs within the coordination group to be 
then paid by the Agency.  

(14) 

In order to ensure the collection of any necessary additional data about the safety of 
medicinal products authorised in accordance with Regulation (EC) No 726/2004, the 
Commission  should  be  empowered  to  require  the  marketing  authorisation  holder  to 
conduct post-authorisation safety studies at the time of the granting of the marketing 
authorisation  or  later,  and  that  requirement  should  be  included  as  a  condition  of  the 
marketing authorisation.  

(15)  Where a medicinal product is authorized subject to the requirement to conduct a post-
authorisation  safety  study  or  subject  to  conditions  or  restrictions  with  regard  to  the 
safe  and  effective  use  of  the  medicinal  product,  the  medicinal  product  should  be 
intensively monitored on the market. Patients and  healthcare  professionals  should be 
encouraged  to  report  all  suspect  adverse  reactions  to  such  medicinal  products,  and  a 
publicly  available  list  of  such  medicinal  products  should  be  kept  up  to  date  by  the 
Agency. 

(16)  Experience has shown that there is a need to clarify the responsibilities of marketing 
authorisation holders for the pharmacovigilance of authorised products. The marketing 
authorisation  holder  should  be  responsible  for  continuously  monitoring  the  safety  of 
his products, for informing the authorities of any changes that might have an impact 
on the marketing authorisation, and for ensuring that the product information is kept 
up to date. As medicinal products could be used outside the terms of their marketing 
authorisations,  these  responsibilities  should  include  providing  all  information 
available, including the results of clinical trials or other studies, as well as reporting of 
the use of the medicinal product which is not in accordance with the summary of the 
product  characteristics.  Likewise  it  is  appropriate  to  ensure  that  all  relevant 
information  collected  on  the  safety  of  the  medicinal  product  is  taken  into  account 
when marketing authorisations are being renewed. 

(17)  Scientific  and  medical  literature  provides  an  important  source  of  information  on 
suspected  adverse  reaction  case  reports.  Currently,  for  active  substances  included  in 
more than one medicinal product, literature cases are reported in a duplicative way. In 
order to enhance the efficiency of reporting, provision should be made for the Agency 

EN 

13 

   EN 

to  monitor  a  defined  list  of  literature  for  a  defined  list  of  active  substances  used  in 
medicinal products for which there are several marketing authorisations.  

(18)  As  a  result  of  the  submission  of  all  adverse  reaction  data  for  medicinal  products 
authorised  by  the  Member  States  directly  to  the  Eudravigilance  database,  it  is  not 
necessary to provide for different reporting rules for medicinal products for human use 
authorised  in  accordance  with  Regulation  (EC)  No  726/2004.  The  rules  on  adverse 
reaction recording and reporting laid down in Directive 2001/83/EC should therefore 
apply to medicinal products for human use authorised in accordance with Regulation 
(EC) No 726/2004. 

(19)  There is a need to increase the shared use of resources between competent authorities 
for  the  assessment  of  periodic  safety  update  reports.  The  procedures  of  Directive 
2001/83/EC should therefore apply for the single assessment of periodic safety update 
reports  for  different  medicinal  products  containing  the  same  active  substance  or 
combination thereof, including joint assessments of products authorised nationally and 
through the centralised procedure.  

(20) 

It  is  appropriate  to  strengthen  the  supervisory  role  for  medicinal  products  authorised 
through  the  centralised  procedure  by  providing  that  the  supervisory  authority  for 
pharmacovigilance  should  be  the  competent  authority  of  the  Member  State  in  which 
the  pharmacovigilance  system  master  file  of  the  marketing  authorisation  holder  is 
sited. 

(21)  The provisions on the surveillance of medicinal products for human use in Regulation 
(EC)  No  726/2004  constitute  specific  provisions  in  the  meaning  of  Article  15(2)  of 
Regulation (EC) No 765/2008 of the European Parliament and of the Council of 9 July 
2008 setting out the requirements for accreditation and market surveillance relating to 
the marketing of products, and repealing Regulation (EEC) No 339/9313. 

(22)  Regulation (EC) No 726/2004 should therefore be amended accordingly, 

HAVE ADOPTED THIS REGULATION: 

Article 1 
Amendments to Regulation (EC) No 726/2004 

Regulation (EC) No 726/2004 is amended as follows: 

(1) 

In Article 5(2) the following sentence is added: 

the  fulfilment  of 

“For 
Pharmacovigilance Risk Assessment Advisory Committee referred to in Article 56(1)(aa).” 

it  shall  be  assisted  by 

its  pharmacovigilance 

tasks, 

the 

13 

OJ L 218, 13.8.2008, p. 30. 

EN 

14 

   EN 

                                                 
(2) 

Article 9(4) is amended as follows: 

(a) 

the following point (aa) is inserted: 

“(aa)  a recommendation on the frequency of submission of periodic safety update reports;” 

(b) 

the following points (ca) and (cb) are inserted: 

“(ca)  details of any measures for the safe use of the medicinal product contained in the risk 
management system to be imposed as conditions of the marketing authorisation; 

(cb) 
if appropriate, the written requirement to conduct post-authorisation safety studies or 
to comply with requirements on adverse reaction recording or reporting which are stricter than 
those referred to in Chapter 3;” 

(c) 

point (f) is replaced by the following: 

“(f) 
the  assessment  report  as  regards  the  results  of  the  pharmaceutical  and  pre-clinical 
tests, the clinical trials and the risk management system and the pharmacovigilance system of 
the medicinal product concerned.” 

(3) 

Article10 is amended as follows:  

(a) 

Paragraph 1 is replaced by the following`: 

"1.  Within  15  days  after  receipt  of  the  opinion  referred  to  in  Article  5(2),  the  Commission 
shall prepare a draft of the decision to be taken in respect of the application.  

Where a draft decision envisages the granting of a marketing authorisation, it shall include or 
make reference to the documents mentioned in points (a) to (d) of Article 9(4). 

Where  a  draft  decision  envisages  the  granting  of  a  marketing  authorisation  subject  to  the 
conditions referred to in points (c), (ca) or (cb) of Article 9(4), it shall lay down deadlines for 
the fulfilment of the conditions where necessary. 

Where  the  draft  decision  is  not  in  accordance  with  the  opinion  of  the  Agency,  the 
Commission shall annex a detailed explanation of the reasons for the differences. 

The draft decision shall be forwarded to Member States and the applicant." 

(b) 

Paragraph 6 is replaced by the following: 

The Agency shall disseminate the documents referred to in points (a) to (d) of Article 
“6. 
9(4), together with any deadlines laid down pursuant to the third subparagraph of paragraph 1 
of this Article.” 

EN 

15 

   EN 

(4) 

The following Article 10a is inserted: 

“Article 10a 

After the granting of a marketing authorisation, the Agency may require a marketing 
1. 
authorisation  holder  to  conduct  a  post-authorisation  safety  study  if  there  are  concerns  about 
the  risks  of  an  authorised  medicinal  product.  The  requirement  shall  be  made  in  writing, 
provide a detailed justification and include the objectives and timeframe for submission and 
conduct of the study. 

2. 
The  Agency  shall  provide  the  marketing  authorisation  holder  with  an  opportunity  to 
present  explanations  on  the  requirement  within  a  time  limit  which  it  shall  specify,  if  the 
marketing  authorisation  holder  requests  this  within  30  days  of  receipt  of  the  written 
requirement.  

On  the  basis  of  explanations  submitted  by  the  marketing  authorisation  holder,  the 
3. 
Commission shall withdraw or confirm the requirement. Where the Commission confirms the 
requirement,  the  marketing  authorisation  shall  be  varied  to  include  the  requirement  as  a 
condition  of  the  marketing  authorisation  and  the  risk  management  system  shall  be  updated 
accordingly.” 

(5) 

Article 14 is amended as follows: 

(a) 

In paragraph 2, the second subparagraph is replaced by the following: 

“To this end, the marketing authorisation holder shall provide the Agency with a consolidated 
version of the file in respect of quality, safety and efficacy, including the evaluation of data 
contained  in  adverse  reactions  reports  and  periodic  safety  update  reports  submitted  in 
accordance  with  Chapter  3,  and  all  variations  introduced  since  the  marketing  authorisation 
was  granted,  at  least  nine  months  before  the  marketing  authorisation  ceases  to  be  valid  in 
accordance with paragraph 1.” 

(b) 

Paragraph 3 is replaced by the following: 

Once  renewed,  the  marketing  authorisation  shall  be  valid  for  an  unlimited  period, 
“3. 
unless  the  Commission  decides,  on  justified  grounds  relating  to  pharmacovigilance  or 
insufficient  exposure  to  the  product,  to  proceed  with  one  additional  five-year  renewal  in 
accordance with paragraph 2.” 

(c) 

Paragraph 8 is replaced by the following: 

In  exceptional  circumstances  and  following  consultation  with  the  applicant,  the 
“8. 
authorisation  may  be  granted  subject  to  a  requirement  for  the  applicant  to  meet  certain 
conditions,  in  particular  concerning  the  safety  of  the  medicinal  product,  notification  to  the 
competent  authorities  of  any  incident  relating  to  its  use,  and  action  to  be  taken.  This 
authorisation may be granted only when the applicant can show that he is unable to provide 
comprehensive  data  on  the  efficacy  and  safety  of  the  medicinal  product  under  normal 
conditions of use, for objective, verifiable reasons and must be based on one of the grounds 
set out in Annex I to Directive 2001/83/EC. Continuation of the authorisation shall be linked 
to the annual reassessment of these conditions.” 

EN 

16 

   EN 

(6) 

The following Article 14a is inserted: 

“Article 14a 

1.  The  marketing  authorisation  holder  shall  incorporate  any  conditions  or  requirements 
referred to in points (c), (ca) and (cb) of Article 9(4) or in Articles 10a, 14(7) and (8) in his 
risk management system. 

2.  The  Agency  shall  include  the  medicinal  products  concerned  by  paragraph  1  in  the  list 
referred to in Article 23. The Agency shall remove a medicinal product from the list when the 
Commission,  on  the  basis  of  an  opinion  of  the  Agency,  concludes  that  the  conditions  have 
been  fulfilled  and  that,  following  the  assessment  of  any  data  resulting  from  the 
implementation of the conditions or requirements, the risk-benefit balance remains positive. 

(7) 

Article 16 is replaced by the following:  

“Article 16 

1. After an authorisation has been granted in accordance with this Regulation, the marketing 
authorisation holder shall, in respect of the methods of manufacture and control provided for 
in  Article  8(3)(d)  and  (h)  of  Directive  2001/83/EC,  take  account  of  scientific  and  technical 
progress and introduce any changes that may be required to enable the medicinal product to 
be  manufactured  and  checked  by  means  of  generally  accepted  scientific  methods.  He  shall 
apply for approval of such variations in accordance with this Regulation.  

2.  The  marketing  authorisation  holder  shall  forthwith  supply  to  the  Agency,  to  the 
Commission  and  to  the  member  States  any  new  information  which  might  entail  the 
amendment of the particulars or documents referred to in Articles 8(3), 10, 10a, 10b and 11, 
or 32(5) of Directive 2001/83/EC, in Annex I thereto, or in Article 9(4) of this Regulation. 

In particular, he shall forthwith inform the Agency and the Commission of any prohibition or 
restriction  imposed  by  the  competent  authorities  of  any  country  in  which  the  medicinal 
product for human use is marketed and of any other new information which might influence 
the  evaluation  of  the  benefits  and  risks  of  the  medicinal  product  for  human  use  concerned. 
The  information  shall  include  both  positive  and  negative  results  of  clinical  trials  or  other 
studies  in  all  indications  and  populations,  whether  or  not  included  in  the  marketing 
authorisation,  as  well  as  data  on  the  use  of  the  medicinal  product  where  such  use  is  not  in 
accordance with the summary of the product characteristics. 

3. The marketing authorisation holder shall ensure that the product information is kept up to 
date  with  the  current  scientific  knowledge  including  the  assessment  conclusions  and 
recommendations  made  public  by  means  of  the  European  medicines  safety  web-portal 
established in accordance with Article 26. 

4. In order that the risk-benefit balance may be continuously assessed, the Agency may at any 
time ask the holder of the marketing authorisation to forward data demonstrating that the risk-
benefit balance remains favourable. 

EN 

17 

   EN 

The Agency may at any time ask the marketing authorisation holder to submit a copy of the 
pharmacovigilance system master file. The holder shall submit the copy seven days after the 
receipt of the request at the latest.” 

(8) 

Article 18 is amended as follows: 

(a) 

Paragraph 1 is replaced by the following: 

“1. 
In the case of medicinal products for human use manufactured within the Community, 
the  supervisory  authorities  for  manufacturing  shall  be  the  competent  authorities  of  the 
Member State or Member States which granted the manufacturing authorisation provided for 
in Article 40(1) of Directive 2001/83/EC in respect of the medicinal product concerned.” 

(b) 

In paragraph 2, the first subparagraph is replaced by the following: 

“In the case of medicinal products imported from third countries, the supervisory authorities 
for  imports  shall  be  the  competent  authorities  of  the  Member  State  or  Member  States  that 
granted  the  authorisation  provided  for  in  Article 40(3)  of  Directive 2001/83/EC  to  the 
importer,  unless  appropriate  agreements  have  been  made  between  the  Community  and  the 
exporting  country  to  ensure  that  those  controls  are  carried  out  in  the  exporting  country  and 
that the manufacturer applies standards of good manufacturing practice at least equivalent to 
those laid down by the Community.” 

(c) 

The following paragraph 3 is added: 

“3. The supervisory authority for pharmacovigilance shall be the competent authority of the 
Member State in which the pharmacovigilance system master file is sited.” 

(9) 

Article 19 is amended as follows: 

(a)  Paragraph 1 is replaced by the following: 

“1. Under the coordination of the Agency, the supervisory authorities for manufacturing and 
imports shall be responsible for verifying on behalf of the Community that the holder of the 
marketing  authorisation  for  the  medicinal  product  for  human  use  or  the  manufacturer  or 
the  requirements  concerning 
the  Community  satisfies 
importer  established  within 
manufacturing and imports laid down in Titles IV and XI of Directive 2001/83/EC.  

Under the coordination of the Agency, the supervisory authorities for pharmacovigilance shall 
be  responsible  for  verifying  on  behalf  of  the  Community  that  the  holder  of  the  marketing 
authorisation  for  the  medicinal  product  for  human  use  satisfies  the  pharmacovigilance 
requirements laid down in Titles IX and XI of Directive 2001/83/EC.” 

EN 

18 

   EN 

(b) 

In paragraph 3, the second subparagraph is replaced by the following: 

“The inspection shall be undertaken by inspectors from the Member States who possess the 
appropriate qualifications; they may be accompanied by a rapporteur or expert appointed by 
the said Committee. The report of the inspectors shall be made available electronically to the 
Commission, the Member States and the Agency." 

(10)  Article 20 is amended as follows: 

(a)  Paragraph 3 is replaced by the following: 

“3.  Following  an  opinion  by  the  Agency,  the  Commission  may  adopt  the  necessary 
provisional measures, which shall be applied immediately. 

A  final  decision  in  respect  of  the  medicinal  product  concerned  shall  be  adopted  within  six 
months, in accordance with the procedure referred to in Article 87(2). 

The  Commission  may  also  adopt  a  decision  addressed  to  the  Member  States  pursuant 
toArticle 127a of Directive 2001/83/EC.” 

(b)  The following paragraph 8 is added: 

“8.  By  way  of  derogation  from  paragraphs  1  to  7  of  this  Article,  where  a  procedure  under 
Articles  31,  36  or  107i  to  107l  of  Directive  2001/83/EC  concerns  a  range  of  medicinal 
products  or  a  therapeutic  class,  medicinal  products  authorised  in  accordance  with  this 
Regulation and which belong to that range or class shall only be included in the procedure of 
Article 31, 36 or of Articles 107i to 107l of the Directive. 

(11)  Chapter 3 of Title II is replaced by the following: 

“Chapter 3 
Pharmacovigilance 

Article 21 

1.  The  obligations  of  marketing  authorisation  holders  laid  down  in  Article  104  of  Directive 
2001/83/EC shall apply to marketing authorisation holders for medicinal products for human 
use authorised in accordance with this Regulation. 

However, holders  of  marketing  authorisations granted before [insert concrete date - date set 
out  in  the  second  paragraph  of  Article  3  of  Regulation  (EC)  No  …/…]  shall  operate  a  risk 
management  system  as  referred  to  in  point  (c)  of  Article  104(3)  of  that  Directive  only  if 
paragraphs 2, 3 and 4 of this Article are complied with. 

2.  The  Agency  may  require  a  marketing  authorisation  holder  to  operate  a  risk  management 
system  as  referred  to  in  point  (c)  of  Article  104(3)  of  Directive  2001/83/EC,  if  there  are 
concerns about the risks affecting the risk-benefit balance of an authorised medicinal product. 
To  this  effect,  the  Agency  shall  also  require  the  marketing  authorisation  holder  to  submit  a 
detailed  description  of  the  risk-management  system  which  he  intends  to  introduce  for  the 
medicinal product concerned. 

EN 

19 

   EN 

The  requirement  shall  be  made  in  writing,  provide  a  detailed  justification,  and  include  the 
timeframe for submission of the detailed description of the risk-management system. 

3. The Agency shall provide the marketing authorisation holder with an opportunity to present 
explanations  on  the  requirement  within  a  time  limit  which  it  shall  specify,  if  the  marketing 
authorisation holder requests this within 30 days of receipt of the written requirement.  

4.  On  the  basis  of  explanations  submitted  by  the  marketing  authorisation  holder,  the 
Commission shall withdraw or confirm the requirement. Where the Commission confirms the 
requirement, the marketing authorisation shall be varied as appropriate to include measures to 
be  taken  in  the  risk  management  system  as  conditions  of  the  marketing  authorisation  as 
referred to in point (ca) of Article 9(4). 

Article 22 

The obligations of marketing authorisation holders laid down in Article 106a(1) of Directive 
2001/83/EC,  and  of  the  Member  States,  the  Agency  and  the  Commission  laid  down  in 
paragraphs  (2),  (3)  and  (4)  of  that  Article  shall  apply  to  safety  announcements  concerning 
medicinal products for human use authorised in accordance with this Regulation.  

Article 23 

The Agency shall establish and make public a list of medicinal products for human use under 
intensive monitoring. 

That  list  shall  include  the  names  and  active  substances  of  medicinal  products  authorised 
pursuant to this Regulation subject to conditions or requirements referred to in points (c), (ca) 
and  (cb)  of  Article  9(4),  or  in  Articles  10a,  14(7)  and  14(8),  and  of  medicinal  products 
authorised pursuant to Directive 2001/83/EC which are referred to in Articles 21a, 22 and 22a 
thereof, and an electronic link to the product information. 

The Agency shall keep the list up to date.  

Article 24 

1. The Agency, in collaboration with the Member States and the Commission, shall set up and 
maintain a database and data processing network (hereinafter ‘the Eudravigilance database’) 
to  collate  pharmacovigilance  information  regarding  medicinal  products  authorised  in  the 
Community and to allow competent authorities to access the information at the same time and 
to share it. 

The Eudravigilance database shall contain information on adverse reactions in human beings 
arising from use of the product within the terms of the marketing authorisation as well as from 
any  other  use,  including  overdose,  misuse,  abuse,  medication  errors,  and  those  occurring  in 
the course of studies with the medicinal product or after occupational exposure. 

2.  The  Eudravigilance  database  shall  be  fully  accessible  to  the  competent  authorities  of  the 
Member  States  and  to  the  Agency  and  the  Commission.  It  shall  also  be  accessible  to 

EN 

20 

   EN 

marketing  authorisation  holders  to  the  extent  necessary  for  them  to  comply  with  their 
pharmacovigilance obligations. 

The Agency shall ensure that health-care professionals and the public have appropriate levels 
of access to the Eudravigilance database, with personal data protection being guaranteed. 

The  data  held  on  the  Eudravigilance  database  shall  be  made  publicly  accessible  in  an 
aggregated format together with an explanation of how to interpret the data.  

3. Individual adverse reaction reports held on the Eudravigilance database may be requested 
by  the  public.  Those  reports  shall  be  provided  by  the  Agency  or  the  national  competent 
authority from which they are requested within 90 days, unless disclosure would compromise 
the anonymity of the subjects of the reports. 

Article 25 

The  Agency,  in  collaboration  with  the  Member  States,  shall  develop  standard  web-based 
structured forms for the reporting of suspected adverse reactions by health-care professionals 
and patients.  

Article 26 

The Agency, in collaboration with the Member States and the Commission, shall set up and 
maintain  a  European  medicines  safety  web-portal  for  the  dissemination  of  information  on 
pharmacovigilance  of  medicinal  products  authorised  in  the  Community.  By  means  of  that 
portal, the Agency shall make public at least the following:  

(1) 

(2) 

(3) 

(4) 

(5) 

(6) 

the members of the committees referred to in points (a) and (aa) of Article 56(1) of 
this Regulation and the members of the coordination group referred to in Article 27 
of  Directive  2001/83/EC  (hereinafter  ‘the  coordination  group’),  together  with  their 
professional qualifications and with the declarations pursuant to Article 63(2) of this 
Regulation; 

a  summary  of  each  meeting  of  the  committees  referred  to  in  points  (a)  and  (aa)  of 
Article  56(1)  of 
the  coordination  group  as  regards 
pharmacovigilance activities; 

this  Regulation  and 

risk management systems for medicinal products authorised in accordance with this 
Regulation; 

the list of medicinal products under intensive monitoring referred to in Article 23 of 
this Regulation; 

a  list  of  the  locations  in  the  Community  where  pharmacovigilance  system  master 
files  are  sited  and  contact  information  for  pharmacovigilance  enquiries,  for  all 
medicinal products authorised in the Community; 

information  about  how  to  report  suspected  adverse  reactions  to  medicinal  products 
and  standard  forms  for  their  web-based  reporting  by  patients  and  health-care 
professionals; 

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(7) 

(8) 

(9) 

(10) 

Community  reference  dates  and  frequency  of  submission  of  periodic  safety  update 
reports established in accordance with Article 107c of Directive 2001/83/EC; 

protocols and public abstracts of results as regards post authorisation safety studies 
conducted in more than one Member State and referred to in Articles 107o and 107q 
of Directive 2001/83/EC; 

the initiation of the procedure under Articles 107i to 107l of Directive 2001/83/EC, 
the  substances  or  products  concerned  and  the  issue  being  addressed,  any  public 
hearings  pursuant  to  that  procedure  and  information  on  how  to  submit  information 
and to participate in public hearings; 

Assessment  conclusions,  recommendations,  opinions  and  decisions  taken  by  the 
committees referred to in points (a) and (aa) of Article 56(1) of this Regulation and 
the coordination group, the national competent authorities and the Commission in the 
framework of the procedures of Articles 28, 28a and 28b of this Regulation and of 
sections 2 and 3 of Chapter 3 of Title IX of Directive 2001/83/EC. 

Article 27 

1.  The  Agency  shall  monitor  selected  medical  literature  for  reports  of  suspected  adverse 
reactions  to  medicinal  products  for  human  use  containing  certain  active  substances.  It  shall 
publish  the  list  of  active  substances  being  monitored  and  the  publications  subject  to  this 
monitoring. 

2.  The  Agency  shall  enter  into  the  Eudravigilance  database  relevant  information  from  the 
selected literature.  

3.  The  Agency  shall,  in  consultation  with  the  Commission,  Member  States  and  interested 
parties, draw up a detailed guide regarding the conduct of medical literature monitoring and 
the entry of relevant information into the Eudravigilance database. 

Article 28 

1.  The  obligations  of  marketing  authorisation  holders  and  of  Member  States  laid  down  in 
Articles 107 and 107a of Directive 2001/83/EC shall apply to the recording and reporting of 
suspected  adverse  reactions  for  medicinal  products  for  human  use  authorised  in  accordance 
with this Regulation. 

2. The obligations of marketing authorisation holders laid down in Article 107b of Directive 
2001/83/EC and the procedures under Article 107b and Article 107c thereof shall apply to the 
submission of periodic safety update reports, the establishment of Community reference dates 
and  changes  to  the  frequency  of  submission  of  periodic  safety  update  reports  for  medicinal 
products for human use authorised in accordance with this Regulation. 

The  rules  for  the  submission  of  periodic  safety  update  reports  laid  down  in  the  second 
subparagraph  of  Article  107c(2)  of  that  Directive  shall  apply  to  holders  of  marketing 
authorisations  which  were  granted  before  [insert  concrete  date  -  date  set  out  in  the  second 
paragraph of Article 3 of Regulation (EC) No …/…] and for which the frequency and dates of 
submission  of  the  periodic  safety  update  reports  are  not  laid  down  as  a  condition  to  the 

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marketing authorisation until another frequency or other dates of submission of the reports are 
laid  down  in  the  marketing  authorisation  or  determined  in  accordance  with  Article  107c  of 
that Directive. 

3.  The  Pharmacovigilance  Risk  Assessment  Advisory  Committee  shall  assess  the  periodic 
safety update reports. 

It shall prepare an assessment report within 90 days of receipt of the periodic safety update 
report and send it to the marketing authorisation holder. 

Within  30  days  of  receipt  of  the  assessment  report,  the  marketing  authorisation  holder  may 
submit comments to the Agency. 

At  its  next  meeting  following  the  end  of  the  period  for  comments  by  the  marketing 
authorisation  holder,  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee  shall 
adopt  the  assessment  report  with  or  without  changes,  taking  into  account  any  comments 
submitted by the marketing authorisation holder.  

4.  Within  30  days  of  receipt  of  the  report  by  the  Pharmacovigilance  Risk  Assessment 
Advisory  Committee,  the  Committee  for  Medicinal  Products  for  Human  Use  shall  consider 
the report and adopt an opinion on the maintenance, variation, suspension or revocation of the 
marketing authorisation concerned.  

Where  the  opinion  states  that  regulatory  action  is  necessary,  the  Commission  shall  adopt  a 
decision to vary, suspend or revoke the marketing authorisation. Article 10 of this Regulation 
shall apply to the adoption of that decision. Where the Commission adopts such decision, it 
may  also  adopt  a  decision  addressed  to  the  Member  States  pursuant  to  Article  127a  of 
Directive 2001/83/EC. 

5.  In  the  case  of  an  assessment  of  periodic  safety  update  reports  concerning  more  than  one 
marketing  authorisation  in  accordance  with  Article  107e(1)  of  Directive  2001/83/EC  which 
includes at least one marketing authorisation granted in accordance with this Regulation, the 
procedure laid down in Articles 107e and 107g of that Directive shall apply. 

6. The opinions and decisions referred to in paragraphs 3 to 5 of this Article shall be made 
public by means of the European medicines safety web-portal referred to in Article 26. 

1.  Regarding  medicinal  products  authorised  in accordance with this Regulation, the Agency 
and marketing authorisation holders shall take the following measures: 

Article 28a 

(a) 

monitor the outcome of risk minimization measures contained in risk 
management systems and of conditions or requirements referred to in 
points  (c),  (ca)  and  (cb)  of  Article 9(4) or in Articles 10a, 14(7) and 
(8) ; 

(b) 

assess updates to the risk management system;  

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(c) 

monitor the data in the Eudravigilance database to determine whether 
there are new or changed risks or whether there are changes to the risk 
benefit balance.  

2.  The  Pharmacovigilance  Risk  Assessment  Advisory  Committee  shall  perform  the  initial 
scrutiny and prioritisation of indications of new or changed risks or changes to the risk-benefit 
balance. Where it considers that follow-up action may be necessary, the assessment of those 
indications  and  any  subsequent  action  as  regards  the  marketing  authorisation  shall  be 
conducted in accordance with Article 28. 

3.  The  Agency  and  marketing  authorisation  holders  shall  inform  each  other  in  the  event  of 
new or changed risks or changes to the risk benefit balance being detected. 

Article 28b 

1.  For  post-authorisation  safety  studies  concerning  medicinal  products  for  human  use 
authorised  in  accordance  with  this  Regulation  which  fulfil  the  criteria  set  out  in  Article 
107n(1) of Directive 2001/83/EC, Articles 107n(2), 107o to 107q and Article 107r (1) thereof 
shall apply. 

2.  Where,  in  accordance  with  the  procedure  referred  to  in  paragraph  1  of  this  Article,  the 
Pharmacovigilance  Risk  Assessment  Advisory  Committee  makes  recommendations  for  the 
variation,  suspension  or  revocation  of  the  marketing  authorisation,  the  Committee  on 
Medicinal  Products  for  Human  Use  shall  adopt  an  opinion  taking  into  account  the 
recommendation and the Commission shall adopt a decision in accordance with Article 10. 

Article 28c 

1.  The  Agency  shall  collaborate  with  the  World  Health  Organisation  in  matters  of 
pharmacovigilance  and  shall  take  the  necessary  steps  to  submit  to  it,  promptly,  appropriate 
and adequate information regarding the measures taken in the Community which may have a 
bearing on public health protection in third countries. 

The Agency shall make  available all  suspected adverse reaction reports that occurred in the 
Community to the World Health Organization. 

2. Information received on abuse of medicinal products including information related to illicit 
drugs shall be exchanged between the Agency and the European Monitoring Centre for Drugs 
and Drug Addiction. 

Article 28d 

Upon  request  of  the  Commission,  the  Agency  shall  participate  in  collaboration  with  the 
Member  States  in  international  harmonization  and  standardization  of  technical  measures  in 
pharmacovigilance.  

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Article 28e  

the  Member  States  shall  cooperate 

The  Agency  and 
to  continuously  develop 
pharmacovigilance  systems  capable  of  achieving  high  standards  of  public  health  protection 
for  all  medicinal  products,  regardless  of  routes  of  authorisation,  including  the  use  of 
collaborative approaches, to maximise use of resources available within the Community. 

The Agency shall perform regular audit of its pharmacovigilance tasks and report the results 
to its Management Board on a two-yearly basis. 

Article 28f 

Article 29 

The  Commission  shall  adopt  any  amendments  which  may  be  necessary  to  update  the 
provisions of this Chapter to take account of scientific and technical progress. 

Those  measures,  designed  to  amend  non-essential  elements  of  this  Regulation,  shall  be 
adopted  in  accordance  with  the  regulatory  procedure  with  scrutiny  referred  to  in  Article 
87(2a). 

Article 29a 

The Commission shall make public a report on the conduct of pharmacovigilance tasks by the 
Agency on [insert concrete date - three-years after the date of application set out in the second 
paragraph of Article 3] at the latest and then every three years thereafter.” 

(12)  Article 56(1) is amended as follows: 

(a) 

the following point (aa) is inserted: 

"(aa)  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee,  which  shall  be 
responsible for providing advice to the Committee for Medicinal Products for Human Use and 
the  coordination  group  on  any  question  relating  to  the  pharmacovigilance  of  medicinal 
products for human use;” 

(b)  point (f) is replaced by the following: 

“(f) 
a  Secretariat,  which  shall  provide  technical,  scientific  and  administrative  support  for 
the  committees  and  ensure  appropriate  coordination  between  them,  and  which  shall  provide 
technical  and  administrative  support  for  the  coordination  group  and  ensure  appropriate 
coordination between it and the committees.” 

(13)  Article 57 is amended as follows: 

(a) 

in paragraph 1, points (c) to (f) are replaced by the following: 

“(c) coordination of the supervision of medicinal products which have been authorised within 
the Community and the provision of advice on the measures necessary to ensure the safe and 
the  evaluation  and 
effective  use  of 

in  particular  by  coordinating 

these  products, 

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implementation  of  pharmacovigilance  obligations  and  systems  and  the  monitoring  of  such 
implementation; 

(d) ensuring the collation and dissemination of information on adverse reactions to medicinal 
products authorised in the Community by means of a database permanently accessible to all 
Member States; 

(e)  assisting  Member  States  with  the  rapid  communication  of  information  concerning 
pharmacovigilance to health-care professionals and coordinating the safety announcements of 
the national competent authorities; 

(f) distributing appropriate pharmacovigilance information to the general public, in particular 
by setting up and maintaining a European medicines safety web-portal;” 

(b) 

In  paragraph  2,  the  following  subparagraph  is  inserted  after  the  first 
subparagraph: 

“For the purposes of the database, the Agency shall establish a list of all medicinal products 
authorised in the Community. To this effect the following measures shall be taken: 

(a) the Agency shall, by -/- (insert date - six-months after the entry into force of the amending 
regulation)  at  the  latest,  make  public  a  format  for  the  electronic  submission  of  medicinal 
product information;  

(b) marketing authorisation holders shall, by -/- (insert date - eighteen months after the entry 
into  force  of  the  amending  regulation)  at  the  latest,  electronically  submit  to  the  Agency 
information for all medicinal products authorised or registered in the Community, using the 
format referred to in point (a); 

(c) from the date set out in point (b), marketing authorisation holders shall inform the Agency 
of  any  new  authorisations  granted  in  the  Community,  using  the  format  referred  to  in  point 
(a).” 

(14)  The following Article 61a is inserted: 

"Article 61a 

1.  The  Pharmacovigilance  Risk  Assessment  Advisory  Committee  shall  be  composed  of  the 
following: 

(a) 

(b) 

ten  members  and  ten  alternates  appointed  by  the  Management  Board,  on  the 
basis of proposals by the national competent authorities; 

five members and five alternates appointed by the Commission, on the basis of 
a  public  call  for  expressions  of  interest,  after  consulting  the  European 
Parliament. 

The alternates shall represent and vote for the members in their absence. 

The  Commission  may  adapt  the  number  of  members  and  alternates  in  the  light  of  technical 
and  scientific  needs.  Those  measures,  designed  to  amend  non-essential  elements  of  this 

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Regulation,  shall  be  adopted  in  accordance  with  the  regulatory  procedure  with  scrutiny 
referred to in Article 87(2a). 

2.  The  members  and  alternates  of  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee  shall  be  appointed  on  the  basis  of  their  relevant  expertise  in  pharmacovigilance 
and risk assessment of medicinal products for human use, in such a way as to guarantee the 
highest levels of specialist qualifications and a broad spectrum of relevant expertise. For this 
purpose,  the  Executive  Director  of  the  Agency  shall  assist  the  Management  Board  and  the 
Commission  in  order  to  ensure  that  the  final  composition  of  the  Committee  covers  the 
scientific areas relevant to its tasks. 

3.  The  members  and  alternates  of  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee shall be appointed for a term of three years, which may be prolonged once. The 
Committee shall elect its Chairman among its members for a term of three years, which may 
be prolonged once.  

4.  Paragraphs  (3),  (4),  (7)  and  (8)  of  Article  61  shall  apply  to  the  Pharmacovigilance  Risk 
Assessment Advisory Committee. 

5.  Members  and  alternates  of  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee 
may  not  seek  or  take  instructions  from  any  national  competent  authority,  organisation  or 
person. They shall carry out the duties assigned to them objectively and impartially. 

6. Representatives of the national competent authorities shall be entitled to attend all meetings 
of  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee  to  facilitate  appropriate 
coordination between the tasks of the Agency and the work of national competent authorities. 
They  may  provide  clarification  or  information  if  invited  to  do  so  but  shall  not  seek  to 
influence discussions.” 

(15)  Article 62 is amended as follows: 

(a)  Paragraph 1 is amended as follows: 

(i) 

the first subparagraph is replaced by the following:  

“Where, in accordance with this Regulation, any of the committees referred to in Article 56(1) 
is  required  to  evaluate  a  medicinal  product,  it  shall  appoint  one  of  its  members  to  act  as 
rapporteur  for  the  coordination  of  the  evaluation.  The  Committee  concerned  may  appoint  a 
second member to act as co-rapporteur.” 

(ii) 

the fourth subparagraph is replaced by the following: 

“If  there  is  a  request  for  re-examination  of  one  of  its  opinions  where  this  possibility  is 
foreseen  in  the  Community  legislation,  the  Committee  concerned  shall  appoint  a  different 
rapporteur and, where necessary, a different co-rapporteur from those appointed for the initial 
opinion. The re-examination procedure may deal only with the points of the opinion initially 
identified  by  the  applicant  and  may  be  based  only  on  the  scientific  data  available  when  the 
Committee adopted the initial opinion. The applicant may request that the Committee consults 
a scientific advisory group in connection with the re-examination.” 

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(b) 

in paragraph 2, the first subparagraph is replaced by the following: 

“  Member  States  shall  transmit  to  the  Agency  the  names  of  national  experts  with  proven 
experience  in  the  evaluation  of  medicinal  products  who  would  be  available  to  serve  on 
working parties or scientific advisory groups of any of the committees referred to in Article 
56(1), together with an indication of their qualifications and specific areas of expertise.” 

(c) 

In paragraph 3, the following subparagraph is added: 

“The  first  and  second  subparagraph  shall  apply  also  to  the  work  of  rapporteurs  in  the 
coordination  group  as  regards  the  fulfilment  of  its  tasks  in  accordance  with  Articles  107c, 
107e, 107g, 107l and 107r of Directive 2001/83/EC.” 

(16)  Article 64(2) is amended as follows: 

(a)  Point (b) is replaced by the following: 

“(b)  for  managing  all  the  Agency  resources  necessary  for  conducting  the  activities  of  the 
committees referred to in Article 56(1), including making available appropriate scientific and 
technical support to those committees, and for making available appropriate technical support 
to the coordination group;” 

(b)  Point (d) is replaced by the following: 

“(d) for ensuring appropriate coordination between the committees referred to in Article 56(1) 
and, where necessary, between the committees and the coordination group;” 

(17) 

In Article 66(g), the figure "67" is replaced by the figure "68". 

(18)  Article 67 is amended as follows: 

(a) 

In paragraph 3, the first subparagraph is replaced by the following: 

“The Agency's revenue shall consist of a contribution from the Community and fees paid by 
undertakings  for  obtaining  and  maintaining  Community  marketing  authorisations  and  for 
other services provided by the Agency or the coordination group as regards the fulfilment of 
its tasks in accordance with in accordance with Articles 107c, 107e, 107g, 107l and 107r of 
Directive 2001/83/EC.” 

(b) Paragraph 4 is replaced by the following: 

“4.  Activities  relating  to  pharmacovigilance,  to  the  operation  of  communications  networks 
and to market surveillance shall be under the permanent control of the Management Board in 
order to guarantee the independence of the Agency. This shall not preclude the collection of 
fees to be paid by marketing authorisation holders for the carrying out of these activities by 
the Agency.” 

(19)  Article 82(3) is replaced by the following: 

“3.  Without  prejudice  to  the  unique,  Community  nature  of  the  content  of  the  documents 
referred  to  in  points  (a)  to  (d)  of  Article  9(4)  and  in  points  (a)  to  (e)  of  Article  34(4),  this 

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Regulation shall not prohibit the use of two or more commercial designs for a given medicinal 
product covered by a single authorisation.” 

(20) 

In Article 83(6), the second sentence is replaced by the following: 

“Article 28(1) and (2) shall apply mutatis mutandis.” 

Article 2 
Transitional provisions 

1. 

2. 

3. 

The  requirement  for  the  inclusion  of  a  summary  of  the  essential  information 
necessary to use the medicine safely and effectively in the summary of the product 
characteristics and the package leaflet provided for in point 3a of Article 11 and in 
point  (aa)  of  Article  59(1)  of  Directive  2001/83/EC  as  amended  by  Directive 
…/…/EC,  which  applies  to  medicinal  products  authorised  pursuant  to  Regulation 
(EC) No 726/2004 by virtue of its Article 9(4)(a) and (d), shall apply to a marketing 
authorisation granted before the date set out in the second paragraph of Article 3 of 
this Regulation from renewal of that authorisation or from the expiry of a period of 
three years starting from that date, whichever is the earliest. 

The  requirement  for  the  marketing  authorisation  holder  to  maintain  and  make 
available  on  request  a  pharmacovigilance  system  master  file  in  respect  of  one  or 
more  medicinal  products  provided  for  in  point  (b)  of  Article  104(3)  of  Directive 
2001/83/EC as amended by Directive …/…/EC, which applies to medicinal products 
authorised  pursuant  to  Regulation  (EC)  No  726/2004  by  virtue  of  Article  21  of 
Regulation  (EC)  No  726/2004  as  amended  by  this  Regulation,  shall  apply  to 
marketing authorisations granted before the date set out in the second paragraph of 
Article 3 of this Regulation or from the expiry of a period of three years starting from 
that date. 

The procedure under Articles 107n to 107r of Directive 2001/83/EC as amended by 
Directive  …/…/EC,  which  apply  by  virtue  of  Article  28b  of  Regulation  (EC)  No 
726/2004  as  amended  by  this  Regulation,  shall  apply  only  to  studies  which  have 
commenced  after  the  date  set  out  in  the  second  paragraph  of  Article  3  of  this 
Regulation. 

Article 3 
Entry into force and application 

This Regulation shall enter into force on day following that of its publication in the Official 
Journal of the European Union. 

It shall apply from [18 months from the entry into force]. 

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Done at Brussels,  

For the European Parliament 
The President 

For the Council 
The President 

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LEGISLATIVE FINANCIAL STATEMENT 

1. 

NAME OF THE PROPOSAL: 

A  Regulation  amending  Regulation  (EC)  726/2004,  and  a  Directive  amending 
Directive 2001/83/EC on Pharmacovigilance. 

2. 

ABM / ABB FRAMEWORK 

Policy Area(s) concerned and associated Activity/Activities: 

Policy area(s): Internal Market (Article 95 of the EC Treaty). 

Activities: 

– 

Improving the protection of public health across the Community in relation to 
the safety of medicinal products; 

– 

Supporting the achievement of the internal market in the pharmaceutical sector; 

3. 

BUDGET LINES 

3.1. 

Budget  lines  (operational  lines  and  related  technical  and  administrative 
assistance lines (ex- B..A lines)) including headings: 

02.030201 – European Medicines Agency — Subsidy under Titles 1 and 2 

02.030202 – European Medicines Agency — Subsidy under Title 3 

3.2. 

Duration of the action and of the financial impact: 

The  assumption  is  that  the  proposed  package  of  a  Regulation  and  Directive  on 
Pharmacovigilance  would  apply  from  late  2011  (year  "n").  The  calculation  in  the 
Annex has been calculated for 2011-2016. 

3.3. 

Budgetary characteristics: 

Budget line 

Type of expenditure 

New 

EFTA 
contribution 

Contributions 
from applicant 
countries 

Heading in 
financial 
perspective 

02.030201 

02.030202 

Non-
comp 

Non-
comp 

Non-
diff14 

NO 

YES 

NO 

No 1a0203 

Non-diff  NO 

YES 

NO 

No 1a0203 

14 

Non-differentiated appropriations hereafter referred to as NDA. 

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4. 

SUMMARY OF RESOURCES 

4.1. 

Financial Resources 

4.1.1. 

Summary of commitment appropriations (CA) and payment appropriations (PA) 

Not applicable 

Co-financing details 

Not applicable 

4.1.2.  Compatibility with Financial Programming 

⌧  Proposal is compatible with existing financial programming. 

4.1.3.  Financial impact on Revenue 

⌧  Proposal has no financial implications on revenue (see details of calculation in 

the Annex) 

4.2. 

Human Resources FTE (including officials, temporary and external staff)  

Not applicable. 

5. 

CHARACTERISTICS AND OBJECTIVES 

5.1. 

Need to be met in the short or long term 

Significant weaknesses of the current EU system of pharmacovigilance have been identified 
through an independent Commission sponsored study, extensive public consultation (in 2006 
and again in 2007) and through detailed analysis by the Commission services. Taken together 
these problems mean that the safety of EU citizens is not optimally protected so that there is 
improving  EU 
to 
an  opportunity 
pharmacovigilance.  

the  public  health  burden  ADRs  by 

reduce 

5.2. 

Value-added  of  Community  involvement  and  coherence  of  the  proposal  with 
other financial instruments and possible synergy 

Considering existing EU legislation, functioning of the single market and the increasing share 
of  centrally  authorised  medicinal  products,  action  of  Member  States  alone  could  not  be 
sufficient to bring full harmonisation of pharmacovigilance rules between Member States and 
the objectives of this legal proposal can only be fully achieved at the Community level.  

5.3. 

Objectives, expected results and related indicators of the proposal in the context 
of the ABM framework 

The high level objective of the proposal is to improve the protection of public health in the 
Community  while  enhancing  the  single  market  in  medicinal  products,  by  strengthening  and 
rationalising EU pharmacovigilance. This will be achieved through the operational objectives 
of: 

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– 

– 

– 

– 

– 

– 

Providing for clear roles and responsibilities for the key responsible parties; 

Rationalising EU decision-making on drug safety issues; 

Strengthening medicines safety transparency and communication; 

Strengthen companies' pharmacovigilance systems; 

Ensure the proactive and proportionate collection of high quality data; 

Involve stakeholders in pharmacovigilance. 

The proposal’s objectives contribute to the strategic goals of the Community framework for 
the authorisation, supervision and surveillance of medicinal products i.e.: 

•  Ensuring that public health is adequately protected across the Community; 

•  Supporting the achievement of the internal market for the pharmaceutical sector. 

5.4.  Method of Implementation (indicative) 

⌧  Centralised Management 

⌧ 

indirectly by delegation to: 

⌧ 

bodies set up by the Communities as referred to in art. 185 of the 
Financial Regulation  

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6. 

MONITORING AND EVALUATION 

6.1.  Monitoring system 

The Commission has established mechanisms for working with the Member States to monitor 
transposition.  

With  regard  to  ex-post  evaluation  the  following  are  considered  relevant,  accepted,  credible, 
easy and robust: 

•  On clear roles and responsibilities and clear standards against which they perform 
their  roles,  a  regular  report  by  the  European  Commission,  pharmacovigilance 
inspections and EMEA audit;  

•  On rationalising EU decision-making, the timing of the establishment of the new 
EMEA committee structure and the number of pharmacovigilance referrals to the 
EMEA; 

•  On  transparency  and  communication,  measure  the  establishment  by  Member 
States of medicines safety websites, the launch of the EU safety web-portal by the 
EMEA and evaluate the inclusion of information; 

•  On oversight of companies' pharmacovigilance systems - inspections; 

•  On  proactive  collection  of  high  quality  data,  measure  the  number  of  risk 
management plans submitted and the concordance between the studies required; 

•  On reporting of adverse reactions, measure the number and quality of ADR and 

PSUR reports evaluated; 

•  On  involving  stakeholders  in  pharmacovigilance,  measure  the  number  and 

proportion of adverse reaction reports received from patients. 

6.2. 

Evaluation 

6.2.1.  Ex-ante evaluation 

During  the  impact  assessment  process  the  Commission  services  extensively  consulted  all 
relevant  stakeholders  using  the  whole  range  of  communication  means.  Two  general  web-
based public consultations were supplemented by questionnaire surveys and workshops with 
specific  stakeholder  groups.  The  Commission  Pharmaceutical  Committee,  the  EMEA 
scientific  committees,  and  the  Heads  of  EEA  Medicines  Agencies,  have  been  consulted. 
Concurrently  comments  of  the  Commission  services  raised  during  the  inter-service  steering 
group meetings were fully taken into consideration. 

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6.2.2.  Measures taken  following  an intermediate/ex-post evaluation (lessons learned from 

similar experiences in the past) 

The study “Assessment of the European Community System of Pharmacovigilance”15, aimed 
specifically to analyse how the European central and EU Member States' medicines agencies 
collaborate  with  each  other,  the  marketing  authorisation  holders  and  other  stakeholders  in 
monitoring 
forward 
recommendations to make the system more robust.  

the  adverse  effects  of  pharmaceutical  products  and 

to  put 

6.2.3.  Terms and frequency of future evaluation 

It  should  be  noted  that  the  proposal  specifically  provides  for  a  three-yearly  report  by  the 
European Commission services on the operation of pharmacovigilance by the Member States, 
for pharmacovigilance inspections, and for EMEA audit. 

The  specific  objective  of  improving  public  health  protection  through  strengthening  and 
rationalising EU pharmacovigilance can be measured by an external study.  

The  two  EU  legal  acts  that  are  being  modified  contain  existing  general  review  clauses 
(Commission report every 10-years) which will apply to the new provisions. 

7. 

ANTI-FRAUD MEASURES  

The European Medicines Agency has specific budgetary control mechanisms and procedures. 
The  Management  Board,  which  comprises  representatives  of  the  Member  States,  the 
Commission  and  the  European  Parliament,  adopts  the  budget  (Article  66(f)  of  Regulation 
(EC) No 726/2004), as well as the internal financial provisions (Article 66(g)). The European 
Court of Auditors examines the execution of the budget each year (Article 68.3).  

Regarding fraud, corruption and other unlawful activities, the provisions of Regulation (EC) 
No  1073/1999  of  the  European  Parliament  and  of  the  Council  of  25  May  1999  concerning 
investigations  conducted  by  the  European  Anti-Fraud  Office  (OLAF)  apply  to  the  EMEA 
without restriction. Besides, a decision concerning co-operation with the OLAF was already 
adopted on 1 June 1999 (EMEA/D/15007/99). 

Finally,  the  Quality  Management  System  applied  by  the  Agency  supports  a  continuous 
review, whose objective is to ensure that the correct procedures are followed and that these 
procedures and policies are pertinent and efficient. Several internal audits are undertaken each 
year as part of this process. 

15 

http://ec.europa.eu/enterprise/pharmaceuticals/pharmacovigilance_acs/docs/acs_consultation_final.pdf 

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ANNEX: details of calculation 

Introduction 

The  Legislative  Financial  Statement  is  proposed  based  on  the  fact  that  the  legislative 
proposals, if adopted, will enable for the first time, pharmacovigilance activities to be the 
subject  of  fees  charged  by  the  European  Medicines  Agency  –EMEA.  The  Legislative 
Financial Statement and the calculations in this annex demonstrate that all costs relating 
to activities resulting from the legislative proposal will be recuperated through fees. On 
this  basis,  the  calculation  in  this  Annex  leads  to  the  conclusion  that  the  proposed 
measures  are  not  expected  to  have  a  significant  financial  impact  on  the  Community 
budget. 

Pharmacovigilance and maintenance activities accounted for 13.5% of the Agency human 
resource (ca. 70 FTEs) and 14.54% of the Agency costs (€ 25.2 million including support 
service).  The  average  cost  of  1  full  time  equivalent  (FTE)  AD  Staff  Member  for  the 
EMEA  in  London  has  been  provided  by  the  EMEA  (draft  2007  costs)  as:  Salary: 
€112.113 and Salary and overheads: €161.708.  

The  Community  assessments  would  require  payment  of  rapporteurs  who  would  receive 
their payment through the Agency. We have assumed fees with 50% of the fee revenue 
retained by EMEA and 50% paid to rapporteurs.  

Fees charged by the EMEA to the pharmaceutical industry 

To support the pharmacovigilance provisions, the following fee estimates can be made: 

Community 
pharmacovigilance 
referrals 

PSURs 
assessed 

Community 
study 
assessments 

Community 
risk 
management 
assessments 

Number (year) 

20 

1000 

300 

100 

Estimated fee  

€72,800 

€6,100  

€6,100  

€12,100  

Total 

20 x €72,800 = 
€1,456,000 

1000 x €6,100 
= €6,100,000 

300 x €6,100 = 
€1,830,000 

100 x 
€12,100 = 
€1,210,000 

Based  on  the  estimates  above  the  additional  annual  income  to  the  EMEA  from 
pharmacovigilance fee revenue will be €10,596,000. 

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Payments  by  the  EMEA  to  rapporteurs  for  Community  pharmacovigilance 

assessments 

It  is  estimated  that  these  scientific  assessments  by  rapporteurs  should  be  subject  to 
payment of half the fee. On this basis the following payments by EMEA to rapporteurs 
can be estimated: 

Community 
pharmacovigilance 
referrals 

PSURs 
assessed 

Community 
study 
assessments 

Community risk 
management assessments 

Number (year) 

20 

1000 

300 

100 

Estimated 
payment to 
rapporteur 

Total 

€36,400  

€3,050  

€3,050  

€6,050 

20 x €36,400 = 
€728,000 

1000 x 
€3,050 = 
€3,050,000 

300 x €3,050 
= €915,000 

100 x €6,050 = €605,000 

Based on the estimates above the new costs to EMEA to pay for rapporteur assessments 
will be €6,230,100. 

Literature monitoring: 

On the basis of estimates from the EMEA (3 additional information analysts if the main 
function  was  outsourced)  and  from  one  private  literature  monitoring  company16 
(€533,333 annually for 3000 monitored substances, doubled to cover uncertainty relating 
to the number of substances and detailed processes), we can estimate the increase in costs 
to the EMEA of approximately €1.56 million per year.  

The new pharmacovigilance committee structure: 

It  is  considered  that  the  amendments  to  the  EMEA  pharmacovigilance  committee 
structure  (including  replacement  of  the  existing  Working  Party)  would  not  lead  to  an 
increase in costs compared the existing costs.  

Revised Community pharmacovigilance referral: 

It is considered that the number of referrals is likely to be in the range 10 to 30 per year. 
If we use the mid point of this range, and assuming the assessment/coordination costs to 
be equivalent to a Type II variation in the centralised procedure, this will represent a cost 
to the EMEA in payments to rapporteurs of 20 x €36,400 = €728,000 and income from 
fees of 20 x €72,800 = €1,46 million. 

16 

Wolters Kluwer Health. 

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Revised transparency and communications provisions: 

This  is  estimated  at  €646,832  on  a  yearly  basis,  covering  4.0  FTEs  to  manage  the 
documents  and  the  website  (including  dealing  with  confidentiality  issues  and  one 
“communication manager” to formulate urgent safety communications).  

One-off information technology costs are also foreseen of €1,000,000 (see section below 
on impact on overall telematics budget).  

Community oversight of non-interventional post-authorisation safety studies 

We can estimate the number of protocols to be scrutinised by the EU committee structure 
as  300  with  a  cost  of  €485,124,  which  compri ses  3  FTEs  for  EMEA  coordination  and 
initial  screening.  Based  on  the  fee  estimates  above  these  procedures  would  attract 
€1,830,000 in industry fees of which half woul d be paid to rapporteurs leaving €915,000 
to the EMEA. 

Community oversight of risk management systems 

The  number  of  additional  Community  assessments  of  risk  management  systems  is 
estimated  to  be  100  per  year.  Assuming  the  assessment/coordination  costs  to  be 
equivalent  to  a  renewal  in  the  centralised  procedure,  this  will  represent  a  cost  to  the 
EMEA in payments to rapporteurs of 100 x €6,050 = €605,000 and income from fees of 
100 x €12,100 = €1.2 million. 

Enhancements to the Community pharmacovigilance database  

Additional one-off development costs for human resources, hardware and software of an 
estimated €2,871,000 in total (see section belo w on impact on overall telematics budget). 

Running the collection and management of pharmacovigilance data  

Additional  staff  of  10  FTE  for  running 
the  collection  and  management  of 
pharmacovigilance data in EudraVigilance from a business perspective (ADR processing) 
would bear an additional cost estimated at €1.62 million.  

PSUR assessment work-sharing: 

Based on the fee estimates above these procedures would attract €6,100,000 in industry 
fees of which half would be paid to rapporteurs leaving €3,050,000 to the EMEA. 

Telematics budget 

The current EMEA programming for telematics "development costs" (as included in the 
EMEA Telematics Master Plan) provides for: 
2010 
2008 
Year 

2009 

2013 

2012 

2011 

Total 
for 
period 
8.0 

1.3 

1.4 

1.0 

1.5 

1.7 

1.0 

Pharmacovigilance 
database costs (€ 
millions to one 
decimal place) 

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12.6 

11.9 

13.1 

13.1 

12.8 

10.4 

74.1 

Total IT annual 
budget (€ millions 
to one decimal 
place) 

Based  on  information  provided  by  the  EMEA  the  transparency  and  communication 
provisions in the proposals will incur a one-off information technology cost of €1 Million 
and  Community  pharmacovigilance  database  enhancements  will  incur  a  one-off 
information technology cost of €2.87 Million.  

It is reasonable to ask the EMEA to re-programme the one-off €2.87 Million required for 
the Community pharmacovigilance database from its existing telematics budget (with or 
without subsidy from any budget surplus for 2008) and to request that the EMEA delivers 
the enhanced  database  functionality  prior to the  expected entry into force date of 2011. 
The one – off costs for transparency and communication (€ 1 Million)  should be borne by 
fees (€ 500 000 in 2012 and 2013). 

Overall impact on EMEA budget 

The  calculations  estimated  a  one-off  increase  of  resources  for  EMEA  of  €3.9  million 
(setting up of the EU Safety Portal and enhancement of Eudravigilance functionality) and 
ongoing  costs  of  €10.1  million  annually,  includ ing  payments  to  rapporteurs,  23  FTEs 
needed in addition to the current Agency staff dealing with pharmacovigilance (increase 
of 38%), and just over €1 million annually for non-staff costs for literature monitoring.  

EMEA 

FTE 

EMEA 

EMEA 

Payments 
to 
rapporteurs 

Income 
Fees 

Analysed options (revised if 
applicable) 

Committee + referrals 
Drug safety transparency and 
communication 
Codification and oversight PASS 

One-off 

 1,000,000

Eudravigilance development 

 2,871,000*

Pharmacovigilance data-processing 

Literature screening by the EMEA 

PSUR Assessment Worksharing 

Risk Management System assessment 

Salaries 
annually 

 646,832

 485,124

 1,617,080
 485,124

 485,124

4

3

10
3

3

Annually  Annually  Annually 

 728,000 

 1,456,000

915,000  1,830,000

1,066,667 

   3,050,000  6,100,000

605,000  1,210,000

Total 

 3,871,000

23

 3,719,284

 1,066,667 

 5,298,000 

10,596,000

*From existing telematics budget (with or without subsidy from any budget surplus for 2008). 

Overall impact on EMEA budget by year is predicted in the table below: 

 EMEA costs 

Year 2011 

Year 2012 

Year 2013 

Year 2014 

Year 2015 

Year 2016 

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One-off 

FTE  

500,000 

500,000 

5 

23 

23 

23 

23 

23 

Salaries annually 

808,540 

3,719,284 

3,719,284 

3,719,284 

3,719,284 

3,719,284 

Other annual costs. 

1,066,667 

1,066,667 

1,066,667 

1,066,667 

1,066,667 

Rapporteurship 

5,298,000 

5,298,000 

5,298,000 

5,298,000 

5,298,000 

Total costs 

808,540 

10,583,951 

10,583,951 

10,083,951 

10,083,951 

10,083,951 

Income Fees 

0 

10,596,000 

10,596,000 

10,596,000 

10,596,000 

10,596,000 

Balance 

-808,540 

12,049 

12,049 

512,049 

512,049 

512,049 

Given the assumptions included in the estimates of work volumes and fee income the net 
income  that  appears  from  2012  onwards  can  be  regarded  as  justified  to  ensure  that  the 
key  public  health  function  of  pharmacovigilance  is  maintained  at  the  EMEA  despite 
income  being  variable  and  some  costs  (e.g.  certain  salaries)  being  fixed.  As  figures  are 
levelled they have not been index linked. 

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