Proposal for a Directive of the European Parliament and of the Council amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use {SEC(2008) 2670} {SEC(2008) 2671}
Date: 2008-10-21
Institutions: European Commission
Subjects: approximation of laws, legal code, medicinal product, pharmaceutical legislation, public health, single market

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COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels, 10.12.2008 
COM(2008) 665 final 

2008/0260 (COD) 

Proposal for a 

DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL  

amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code 
relating to medicinal products for human use 

{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 

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in  the  form  of  post  authorisation  safety  studies,  together  with  rationalised  single 
case and periodic reporting of suspected adverse reactions; 

•  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. 

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

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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 
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. 

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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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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.  

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.  

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), 

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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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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. 

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

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2008/0260 (COD) 

Proposal for a 

DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL  

amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community 
code relating to medicinal products for human use 

(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) 

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 
use11  lays  down  harmonised  rules  for  the  authorisation,  supervision  and 
pharmacovigilance of medicinal products within the Community.  

Pharmacovigilance rules are necessary for the protection of public health in order 
to prevent, detect and assess 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 311, 28.11.2001, p. 67.  

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(4)  While taking into account the fact that the regulation of medicinal products should 
be  fundamentally  aimed  at  safeguarding  public  health,  this  aim  should  be 
achieved  by  means  that  do  not  impede  the  free  movement  of  safe  medicinal 
products  within  the  Community.  It  has  emerged  from  the  assessment  of  the 
Community system of pharmacovigilance that divergent Member State action on 
safety  issues  of  medicinal  products  is  creating  barriers  to  the  free  movement  of 
medicinal  products.  In  order  to  prevent  or  eliminate  those  obstacles  the  existing 
pharmacovigilance  provisions  at  Community  level  should  be  strengthened  and 
rationalised.  

(5) 

(6) 

(7) 

(8) 

For  the  sake  of  clarity,  the  definition  of  adverse  reaction  should  be  amended  to 
ensure  that  it  not  only  covers  noxious  and  unintended  effects  derived  from  the 
authorised  use  of  a  medicinal  product  at  the  normal  doses,  but  also  medication 
errors  and  uses  outside  the  authorised  summary  of  the  product  characteristics, 
including the misuse and abuse of the product.  

The marketing authorisation holder should establish a pharmacovigilance system 
to  ensure  the  monitoring  and  supervision  of  one  or  more  of  its  authorised 
medicinal  products,  recorded  in  a  Pharmacovigilance  System  Master  File 
permanently  accessible  for 
inspection.  The  competent  authorities  should 
undertake the supervision of those systems. A summary of the pharmacovigilance 
system should be therefore submitted with the marketing authorisation application 
and  include  a  reference  to  the  site  where  the  Pharmacovigilance  System  Master 
File  for  the  medicinal  product  concerned  is  maintained  and  accessible  for 
inspection.  

The planning of pharmacovigilance for each individual medicinal product by the 
marketing  authorisation  holder  should  take  place  in  the  context  of  a  risk 
management system and should be proportionate to the identified risks, potential 
risks, and the need for additional information on the medicinal product. It should 
also be foreseen that any key measures contained in a risk management system are 
included in the marketing authorisation as conditions.  

In order to ensure the collection of any necessary additional data about the safety 
of authorised medicinal products, competent authorities should be empowered to 
require  post-authorisation  safety  studies  at  the  time  of  the  granting  of  the 
marketing  authorisation  or  later,  and  this  requirement  should  be  included  as  a 
condition of the marketing authorisation.  

(9)  Where a medicinal product is authorized subject to the requirement to conduct a 
post-authorisation  safety  study  or  where  there  are  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 maintained up to date by the European Medicines Agency established 

EN 

11 

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by 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 Agency12 (hereinafter referred to as the ‘Agency’).  

(10) 

In  order  to  make  it  possible  for  the  healthcare  professionals  and  patients  to 
identify  easily  the  most  relevant  information  about  the  medicines  they  use,  the 
summary  of  the  product  characteristics  and  the  package  leaflet  should  include  a 
concise  section  on  the  key  information  about  the  medicinal  product  and 
information how to minimize its risks and maximize its benefits.  

(11)  Experience has shown that the responsibilities of marketing authorisation holders 
for  the  pharmacovigilance  of  authorised  products  should  be  clarified.  The 
marketing authorisation holder should be responsible for continuously monitoring 
the safety of his products, for informing the authorities of any changes that might 
impact  on  the  marketing  authorisation,  and  for  ensuring  that  the  product 
information is maintained 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 the renewal of marketing authorisations should consider 
all relevant information collected on the safety of the medicinal product.  

(12) 

In  order  to  ensure  close  cooperation  between  the  Member  States  in  the  area  of 
pharmacovigilance, the mandate of the coordination group set up by Article 27 of 
Directive 2001/83/EC should be enlarged to include the examination of questions 
related  to  the  pharmacovigilance  of  all  medicinal  products  authorised  by  the 
Member States. In order to fulfil its new tasks, the coordination group should be 
further  strengthened  through  the  adoption  of  clear  rules  as  regards  the  expertise 
required,  the  adoption  of  opinions,  transparency,  independence  and  professional 
secrecy  of  its  members,  and  the  need  for  cooperation  between  Community  and 
national bodies.  

(13)  With a view to ensuring that the same level of scientific expertise in the area of 
pharmacovigilance decision-making at both Community and national level, when 
fulfilling  pharmacovigilance  tasks  the  coordination  group  should  be  able  to  rely 
on the advice of the Pharmacovigilance Risk Assessment Advisory Committee of 
the Agency.  

(14) 

In order to avoid duplication of work, a single opinion should be adopted by the 
coordination  group  for  pharmacovigilance  assessments  concerning  products 
authorised  in  more  than  one  Member  State.  The  agreement  within  the 
coordination  group  should  suffice  for  pharmacovigilance  measures  to  be 

12 

OJ L 136, 30.4.2004, p. 1.  

EN 

12 

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implemented  throughout  the  Community.  Where  no  agreement  is  found  in  the 
coordination group, the Commission should be authorised to adopt a decision to 
that effect, addressed to the Member States.  

(15)  A  single  assessment  should  also  be  conducted  in  the  case  of  pharmacovigilance 
issues  which  concern  products  authorised  by  the  Member  States  and  products 
authorised  in  accordance  with  Regulation  (EC)  No  726/2004.  In  such  cases,  the 
Commission should adopt harmonised measures for all products concerned on the 
basis of a Community assessment.  

(16)  Member States should operate a pharmacovigilance system to collect information 
useful  in  the  surveillance  of  medicinal  products  including  information  on 
suspected  adverse  drug  reactions,  on  misuse,  abuse  and  medication  errors,  and 
ensure its quality through the follow up of suspected adverse drug reaction cases.  

(17)  To  further  increase  the  coordination  of  resources  between  the  Member  States, 
Member State should be authorised to delegate certain pharmacovigilance tasks to 
another Member State.  

(18) 

(19) 

In  order  to  simplify  the  reporting  of  suspected  adverse  reactions  the  marketing 
authorisation holders and the Member States should report those reactions only to 
the Community pharmacovigilance database and data-processing network referred 
to  in  Article  57(1)(d)  of  Regulation  (EC)  No  726/2004  (hereinafter  ‘the 
Eudravigilance database’).  

to 

the 

increase 

level  of 

In  order 
the  processes  of 
pharmacovigilance,  the  Member  States  should  create  and  maintain  medicines 
safety web-portals.  To  the same  end,  the  marketing  authorisation  holders  should 
provide  the  authorities  with  prior  warning  about  safety  announcements  and  the 
authorities should provide each other with such a warning. 

transparency  on 

(20)  Community  rules  on  pharmacovigilance  should  continue  to  rely  on  the  crucial 
safety monitoring role of healthcare professionals, and should take account of the 
fact that patients are also well placed to report adverse reactions to medicines. It is 
therefore  appropriate  to  facilitate  the  reporting  of  suspected  adverse  reactions  to 
medicinal  products  by  both  healthcare  professionals  and  patients,  and  to  make 
available to them methods for such reporting.  

(21)  As  a  result  of  the  submission  of  all  adverse  reaction  data  directly  to  the 
Eudravigilance  database,  it  is  appropriate  to  amend  the  scope  of  periodic  safety 
update  reports  so  that  they  present  an  analysis  of  the  risk-benefit  balance  of  a 
medicinal product rather than a detailed listing of individual case reports already 
submitted to the Eudravigilance database. 

(22)  Requirements for periodic safety update reports should be proportional to the risks 
posed by medicinal products. Periodic safety update reporting should therefore be 
linked  to  the  risk  management  system  for  newly  authorised  medicinal  products 

EN 

13 

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and  routine  reporting  should  not  be  necessary  for  generic,  well-established  use, 
informed  consent,  homeopathic,  or  traditional  use  registered  herbal  medicinal 
products. However, in the interest of public health the authorities should require 
periodic  safety  update  reports  for  such  products  when  there  is  a  need  to  assess 
their risk or review the adequacy of product information. 

(23)  There  is  a  need  to  increase  the  shared  use  of  resources  between  competent 
authorities for the assessment of periodic safety update reports. Provision should 
be  made  for  a  single  assessment  of  periodic  safety  update  reports  for  medicinal 
products authorised in more than one Member State. Moreover, procedures should 
be  established  to  set  single  frequency  and  submission  dates  of  periodic  safety 
update  reports  for  all  products  containing  the  same  active  substance  or 
combination thereof.  

(24)  Following  a  single  assessment  of  periodic  safety  update  reports,  any  resulting 
measures  as  regards  the  maintenance,  variation,  suspension  or  revocation  of  the 
marketing  authorisations  concerned  should  be  adopted  through  a  Community 
procedure leading to a harmonised result.  

(25)  The  Member  States  should  automatically  submit  certain  safety  issues  related  to 
medicinal products to the Agency thereby triggering a Community assessment of 
the  issue.  Therefore  it  is  appropriate  to  establish  rules  to  ensure  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. As this procedure is triggered on the basis of a set of binding criteria, 
it  should  take  precedence  over  other  procedures  which  could  also  be  used  to 
address safety issues, such as those referred to in Articles 31 and 36 of Directive 
2001/83/EC.  

(26) 

It  is  necessary  to  introduce  harmonised  guiding  principles  and  regulatory 
supervision  of  post-authorisation  safety  studies  that  are  non-interventional,  that 
are  initiated,  managed  or  financed  by  the  marketing  authorisation  holder,  that 
involve the collection of data from patients or healthcare professionals thus falling 
outside the scope of Directive 2001/20/EC of the European Parliament and of the 
Council  of  4 April 2001  on  the  approximation  of  the  laws,  regulations  and 
administrative provisions of the Member States relating to the implementation of 
good  clinical  practice  in  the  conduct  of  clinical  trials  on  medicinal  products  for 
human  use13.  Supervision  of  such  studies  should  be  the  responsibility  of  the 
national competent authority for studies to be conducted in one Member State and 
of the Pharmacovigilance Risk Assessment Advisory Committee for studies to be 
conducted in more than one Member State. Provision should also be made for the 
subsequent  follow-up,  if  appropriate,  as  regards  the  terms  of  the  marketing 

13 

OJ L 121, 1.5.2001, p. 34.  

EN 

14 

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(27) 

(28) 

(29 

authorisations  with  a  view  to  the  adoption  of  harmonised  measures  across  the 
Community.  

In order to enforce the provisions related to the pharmacovigilance, the Member 
States  should  ensure  that  effective,  proportionate  and  dissuasive  penalties  are 
applied 
for  non-compliance  with 
pharmacovigilance obligations. 

to  marketing  authorisation  holders 

In  order  to  protect  public  health,  there  should  be  adequate  funding  of  activities 
related  to  pharmacovigilance  by  the  national  competent  authorities.  It  should  be 
possible to ensure adequate funding for pharmacovigilance activities through the 
collection of fees. However, the management of those collected funds should be 
under  the  permanent  control  of  the  national  competent  authorities  in  order  to 
guarantee their independence. 

It  should  be  possible  for  Member  States  to  allow,  under  certain  conditions,  to 
deviate  from  certain  provisions  of  Directive  2001/83/EC  related  to  the 
requirements  for  labelling  and  packaging  in  order  to  address  severe  availability 
problems related to the potential lack of authorised products or of products placed 
on the market or shortages thereof. 

(30)  Since the objective of this directive of improving the safety of medicines placed 
on the market in the Community in a harmonised way across the Member States 
cannot be sufficiently achieved by the Member States and can be better achieved 
at Community level, the Community may adopt measures, in accordance with the 
principle of subsidiarity as set out in Article 5 of the Treaty. In accordance with 
the principle of proportionality, as set out in that Article, this directive does not go 
beyond what is necessary in order to achieve this objective. 

(31)  The  provisions  on  the  surveillance  of  medicinal  products  for  human  use  in 
Directive  2001/83/EC  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 339/9314. 

(32)  Directive 2001/83/EC should therefore be amended accordingly, 

14 

OJ L 218, 13.8.2008, p. 30. 

EN 

15 

   EN 

                                                 
HAVE ADOPTED THIS DIRECTIVE: 

Article 1 
Amendments to Directive 2001/83/EC 

Directive 2001/83/EC is amended as follows: 

1. 

Article 1 is amended as follows: 

(a) 

point 11 is replaced by the following: 

“(11)  Adverse  reaction:  A  response  to  a  medicinal  product  which  is  noxious  and 
unintended.”; 

(b)  point 14 is replaced by the following: 

“(14)  Suspected  adverse  reaction:  An  adverse  reaction  in  respect  of  which  a  causal 
relationship between the event and the medicinal product cannot be excluded.”; 

(c) 

point 15 is replaced by the following: 

“(15)  Post-authorisation safety  study:  Any  study  with  an  authorised  medicinal  product 
conducted  with  the  aim  of  identifying,  characterising  or  quantifying  a  safety  hazard, 
confirming the safety profile of the medicinal product, or of measuring the effectiveness 
of risk management measures.”; 

(d)  The following points 28b, 28c and 28d are inserted: 

“(28b) Risk management system: a set of pharmacovigilance activities and interventions 
designed  to  identify,  characterise,  prevent  or  minimise  risks  relating  to  a  medicinal 
product, including the assessment of the effectiveness of those interventions. 

(28c)  Pharmacovigilance  system:  a  system  utilized  by  marketing  authorisation  holders 
and  by  Member  States  to  fulfil  the  tasks  and  responsibilities  listed  in  Title  IX  and 
designed to monitor the safety of authorised medicinal products and detect any change to 
their risk-benefit balance. 

(28d)  Pharmacovigilance  system  master 
the 
pharmacovigilance system utilized by the marketing authorisation holder with respect to 
one or more authorised medicinal products.” 

file:  A  detailed  description  of 

2. 

Article 8(3) is amended as follows: 

(a) 

point (ia) is replaced by the following: 

EN 

16 

   EN 

“(ia)  A summary of the applicant's pharmacovigilance system which shall include the 
following elements:  

− 

− 

− 

− 

− 

proof that the applicant has the services of a qualified person responsible 
for pharmacovigilance; 

the Member State where the qualified person resides;  

the contact details for the qualified person;  

a statement signed by the applicant to the effect that the applicant has the 
necessary means to fulfil the tasks and responsibilities listed in Title IX;  

a reference to the site where the pharmacovigilance system master file for 
the medicinal product is maintained.”; 

(b) 

the following point (iaa) is inserted: 

“(iaa)  A  detailed  description  of  the  risk-management  system  which  the  applicant  will 
introduce for the medicinal product concerned.” 

(c) 

point (l) is replaced by the following: 

“(l)  Copies of the following: 

− 

− 

any authorisation obtained in another Member State, including a summary 
of  the  data  contained  in  periodic  safety  reports  and  adverse  reactions 
reports, or in a third country to place the medicinal product on the market, 
together  with  a  list  of  those  Member  States  in  which  an  application  for 
authorisation  submitted  in  accordance  with  this  Directive  is  under 
examination; 

copies  of  the  summary  of  the  product  characteristics  proposed  by  the 
applicant  in  accordance  with  Article  11  or  approved  by  the  competent 
authorities of the Member State in accordance with Article 21. Copies of 
the package leaflet proposed in accordance with Article 59 or approved by 
the competent authorities of the Member State in accordance with Article 
61. 

− 

details of any decision to refuse authorization, whether in the Community 
or in a third country, and the reasons for such a decision.” 

(d)  point (n) is deleted. 

(e) 

the following subparagraphs are added: 

EN 

17 

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“The risk management system referred to in point (iaa) of the first subparagraph shall be 
proportionate to the identified risks and the potential risks of the medicinal product, and 
the need for post-authorisation safety data. 

The  information  referred  to  in  point  (l)  of  the  first  subparagraph  shall  be  updated  on  a 
regular basis.” 

3. 

Article 11 is amended as follows: 

(a) 

the following point 3a is inserted: 

“(3a)  a summary of the essential information necessary to use the medicine safely and 
effectively;  

(b) 

the following subparagraph is added: 

“For the purposes of point (3a) of the first subparagraph, for medicinal products included 
on the list referred to in Article 23 of Regulation (EC) No 726/2004, the summary shall 
include  the  statement:  “This  medicinal  product  is  under  intensive  monitoring.  All 
suspected adverse reactions should be reported to <name and web-address of the national 
competent authority>.” 

4. 

Article 16g(1) is replaced by the following: 

“1. Articles 3(1) and (2), 4(4), 6(1), 12, 17(1), 19, 20, 23, 24, 25, 40 to 52, 70 to 85, 101 
to  108b,  111(1)  and  (3),  112,  116,  117,  118,  122,  123,  125,  126,  second  subparagraph, 
and 127 of this Directive as well as Commission Directive 2003/94/EC(*) shall apply, by 
analogy, to traditional-use registration granted under this Chapter. 

___________________ 
(*) OJ L 262, 14.10.2003, p. 22.” 

5. 

Article 17 is amended as follows: 

(a) 

In the second subparagraph of paragraph 1, the figure ‘27’ is replaced by 
the figure ‘28’; 

(b) 

In paragraph 2, the figure ‘27’ is replaced by the figure ‘28’; 

In Article 18, the figure ‘27’ is replaced by the figure ‘28’. 

In Article 21, paragraphs 3 and 4 are replaced by the following: 

“3. 
the  marketing  authorisation 

The  national  competent  authorities  shall  make  publicly  available  without 
the  product 

the  summary  of 

together  with 

6. 

7. 

delay 

EN 

18 

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characteristics  and  any  conditions  established  in  accordance  with  Articles  21a,  22  and 
22a,  together  with  any  deadlines  for  their  fulfilment,  for  each  medicinal  product  which 
they have authorised. 

4. 

The national competent authorities shall draw up an assessment report and 
comments on the file  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. The assessment report shall be updated whenever new 
information becomes available which is of importance for the evaluation of the quality, 
safety or efficacy of the medicinal product concerned. 

The  national  competent  authorities  shall  make  publicly  accessible  without  delay  the 
assessment  report,  together  with  the  reasons  for  their  opinion,  after  deletion  of  any 
information  of  a  commercially  confidential  nature.  The  justification  shall  be  provided 
separately for each indication applied for.” 

8. 

The following Article 21a is inserted: 

“Article 21a 

A  marketing  authorisation  may  be  granted  subject  to  one  or  more  of  the  following 
conditions:  

(1) 

to  take  certain  measures  for  the  safe  use  of  the  medicinal  product 
contained in the risk management system; 

(2) 

to conduct post-authorisation safety studies; 

(3) 

(4) 

to  comply  with  requirements  on  adverse  reaction  recording  or  reporting 
which are stricter than those referred to in Title IX; 

any  other  conditions  or  restrictions  with  regard  to  the  safe  and  effective 
use of the medicinal product. 

The marketing authorisation shall lay down deadlines for the fulfilment of the conditions 
where necessary. “ 

9. 

Article 22 is replaced by the following:  

“Article 22 

In  exceptional  circumstances  and  following  consultation  with  the  applicant,  the 
authorisation  may  be  granted  subject  to  a  requirement  for  the  applicant  to  meet  certain 

EN 

19 

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conditions, in particular concerning the safety of the medicinal product, notification to the 
national 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. 

Continuation  of  the  authorisation  shall  be  linked  to  the  annual  reassessment  of  these 
conditions.” 

EN 

20 

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10. 

The following Articles 22a and 22b are inserted: 

“Article 22a 

1. After the granting of a marketing authorisation, the national competent authority may 
require  a  marketing  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 national competent authority 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.  

3.  On  the  basis  of  explanations  submitted  by  the  marketing  authorisation  holder,  the 
national  competent  authority  shall  withdraw  or  confirm  the  requirement.  Where  the 
national competent authority 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. 

Article 22b 

1. The marketing authorisation holder shall be required to incorporate any conditions or 
requirements referred to in Articles 21a, 22 or 22a in his risk management system. 

2. The Member States shall inform the Agency of the marketing authorisations that they 
have granted subject to conditions or requirements pursuant to Articles 21a, 22 or 22a.  

The  Agency  shall  include  the  medicinal  products  concerned  in  the  list  referred  to  in 
Article  23  of  Regulation  (EC)  No  726/2004.  The  Agency  shall  remove  a  medicinal 
product from the list when the national competent authority concludes that the conditions 
or  requirements  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.” 

11. 

Article 23 is replaced by the following: 

“Article 23 

1. 

After an authorisation has been granted, the marketing authorisation holder shall, 
in  respect  of  the  methods  of  manufacture  and  control  provided  for  in  Article 

EN 

21 

   EN 

8(3)(d) and (h), 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. 

Those changes shall be subject to the approval of the competent authority of the 
Member State concerned.  

2. 

The  marketing  authorisation  holder  shall  forthwith  supply  to  the  national 
competent authority 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), or Annex I. 

In particular, he shall forthwith inform the national competent authority 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. 

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  of 
Regulation (EC) No 726/2004. 

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

The  national  competent  authority  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.” 

3. 

4. 

12. 

Article 24 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  national  competent 
authority 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 Title IX, and all variations introduced since 

EN 

22 

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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: 

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

13. 

14. 

The title "Chapter 4 Mutual recognition and decentralised procedure" is deleted. 

Article 27 is amended as follows: 

(a)  Paragraph 1 is replaced by the following: 

“1. A coordination group shall be set up for the following purposes: 

(a) the examination of any question relating to a marketing authorisation of a medicinal 
product in two or more Member States in accordance with the procedures laid down in 
Chapter 4; 

(b) the examination of questions related to the pharmacovigilance of medicinal products 
authorised by the Member States, in accordance with Articles 107c, 107e, 107g, 107l and 
107r; 

(c)  the  examination  of  questions  related  to  the  variations  to  the  terms  of  marketing 
authorisations granted by the Member States, in accordance with Article 35(1). 

The Agency shall provide the secretariat of this coordination group. 

For the fulfilment of its pharmacovigilance tasks, the coordination group shall be assisted 
by  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee  referred  to  in  Article 
56(1)(aa) of Regulation (EC) No 726/2004.” 

(b) 

In paragraph 2, the following subparagraphs are added: 

“Members  of  the  coordination  group  and  experts  shall,  for  the  fulfilment  of  their  tasks, 
rely  on  the  scientific  and  regulatory  resources  available  to  national  marketing 
authorisation  bodies.  Each  national  competent  authority  shall  monitor  the  level  of 
expertise  of  the  evaluations  carried  out  and  facilitate  the  activities  of  nominated 
coordination group members and experts. 

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Article  63  of  Regulation  (EC)  No  726/2004  shall  apply  to  the  coordination  group  as 
regards the transparency and independence of its members.” 

(c)  The following paragraphs 4, 5, 6 and 7 are added: 

The Executive Director of the Agency or his representative and representatives of 

“4. 
the Commission shall be entitled to attend all meetings of the coordination group. 

5. 
The  members  of  the  coordination  group  shall  ensure  that  there  is  appropriate 
coordination  between  the  tasks  of  that  group  and  the  work  of  national  competent 
authorities, including the consultative bodies concerned with the marketing authorisation. 

6. 
Save where otherwise provided for in this Directive, the coordination group shall 
use  its  best  endeavours  to  take  decisions  by  consensus.  If  such  a  consensus  cannot  be 
reached, the position of the majority of members shall prevail. 

7. 
Members of the coordination group shall be required, even after their duties have 
ceased, not to disclose information of the kind covered by the obligation of professional 
secrecy.” 

15. 

After Article 27 the following is inserted: 

“Chapter 4 Mutual recognition and decentralised procedure" 

16. 

Article 31(1) is amended as follows:  

(a) 

the first subparagraph is replaced by the following: 

“The Member States or the Commission or the applicant or the marketing authorisation 
holder  shall,  in  specific  cases  where  the  interests  of  the  Community  are  involved,  refer 
the matter to the Committee for application of the procedure laid down in Articles 32, 33 
and 34 before any decision is reached on a request for a marketing authorisation or on the 
suspension or revocation of an authorisation, or on any other variation to the terms of a 
marketing authorisation which appears necessary.” 

(b) 

the following subparagraph is inserted after the first subparagraph: 

“However,  where  one  of  the  criteria  listed  in  Article  107i(1)  is  met,  the  procedure  laid 
down in Articles 107i to 107l shall apply.” 

17. 

In Article 36(1) the following subparagraph is added: 

“However,  where  one  of  the  criteria  listed  in  Article  107i(1)  is  met,  the  procedure  laid 
down in Articles 107i to 107l shall apply.” 

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18. 

Article 59(1) is amended as follows: 

(a) 

the following point (aa) is inserted: 

“(aa)  a summary of the essential information necessary to use the medicine safely and 
effectively;”  

(b) 

the following second and third subparagraphs are added: 

“The information referred to in point (aa) of the first subparagraph shall be presented in a 
box surrounded by a black border. Any new or amended text shall for a period of 1-year 
be  presented  in  bold  text  and  preceded  by  the  following  symbol   and  text  "New 
information".  

For medicinal products included on the list referred to in Article 23 of Regulation (EC) 
No  726/2004,  the  following  additional  statement  shall  be  included  “This  medicinal 
product is under intensive monitoring. All suspected adverse reactions should be reported 
to <name and web-address of the national competent authority>".” 

19. 

Article 63(3) is replaced by the following: 

‘3. When the product is not intended to be delivered directly to the patient, or when the 
product  is  necessary  to  address  severe  availability  problems,  the  competent  authorities 
may,  subject  to  measures  they  consider  necessary  to  safeguard  human  health,  grant  an 
exemption to the obligation that certain particulars should appear on the labelling and in 
the package leaflet and that the leaflet must be in the official language or languages of the 
Member State in which the product is placed on the market.’ 

20. 

In Article 65, the following point (g) is added: 

“(g) the summary of the essential information necessary to use the medicine safely and 
effectively provided for in Article 11(3a) and Article 59(1)(aa).” 

21. 

Title IX is replaced by the following: 

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“TITLE IX 
PHARMACOVIGILANCE 

CHAPTER 1 
General provisions 

Article 101 

1.  Member  States  shall  operate  a  pharmacovigilance  system  for  the  fulfilment  of  their 
pharmacovigilance  tasks  and  their  participation  in  Community  pharmacovigilance 
activities.  

The  pharmacovigilance  system  shall  be  used  to  collect  information  on  the  risks  of 
medicinal  products  as  regards  patients'  or  public  health.  That  information  shall 
particularly  refer  to  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.  Member  States  shall  by  means  of  the  pharmacovigilance  system  referred  to  in 
paragraph 1 evaluate all information scientifically, consider options for risk minimisation 
and  prevention  and  take  regulatory  action  as  necessary.  They  shall  perform  a  regular 
audit  of  their  pharmacovigilance  system  and  report  the  results  to  the  Commission  on 
[insert concrete date - two-years after the date of transposition referred to in Article 3(1)] 
at the latest and then every two years thereafter. 

3.  Each  Member  State  shall  designate  a  competent  authority  for  the  conduct  of 
pharmacovigilance tasks. 

4. The Commission may request Member States to participate, under the coordination of 
the Agency, in international harmonization and standardization of technical measures in 
pharmacovigilance.  

The Member States shall:  

Article 102  

(1) 

take all appropriate measures to encourage doctors, pharmacists and other 
health-care  professionals  to  report  suspected  adverse  reactions  to  the 
national competent authority or the marketing authorisation holder; 

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(2) 

(3) 

ensure that adverse reaction reports contain the highest quality information 
possible;  

through  the  methods  of  collecting  information  and  where  necessary 
through  the  follow  up  of  adverse  reaction  reports,  ensure  that  any 
biological  medicinal  product  prescribed,  dispensed,  or  sold  in  their 
territory which is the subject of an adverse reaction report is identifiable; 

(4) 

take  the  necessary  measures  to  ensure  that  a  marketing  authorisation 
holder  who  fails  to  discharge  the  obligations  laid  down  in  this  Title  is 
subject to effective, proportionate and dissuasive penalties. 

For  the  purposes  of  point  (1)  of  the  first  paragraph  the  Member  States  may  impose 
specific  requirements  on  doctors,  pharmacists  and  other  health-care  professionals  in 
respect of the reporting of suspected serious or unexpected adverse reactions. 

Article 103  

A Member State may delegate any of the tasks entrusted to it under this Title to another 
Member State subject to a written agreement of the latter. 

The  delegating  Member  State  shall  inform  the  Commission,  the  Agency  and  all  other 
Member  States  of  the  delegation  in  writing.  The  delegating  Member  State  and  the 
Agency shall make that information public. 

Article 104 

1.  The  marketing  authorisation  holder  shall  be  required  to  operate  a  pharmacovigilance 
system for the fulfilment of his pharmacovigilance tasks equivalent to the system under 
Article 101(1).  

2.  The  marketing  authorisation  holder  shall  by  means  of  the  system  referred  to  in 
paragraph 1 evaluate all information scientifically, consider options for risk minimisation 
and prevention and take appropriate measures as necessary. 

The  marketing  authorisation  holder  shall  be  required  to  perform  a  regular  audit  of  his 
pharmacovigilance  system.  He  shall  place  a  note  concerning  the  main  findings  of  the 
audit  on  the  pharmacovigilance  system  master  file  and,  based  on  the  audit  findings, 
ensure that an appropriate corrective action plan is prepared and followed. 

3. As part of the pharmacovigilance system, the marketing authorisation holder shall be 
required to:  

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(a) 

have  permanently  and  continuously  at  his  disposal  an  appropriately 
qualified person responsible for pharmacovigilance; 

(b)  maintain  and  make  available  on  request  a  pharmacovigilance  system 

master file; 

(c) 

operate a risk management system for each medicinal product; 

(d)  monitor the outcome of risk minimization measures which are contained in 
the  risk  management  plan  or  which  are  laid  down  as  conditions  or 
requirements in the marketing authorisation pursuant to Articles 21a, 22 or 
22a; 

(e) 

to 

the 

assess  updates 
system  and  monitor 
pharmacovigilance  data  to  determine  whether  there  are  new  or  changed 
risks or whether there are changes to the benefit-risk balance of medicinal 
products. 

risk  management 

The qualified person referred to in point (a) of the first subparagraph shall reside in the 
Community  and  shall  be  responsible  for  the  establishment  and  maintenance  of  the 
pharmacovigilance system. The marketing authorisation holder shall submit the name and 
contact details of the qualified person to the competent authority and the Agency. 

Article 104a 

1. 

2. 

By  way  of  derogation  from  point  (c)  of  Article  104(3),  holders  of  marketing 
authorisations  granted  before  [insert  concrete  date  -  date  set  out  in  the  second 
subparagraph of Article 3(1) of Directive …/…/EC] shall be required to operate 
a  risk  management  system  only  if  paragraphs  2,  3  and  4  of  this  Article  are 
complied with.  

The national competent authority may require a marketing authorisation holder 
to  operate  a  risk  management  system,  as  referred  to  in  point  (c)  of  Article 
104(3), if there are concerns about the risks affecting the risk-benefit balance of 
an authorised medicinal product. To this effect, the national competent authority 
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. 

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  national  competent  authority  shall  provide  the  marketing  authorisation 
holder with an opportunity to present explanations on the requirement within a 

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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  national  competent  authority  shall  withdraw  or  confirm  the  requirement. 
Where the national competent authority confirms the requirement, the marketing 
authorisation  shall  be  varied  as  appropriate  to  include  measures  of  the  risk 
management  system as conditions of the marketing authorisation as referred  to 
in point 1 of Article 21a. 

Article 105 

The management of funds intended for activities connected with pharmacovigilance, the 
operation  of  communication  networks  and  market  surveillance  shall  be  under  the 
permanent  control  of  the  national  competent  authorities  in  order  to  guarantee  their 
independence. 

The  first  paragraph  shall  not  preclude  the  collection  of  fees  to  be  paid  by  marketing 
authorisation  holders  for  the  carrying  out  of  those  activities  by  the  national  competent 
authorities. 

CHAPTER 2 
Transparency and communications 

Article 106 

Each  Member  State  shall  set  up  and  maintain  a  national  medicines  safety  web-portal 
which  shall  be  linked  to  the  European  medicines  safety  web-portal  established  in 
accordance with Article 26 of  Regulation  (EC)  No  726/2004. By  means  of  the  national 
medicines safety web-portals, the Member States shall make public at least the following: 

(1) 

(2) 

(3) 

risk  management  systems  for  medicinal  products  authorised 
accordance with this Directive; 

in 

the  list  of  medicinal  products  under  intensive  monitoring  referred  to  in 
Article 23 of Regulation (EC) No 726/2004; 

web-based  structured  forms  for  the  reporting  of  suspected  adverse 
reactions  by  healthcare  professionals  and  patients  based  on  the  forms 
referred to in Article 25 of Regulation (EC) No 726/2004. 

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Article 106a 

1.  As  soon  as  the  marketing  authorisation  holder  has  the  intention  to  make  a  public 
announcement  relating  to  information  on  pharmacovigilance  concerns  to  the  use  of  a 
product, and in any event before the public announcement is made, he shall be required to 
inform the Member State competent authorities, the Agency and the Commission. 

The  marketing  authorisation  holder  shall  be  required  to  ensure  that  information  to  the 
public is presented objectively and is not misleading.  

2.  Unless  urgent  public  announcements  are  required  for  the  protection  of  public  health, 
the Member States, the Agency and the Commission shall inform each other not less than 
twenty-four  hours  prior  to  a  public  announcement  relating  to  information  on 
pharmacovigilance concerns.  

3.  For  active  substances  contained  in  medicinal  products  authorised  in  more  than  one 
Member  State,  the  Agency  shall  be  responsible  for  the  coordination  between  national 
competent  authorities  of  safety  announcements  and  shall  provide  timetables  for  the 
information being made public. 

Under  the  coordination  of  the  Agency,  the  Member  States  shall  make  all  reasonable 
efforts to agree on common safety messages and the timetables for their distribution. The 
Pharmacovigilance  Risk  Assessment  Advisory  Committee  shall,  at  the  request  of  the 
Agency, provide advice on those safety announcements. 

4.  When  the  Agency  or  national  competent  authorities  make  information  referred  to  in 
paragraphs  2  and  3  public,  any  information  of  a  personal  or  commercially  confidential 
nature  shall  be  deleted  unless  its  public  disclosure  is  necessary  for  the  protection  of 
public health. 

CHAPTER 3 
Recording, reporting and assessment of pharmacovigilance data 

Section 1 
Recording and reporting of adverse reactions 

Article 107 

1.  Marketing  authorisation  holders  shall  be  required  to  record  all  suspected  adverse 
reactions  in  the  Community  or  in  third  countries  which  are  brought  to  their  attention, 

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whether reported spontaneously by patients or healthcare professionals or occurring in the 
context of a post-authorisation safety study.  

Marketing  authorisation  holders  shall  be  required  to  ensure  that  those  reports  are 
accessible at a single point within the Community. 

By way of derogation to the first subparagraph, suspected adverse reactions occurring in 
the context of a clinical trial shall be recorded and reported in accordance with Directive 
2001/20/EC. 

2.  The  marketing  authorisation  holder  may  not  refuse  reports  of  suspected  adverse 
reactions received electronically from patients and health-care professionals.  

3.  Marketing  authorisation  holders  shall  be  required  to  submit  electronically  to  the 
database  and  data-processing  network  referred  to  in  Article  24  of  Regulation  (EC)  No 
726/2004  (hereinafter  referred  to  as  ‘the  Eudravigilance  database’)  information  on  all 
serious  suspected  adverse  reactions  that  occur  in  the  Community  and  in  third  countries 
within 15 days following the receipt of the report or, in the absence of a report, following 
the day on which the holder concerned gained knowledge of the event. 

Marketing  authorisation  holders  shall  be  required  to  submit  electronically  to  the 
Eudravigilance database information on all non-serious suspected adverse reactions that 
occur  in  the  Community,  within  90  days  following  the  receipt  of  the  report  or,  in  the 
absence of a report, following the day on which the holder concerned gained knowledge 
of the event.  

For  medicinal  products  containing  the  active  substances  referred  to  in  the  list  of 
publications  monitored  by  the  Agency  pursuant  to  Article  27  of  Regulation  (EC)  No 
726/2004,  marketing  authorisation  holders  shall  not  be  required  to  report  to  the 
Eudravigilance  database  the  suspected  adverse  reactions  recorded  in  the  listed  medical 
literature,  but  they  shall  monitor  all  other  medical  literature  and  report  any  suspected 
adverse reactions. 

4.  Member  States  shall  access  reports  on  adverse  reactions  through  the  Eudravigilance 
database  and  shall  assess  the  quality  of  the  data  received  from  marketing  authorisation 
holders. They shall, as appropriate, involve patients and health-care professionals in the 
follow  up  of  any  reports  they  receive  and  request  follow  up  of  such  reports  to  be 
conducted  by  the  marketing  authorisation  holders.  The  marketing  authorisation  holders 
shall  be  required  to  report  any  follow  up  information  received  to  the  Eudravigilance 
database. 

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Article 107a 

1.  The  Member  States  shall  record  all  suspected  adverse  reactions  that  occur  in  their 
territory which are brought to their attention from healthcare professionals and patients. 

Member States shall ensure that reports of such reactions are submitted by means of the 
national medicines safety web-portals. 

2. Member States shall, within 15 days following the receipt of the reports referred to in 
paragraph 1, submit the reports electronically to the Eudravigilance database.  

Marketing  authorisation  holders  shall  access  those  reports  through  the  Eudravigilance 
database. 

3.  The  Member  States  shall  ensure  that  reports  of  medication  errors  brought  to  their 
attention in the framework of suspected adverse reaction reporting for medicinal products 
are made available to the Eudravigilance database and to any authorities responsible for 
patient  safety  within  that  Member  State.  They  shall  also  ensure  that  the  authorities 
responsible  for  medicinal  products  within  that  Member  State  are  informed  of  any 
suspected  adverse  reactions  brought  to  the  attention  of  the  authorities  responsible  for 
patient safety within that Member State.  

Section 2 
Periodic safety update reports 

Article 107b 

Marketing  authorisation  holders  shall  be  required  to  submit  to  the  Agency 

1. 
periodic safety update reports containing: 

(a) 

summaries  of  data  relevant  to  the  benefits  and  risks  of  the  medicinal 
product; 

(b) 

a scientific evaluation of the risk-benefit balance of the medicinal product; 

(c) 

all  data  relating  to  the  volume  of  sales  of  the  medicinal  product  and  any 
data  in  possession  of  the  marketing  authorisation  holder  relating  to  the 
volume of prescriptions. 

The evaluation referred to in point (b) shall be based on all available data, including data 
from clinical trials in unauthorised indications and populations. 

The periodic safety update reports shall be submitted electronically. 

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The  Agency  shall  distribute  the  reports  referred  to  in  paragraph  1  to  the 
2. 
Pharmacovigilance Risk Assessment Advisory Committee, the Committee for Medicinal 
Products for Human Use and the coordination group. 

By  way  of  derogation  from  paragraph  1  of  this  Article,  holders  of  marketing 
3. 
authorisations for medicinal products referred to in Articles 10, 10a or 10c, and holders of 
registrations for medicinal products referred to in Articles 14 or 16a, shall be required to 
submit periodic safety update reports for such products only in the following cases: 

(a)  where such obligation has been laid down as a condition in the marketing 

authorisation in accordance with Article 21a or Article 22; or  

(b)  where  a  Community  reference  date  and  the  corresponding  frequency  of 
submission  of  periodic  safety  update  reports  have  been  determined  in 
accordance  with  paragraphs  3  and  4  of  Article  107c,  subject  to  the 
conditions laid down in Article 107c(5). 

Article 107c 

1. The frequency of submission of the periodic safety update reports shall be specified in 
the marketing authorisation.  

It shall be counted from the date of the authorisation. 

2. Holders of marketing authorisations which were granted before [insert concrete date - 
date set out in the second subparagraph of Article 3(1)], and for which the frequency and 
dates of submission of the periodic safety update reports are not laid down as a condition 
to  the  marketing  authorisation,  shall  submit  the  periodic  safety  update  reports  in 
accordance  with  the  second  subparagraph  of  this  paragraph  until  another  frequency  or 
other dates of submission of the reports are laid down in the marketing authorisation or 
determined in accordance with paragraphs 3, 4, 5 or 6..  

Periodic  safety  update  reports  shall  be  submitted  to  the  competent  authorities 
immediately upon request or in accordance with the following: 

(a)  where a product has not yet been placed on the market, at least every six 

months after authorisation and until the placing on the market; 

(b)  where a product has been placed on the market, at least every six months 
during the first two years following the initial placing on the market, once 
a year for the following two years and at three-yearly intervals thereafter. 

3. Where products that are subject to different marketing authorisations contain the same 
active  substance  or  combination  thereof,  the  frequency  and  dates  of  submission  of  the 
periodic safety update reports resulting from the application of paragraphs 1 and 2 may 

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be amended to provide for a single frequency for the submission of the reports relating to 
all  such  products  and  to  provide  for  a  Community  reference  date  from  which  the 
frequency is counted.  

This single frequency for the submission of the reports and the Community reference date 
may  be  determined,  after  consultation  of  the  Pharmacovigilance  Risk  Assessment 
Advisory Committee, by one of the following: 

(a) 

the Committee for Medicinal Products for Human Use, where at least one 
of  the  marketing  authorisations  for the  medicinal  products  containing  the 
active  substance  concerned  has  been  granted  in  accordance  with  the 
procedure of Regulation (EC) No 726/2004; 

(b) 

the coordination group, in other cases than those referred to in point (a). 

4. For the purposes of paragraph 3, the Community reference date for products containing 
the same active substance or combination thereof shall be one of the following: 

(a) 

(b) 

the date of the first authorisation in the Community of a medicinal product 
containing that active substance or combination; 

if the date referred to in point (a) cannot be ascertained, the earliest of the 
known  dates  of  the  marketing  authorisations  for  medicinal  product 
containing that active substance or combination. 

5.  When  establishing  Community  reference  dates  and  the  frequency  of  submission  of 
periodic safety update reports, or subsequently, the Committee for Medicinal Products for 
Human  Use  or  the  coordination  group,  as  appropriate,  may  require  that  periodic  safety 
update  reports  are  also  submitted  for  medicinal  products  referred  to  in  Article  107b(3), 
under the following conditions: 

(a) 

the  obligation  to  submit  the  reports  shall  apply  for  a  specific  period 
determined  by  the  Committee  or  the  coordination  group,  as  appropriate; 
and 

(b) 

the  obligation  shall  be  based  on  one  of  the  following  grounds  relating  to 
the protection or promotion of public health: 

(i) 

evidence is available that product information relating to the safe use 
of the medicinal products concerned is out of date;  

(ii) 

a  need  to  update  warnings  in  product  information  based  on  new 
information has been identified. 

6. Marketing authorisation holders shall be allowed to submit requests to the Committee 
for  Medicinal  Products  for  Human  Use  or  the  coordination  group,  as  appropriate,  to 

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determine Community reference dates or to change the frequency of submission periodic 
safety update reports on one of the following grounds:  

(a) 

for reasons related to public health;  

(b) 

in order to avoid duplication of assessment; 

(c) 

in order to achieve international harmonisation. 

Such requests shall be submitted in writing and shall be duly justified. 

7. The Agency shall make public a list of Community reference dates and frequency of 
submission of periodic safety update reports by means of the European medicines safety 
web-portal.  

Any  change  to  the  dates  of  submission  and  frequency  of  periodic  safety  update  reports 
specified in the marketing authorisation as a result of the application of paragraphs 3, 4, 5 
and 6 shall take effect six months after the date of such publication. 

Article 107d 

The  national  competent  authorities  shall  assess  periodic  safety  update  reports  to 
determine whether there are new or changed risks or whether there are changes to the risk 
benefit balance of medicinal products. 

Article 107e 

1. A single assessment of periodic safety update reports shall be performed for medicinal 
products authorised in more than one Member State and, in the cases of paragraphs 3 to 6 
of  Article  107c,  for  all  medicinal  products  containing  the  same  active  substance  or 
combination  thereof  and  for  which  a  Community  reference  date  and  frequency  of 
periodic safety update reports has been established.  

The assessment shall be conducted by either of the following: 

(a) 

(b) 

a  Member  State  appointed  by  the  coordination  group  where  none  of  the 
marketing  authorisations  concerned  has  been  granted  in  accordance  with 
the procedure of Regulation (EC) No 726/2004;  

a  rapporteur  appointed  by  the  Pharmacovigilance  Risk  Assessment 
Advisory  Committee,  where  at  least  one  of  the  marketing  authorisations 
concerned  has  been  granted  in  accordance  with  the  procedure  of 
Regulation (EC) No 726/2004. 

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When  selecting  the  Member  State  in  accordance  with  point  (a)  of  the  second 
subparagraph, the coordination group shall take into account whether any Member State 
is acting as a reference Member State, in accordance with Article 28(1). 

2.  The  Member  State  or  rapporteur,  as  appropriate,  shall  prepare  an  assessment  report 
within 90 days of receipt of the periodic safety update report and send it to the marketing 
authorisation holder and the Pharmacovigilance Risk Assessment Advisory Committee. 

Within  30  days  of  receipt  of  the  assessment  report,  the  marketing  authorisation  holder 
may submit comments to the Agency. The Agency shall make such comments available 
to  the  Member  State  or  rapporteur  and  to  the  Pharmacovigilance  Risk  Assessment 
Advisory Committee. 

3.  At  its  next  meeting  following  the  end  of  the  period  for  comments  by  the  marketing 
authorisation holder referred to in paragraph 2, the Pharmacovigilance Risk Assessment 
Advisory  Committee  shall  adopt  the  assessment  report  with  or  without  changes,  taking 
into account any comments submitted in accordance with that paragraph. 

Article 107f 

Following  the  assessment  of  periodic  safety  update  reports,  the  national  competent 
authorities  shall  consider  whether  any  action  concerning  the  terms  of  the  marketing 
authorisation for the medicinal product concerned is necessary. 

They shall maintain, vary, suspend or revoke the marketing authorisation as appropriate. 

Article 107g 

1.  In  the  case  of  a  single  assessment  of  periodic  safety  update  reports  concerning  more 
than  one  marketing  authorisation  in  accordance  with  Article  107e(1)  which  does  not 
include  any  marketing  authorisation  granted  in  accordance  with  Regulation  (EC)  No 
726/2004,  the  coordination  group  shall,  within  30  days  of  receipt  of  the  report  of  the 
Pharmacovigilance Risk Assessment Advisory Committee, consider the report and adopt 
an  opinion  on  the  maintenance,  variation,  suspension  or  revocation  of  the  marketing 
authorisations concerned, including a timetable for the implementation of the opinion.  

2. If the opinion of the coordination group is adopted by consensus, the chairman shall 
record  the  agreement  and  inform  the  marketing  authorisation  holder  accordingly.  The 
Member  States  shall  maintain,  vary,  suspend  or  revoke  the  marketing  authorisations 
concerned as necessary to comply with the opinion within the determined time table for 
implementation, and they shall inform the Commission and the coordination group. 

EN 

36 

   EN 

If an opinion by consensus cannot be adopted, the majority opinion shall be forwarded to 
the Commission which shall apply the procedure laid down in Articles 33 and 34. 

3.  In  the  case  of  a  single  assessment  of  periodic  safety  update  reports  concerning  more 
than  one  marketing  authorisation  in  accordance  with  Article  107e(1)  which  includes  at 
least one marketing authorisation granted in accordance with the procedure of Regulation 
(EC) No 726/2004, the Committee for Medicinal Products for Human Use shall, within 
30  days  of  receipt  of  the  report  of  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee,  consider  the  report  and  adopt  an  opinion  on  the  maintenance,  variation, 
suspension or revocation of the marketing authorisations concerned.  

4. On the basis of the opinion of the Committee for Medicinal Products for Human Use 
referred to in paragraph 3, the Commission shall: 

(a) 

adopt a decision addressed to the Member States concerning the measures 
to be taken in respect of marketing authorisations granted by the Member 
States and concerned by the procedure under this section; and 

(b)  where  the  opinion  states  that  regulatory  action  is  necessary,  adopt  a 
decision to vary, suspend or revoke the marketing authorisations granted in 
accordance  with  Regulation  (EC)  No  726/2004  and  concerned  by  the 
procedure under this section.  

Articles 33 and 34 of this Directive shall apply to the adoption of the decision referred to 
in point (a) of the first subparagraph of this paragraph and to its implementation by the 
Member States.  

Article 10 of Regulation (EC) No 726/2004 shall apply to the decision referred to in point 
(b)  of  the  first  subparagraph  of  this  paragraph.  Where  the  Commission  adopts  such 
decision, it may also adopt a decision addressed to the Member States pursuant to Article 
127a of this Directive. 

Article 107h 

1. Regarding medicinal products authorised in accordance with this Directive, the Agency 
and national competent authorities shall take the following measures:  

(a)  monitor  the  outcome  of  risk  minimization  measures  contained  in  risk 
management  systems  and  of  conditions  or  requirements  referred  to  in 
Articles 21a, 22 or 22a;  

(b) 

assess updates to the risk management system; 

EN 

37 

   EN 

(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.  

Member  States  shall  ensure  that  the  marketing  authorisation  holders  also  take  the 
measures set out in points (a), (b) and (c). 

2. The Pharmacovigilance Risk Assessment Advisory Committee shall perform the initial 
scrutiny and prioritisation of indications of new or changing 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 Articles 107d to 107g. 

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

Member States shall ensure that marketing authorisation holders inform the Agency and 
national competent authorities in the event of new or changed risks or changes to the risk 
benefit balance being detected. 

Section 3 
Community procedure 

Article 107i 

1. A Member State shall initiate the procedure under this section, by informing the other 
Member States, the Agency and the Commission, in any of the following cases: 

(a) 

it considers suspending or revoking of a marketing authorisation; 

(b) 

it considers prohibiting the supply of a medicinal product;  

(c ) 

it considers refusing the renewal of a marketing authorisation; 

(d) 

it  is  informed  by  the  marketing  authorisation  holder  that,  on  the  basis  of 
safety  concerns,  he  has  interrupted  the  placing  on  the  market  of  a 
medicinal  product  or  withdrawn  a  marketing  authorisation,  or  that  he 
intends to do so; 

(e) 

it  considers  that  new  contraindications,  a  reduction  in  the  recommended 
dose, or a restriction to the indications is necessary; 

EN 

38 

   EN 

(f) 

it  has  conducted  a  pharmacovigilance  inspection  and  found  serious 
deficiencies. 

2. The information referred to in paragraph 1 may relate to individual medicinal products 
or to a range of medicinal products or a therapeutic class. 

If  the  Agency  identifies  that  the  issue  relates  to  more  medicinal  products  than  those 
which are covered by the information or that it is common to all products belonging to 
the  same  range  or  therapeutic  class,  it  shall  extend  the  scope  of  the  procedure 
accordingly. 

Where  the  scope  of  the  procedure  initiated  under  this  section  concerns  a  range  of 
products  or  therapeutic  class,  medicinal  products  authorised  in  accordance  with 
Regulation (EC) No 726/2004 which belong to that range or class shall also be included 
in the procedure.  

3. At the time of the information referred to in paragraph 1, the Member State shall make 
available  to  the  Agency  all  relevant  scientific  information  available  to  it  and  any 
assessment by the Member State. 

Article 107j 

1.  After  initiation  of  the  procedure  under  this  section,  where  urgent  action  to  protect 
public  health  is  necessary,  the  Member  State  concerned  may  suspend  the  marketing 
authorisation or prohibit the use of a medicinal product. It shall inform the Agency, the 
Commission and the other Member States not later than the following working day. 

2.  At  any  stage  of  the  procedure  under  this  section,  the  Commission  may  request  the 
Member  States  in  which  the  product  is  authorised  to  take  temporary  measures 
immediately. 

3. Where the scope of the procedure, as determined in accordance with Article 107i(2), 
concerns  a  range  of  products  or  therapeutic  class  which  includes  medicinal  products 
authorised in accordance with Regulation (EC) No 726/2004 the Commission may at any 
stage of the procedure initiated under this section take temporary measures immediately 
in relation to those marketing authorisations. 

Article 107k 

1.  Following  the  information  referred  to  in  Article  107i(1),  the  Agency  shall  publicly 
announce the initiation of the procedure by means of the European medicines safety web-
portal. 

EN 

39 

   EN 

The announcement shall specify the matter submitted, the medicinal products and, where 
applicable,  the  substances  concerned.  It  shall  contain  information  on  the  right  of  the 
marketing  authorisation  holders  and  the  public  to  submit  to  the  Agency  information 
relevant to the procedure and it shall state how such information may be submitted.  

2. The Pharmacovigilance Risk Assessment Advisory Committee shall assess the matter 
which  has  been  submitted.  For  the  purposes  of  that  assessment,  it  may  hold  a  public 
hearing.  

Public  hearings  shall  be  announced  by  means  of  the  European  medicines  safety  web-
portal.  The  announcement  shall  include  information  on  how  marketing  authorisation 
holders and the public can participate.  

The Agency shall provide the opportunity, to all those who request it, to participate in the 
hearing either in person or through the use of web-based technology. 

Where  a  marketing  authorisation  holder  or  another  person  intending  to  submit 
information has commercially confidential data relevant to the issue of the procedure, he 
may  request  to  present  those  data  to  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee in a non-public hearing. 

3. Within 60 days of the information submitted, the Pharmacovigilance Risk Assessment 
Advisory  Committee  shall  make  a  recommendation,  stating  the  reasons  on  which  it  is 
based. The recommendation shall be any or a combination of the following: 

(a) 

(b) 

(c) 

(d) 

(e) 

(f) 

no further evaluation or action is required at Community level; 

the  marketing  authorisation  holder  should  conduct  further  evaluation  of 
data together with the follow up of the results of that evaluation; 

the  marketing  authorisation  holder  should  sponsor  a  post-authorisation 
safety  study  together  with  the  follow  up  evaluation  of  the  results  of  that 
study;  

the  Member  States  or  marketing  authorisation  holders  should  implement 
risk minimisation measures; 

the marketing authorisation should be suspended, revoked or not renewed; 

the marketing authorisation should be varied.  

For the purposes of point (d) of the first subparagraph, the recommendation shall specify 
the risk minimisation measures recommended and any conditions or restrictions to which 
the marketing authorisation should be made subject. 

EN 

40 

   EN 

Where, in the cases referred to in point (f) of the first subparagraph, it is recommended to 
change or add information in the summary of product characteristics or the labelling or 
package leaflet, the recommendation shall suggest the wording of such changed or added 
information  and  where  such  wording  should  be  placed  in  the  summary  of  the  product 
characteristics, labelling or package leaflet. 

Article 107l 

1. Where the scope of the procedure, as determined in accordance with Article 107i(2), 
does not include any marketing authorisation granted in accordance with the procedure of 
Regulation  (EC)  No  726/2004,  the  coordination  group  shall,  within  30  days  of  the 
recommendation  of  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee, 
consider  the  recommendation  and  adopt  an  opinion  on  the  maintenance,  variation, 
suspension,  revocation  or  refusal  of  the  renewal  of  the  marketing  authorisations 
concerned, including a timetable for the implementation of the opinion.  

2. If the opinion  of the coordination group is adopted by consensus, the chairman shall 
record  the  agreement  and  inform  the  marketing  authorisation  holder  accordingly.  The 
Member States shall maintain, vary, suspend, revoke or refuse renewal of the marketing 
authorisation  as  necessary  to  comply  with the  opinion  within  the  determined  time  table 
for implementation, and they shall inform the Commission and the coordination group. 

If an opinion by consensus cannot be adopted, the majority opinion shall be forwarded to 
the  Commission  which  shall  apply  the  procedure  laid  down  in  Articles  33  and  34. 
However, by way of derogation from Article 34(1), the procedure referred to in Article 
121(2) shall apply. 

3. Where the scope of the procedure, as determined in accordance with Article 107i(2), 
includes at least one marketing authorisation granted in accordance with the procedure of 
Regulation  (EC)  No  726/2004,  the  Committee  for  Medicinal  Products  for  Human  Use 
shall, within 30 days of the recommendation of the Pharmacovigilance Risk Assessment 
Advisory  Committee,  consider  the  recommendation  and  adopt  an  opinion  on  the 
maintenance, variation, suspension, revocation or refusal of the renewal of the marketing 
authorisations concerned.  

4. On the basis of the opinion of the Committee for Medicinal Products for Human Use 
referred to in paragraph 3, the Commission shall: 

(a) 

adopt a decision addressed to the Member States concerning the measures 
to be taken in respect of marketing authorisations granted by the Member 
States and concerned by the procedure under this section; and 

EN 

41 

   EN 

(b)  where the opinion is that regulatory action is necessary, adopt a decision to 
vary,  suspend,  revoke  or  refuse  renewal  of  the  marketing  authorisations 
granted  in  accordance  with  Regulation  (EC)  No  726/2004  and  concerned 
by the procedure under this section. 

Articles 33 and 34 of this Directive shall apply to the adoption of the decision referred to 
in point (a) of the first subparagraph of this paragraph and to its implementation by the 
Member States. However, by way of derogation from Article 34(1) of this Directive, the 
procedure referred to in Article 121(2) thereof shall apply. 

Article 10 of Regulation (EC) No 726/2004 shall apply to the decision referred to in point 
(b)  of  the  first  subparagraph  of  this  paragraph.  However,  by  way  of  derogation  from 
Article 10(2) of that Regulation, the procedure referred to in Article 87(2) thereof shall 
apply.  Where  the  Commission  adopts  such  decision,  it  may  also  adopt  a  decision 
addressed to the Member States pursuant to Article 127a of this Directive. 

Section 4 
Publication of assessments 

Article 107m 

The Agency shall make public the recommendations, opinions and decisions referred to 
in Articles 107b to 107l by means of the European medicines safety web-portal. 

CHAPTER 4 
Supervision of post-authorisation safety studies 

Article 107n 

1. This Chapter shall apply to non-interventional post-authorisation safety studies which 
are  initiated,  managed  or  financed  by  the  marketing  authorisation  holder, voluntarily or 
following  a  requirement  in accordance with Articles 21a or 22a, and which involve the 
collection of data from patients or health-care professionals. 

2. The studies shall not be performed where the act of conducting the study promotes the 
use of a medicinal product. 

EN 

42 

   EN 

Article 107o 

1.  Before  a  study  is  conducted,  the  marketing  authorisation  holder  shall  be  required  to 
submit a draft protocol to the national competent authority, for studies to be conducted in 
only  one  Member  State,  and  to  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee, for studies to be conducted in more than one Member State. 

2. Within 60 days of the submission of the draft protocol the national competent authority 
or  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee,  as  appropriate,  may 
issue  

(a) 

a  letter  of objection, which  shall be based on detailed grounds, in any of 
the following cases: 

(i) 

it considers that the study is a clinical trial falling under the scope of 
Directive 2001/20/EC; 

(ii) 

it  considers  that  the  conduct  of  the  study  promotes  the  use  of  a 
medicinal product;  

(iii) 

it  considers  that  the  design  of  the  study  does  not  fulfil  the  study 
objectives; or 

(b) 

a recommendation on the draft protocol.  

3.  After  the  expiry  of  the  period  referred  to  in  paragraph  2  the  marketing  authorisation 
holder may commence the study. However, where a letter of objection referred to in point 
(a)  of  paragraph  2  has  been  issued,  the  study  may  commence  only  with  the  written 
approval  from  the  national  competent  authority  or  the  Pharmacovigilance  Risk 
Assessment Advisory Committee, as appropriate.  

Where  a  recommendation  referred  to  in  point  (b)  of  paragraph  2  has  been  issued,  the 
marketing  authorisation  holder  shall  take  that  recommendation  into  account  before 
commencing the study. 

Article 107p 

1.  After  a  study  has  been  commenced,  major  amendments  to  the  protocol  shall  be 
submitted to the national competent authority or the Pharmacovigilance Risk Assessment 
Advisory Committee, as appropriate. 

2.  During  the  conduct  of  a  study,  the  marketing  authorisation  holder  shall  continuously 
monitor  the  data  generated  and  its  implications  for  the  risk-benefit  balance  of  the 
medicinal product concerned. 

EN 

43 

   EN 

Any  new  information  which  might  influence  the  risk-benefit  balance  of  the  medicinal 
product  shall  be  communicated  to  the  national  competent  authority  in  accordance  with 
Article 23. 

3. Payments to healthcare professionals for participating in the studies shall be restricted 
to compensation of time and expenses incurred. 

Article 107q 

1.  Upon  completion  of  the  study,  final  study  reports  shall  be  submitted  to  the  national 
competent  authority  or  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee 
within 12 months of the last patient visit unless a written waiver has been given by the 
national  competent  authority  or  the  Pharmacovigilance  Risk  Assessment  Advisory 
Committee, as appropriate. 

2. The marketing authorisation holder shall consider whether the results of the study have 
an impact on the terms of the marketing authorisation and shall if necessary submit to the 
national competent authorities an application to vary the marketing authorisation.  

3. The marketing authorisation holder shall electronically submit an abstract of the study 
results  to  the  national  competent  authority  or  the  Pharmacovigilance  Risk  Assessment 
Advisory Committee. 

For  studies  conducted  in  more  than  one  Member  State,  the  Pharmacovigilance  Risk 
Assessment Advisory Committee may decide that the abstract is made public by means of 
the  European  medicines  safety  web-portal,  after  deletion  of  any  information  of  a 
commercially confidential nature. 

Article 107r 

1. Based on the results of the study and after consultation of the marketing authorisation 
holder,  the  Pharmacovigilance  Risk  Assessment  Advisory  Committee  may  make 
recommendations concerning the terms of the marketing authorisation, stating the reasons 
on which they are based. Those recommendations shall be made public by means of the 
European medicines safety web-portal. 

2.  When  recommendations  for  the  variation,  suspension  or  revocation  of  the  marketing 
authorisation are made for a medicinal product authorised by the Member States pursuant 
to this Directive, the coordination group shall adopt an opinion on the matter taking into 
account the recommendation referred to in paragraph 1 and including a timetable for the 
implementation of the opinion. 

EN 

44 

   EN 

If  the  opinion  of  the  coordination  group  is  adopted  by  consensus,  the  chairman  shall 
record  the  agreement  and  inform  the  marketing  authorisation  holder  accordingly.  The 
Member  States  shall  vary,  suspend  or  revoke  the  marketing  authorisation  concerned  as 
necessary 
table  for 
the  opinion  within 
implementation, and they shall inform the Commission and the coordination group. 

to  comply  with 

the  determined 

time 

If an opinion by consensus cannot be adopted, the majority opinion shall be forwarded to 
the Commission which shall apply the procedure laid down in Articles 33 and 34. 

CHAPTER 5 
Guidelines, adaptation and review 

Article 108 

Following  consultation  with  the  Agency,  Member  States  and  interested  parties,  the 
Commission shall adopt and make public guidelines on good pharmacovigilance practice 
for medicinal products authorised in accordance with Article 6(1) in the following areas: 

(1) 

(2) 

(3) 

(4) 

(5) 

(6) 

(7) 

the establishment and operation of the pharmacovigilance system by the 
marketing  authorisation  holder  and  the  content  and  maintenance  of  the 
pharmacovigilance system master file; 

quality  assurance  and  quality  control  by  the  marketing  authorisation 
holder,  the  national  competent  authorities  and  the  Agency  of  their 
performance of pharmacovigilance activities. 

the use of internationally agreed terminologies, formats and standards for 
the conduct of pharmacovigilance; 

the  methodology  for  the  monitoring  of  data  in  the  Eudravigilance 
database to determine whether there are new or changed risks; 

the format of electronic reporting of adverse reactions by Member States 
and marketing authorisation holders; 

the format of electronic periodic safety update reports; 

the  format  of  protocols,  abstracts  and  final  study  reports  for  the  post-
authorisation safety studies; 

(8) 

the procedures and formats for pharmacovigilance communications. 

EN 

45 

   EN 

Those guidelines shall take account of international harmonisation work carried out in the 
field  of  pharmacovigilance  and  shall  where  necessary  be  revised  to  take  account  of 
technical and scientific progress. 

Article 108a 

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

Those  measures,  designed  to  amend  non-essential  elements  of  this  Directive,  shall  be 
adopted in accordance with the regulatory procedure with scrutiny referred to in Article 
121(2a).  

Article 108b 

The Commission shall make public a report on the  conduct of  pharmacovigilance tasks 
by the Member States on [insert concrete date: three-years after the date of transposition 
referred to in Article 3(1)] at the latest and then every three years thereafter.” 

22. 

Article 111 is amended as follows: 

(a) 

paragraph 1 is amended as follows: 

(i) 

the first subparagraph is replaced by the following: 

“Under  the  coordination  of  the  Agency,  the  competent  authority  of  the  Member  State 
concerned  shall  ensure  that  the  legal  requirements  governing  medicinal  products  are 
complied  with,  by  means  of  repeated  inspections,  and  if  necessary  unannounced 
inspections, and, where appropriate, by asking an Official Medicines Control Laboratory 
or a laboratory designated for that purpose to carry out tests on samples. ” 

(ii) 

In the fifth subparagraph point (d) is replaced by the following: 

“(d) inspect the premises, records, documents and pharmacovigilance system master file 
of marketing authorisation holders or any firms employed by the marketing authorisation 
holder to perform the activities described in Title IX.” 

(b)  Paragraph 3 is replaced by the following: 

“3.  After  every  inspection  as  referred  to  in  paragraph  1,  the  competent  authority  shall 
report on whether the manufacturer, importer or wholesaler complies with the principles 
and guidelines of good manufacturing practice and good distribution practice referred to 

EN 

46 

   EN 

in Articles 47 and 84, or on whether the marketing authorisation holder complies with the 
requirements laid down in Title IX. 

The competent authority which carried out the inspection shall communicate the content 
of  those  reports  to  the  manufacturer,  importer,  marketing  authorisation  holder,  or 
wholesale distributor who has undergone the inspection. 

Before adopting the report, the competent authority shall give the manufacturer, importer, 
marketing  authorisation  holder,  or  wholesale  distributor  concerned  the  opportunity  to 
submit their comments.” 

(c)  Paragraph 7 is replaced by the following: 

“7. 
If  the  outcome  of  the  inspection  as  referred  to  in  points  (a),  (b)  and  (c)  of 
paragraph 1 is that the manufacturer does not comply with the principles and guidelines 
of  good  manufacturing  practice  as  provided  for  by  Community  legislation,  the 
information shall be entered in the Community database as referred to in paragraph 6.” 

(d)  The following paragraph 8 is added: 

“8. 
If  the  outcome  of  the  inspection  as  referred  to  in  paragraph  1(d)  is  that  the 
marketing  authorisation  holder  does  not  comply  with  the  pharmacovigilance  system  as 
described in the pharmacovigilance system master file and with Title IX, the competent 
authority of the  Member State concerned shall bring the deficiencies to the attention of 
the marketing authorisation holder and give him the opportunity to submit his comments. 

In  such  case  the  Member  State  concerned  shall  inform  the  other  Member  States,  the 
Agency and the Commission.  

Where  appropriate,  the  Member  State  concerned  shall  take  the  necessary  measures  to 
ensure  that  a  marketing  authorisation  holder  is  subject  to  effective,  proportionate  and 
dissuasive penalties.” 

23. 

Article 116 is replaced by the following: 

“Article 116 

The  competent  authorities  shall  suspend,  revoke,  withdraw  or  vary  a  marketing 
authorisation if the view is taken that the product is harmful or that it lacks therapeutic 
efficacy,  or  that  the  risk-benefit  balance  is  not  positive,  or  that  its  qualitative  and 
quantitative composition is not as declared. Therapeutic efficacy shall be considered to be 
lacking  when  it  is  concluded  that  therapeutic  results  cannot  be  obtained  from  the 
medicinal product. 

EN 

47 

   EN 

An  authorisation  shall  also  be  suspended,  revoked,  withdrawn  or  varied  where  the 
particulars supporting the application as provided for in Article 8 or Articles 10 to 11 are 
incorrect  or  have  not  been  amended  in  accordance  with  Article  23,  or  where  any 
conditions or requirements referred to in Articles 21a, 22 or 22a have not been fulfilled or 
where the controls referred to in Article 112 have not been carried out.” 

24. 

Article 117 is amended as follows: 

(a) 

paragraph 1 is amended as follows: 

(i) 

point (a) in is replaced by the following: 

“(a) the medicinal product is harmful; or” 

(ii)  point (c) is replaced by the following: 

“(c) the risk-benefit balance is not favourable; or“ 

(b)  The following paragraph 3 is added: 

“3. 

The competent authority may prohibit the supply of the product to new patients.” 

25. 

In Article 122(2) the following subparagraph is added: 

“The Member States shall send electronically all inspection reports to the Agency. “ 

26. 

Article 123(4) is replaced by the following: 

“4.  The  Agency  shall  make  public  annually  a  list  of  the  medicinal  products  which  are 
prohibited in the Community.” 

27. 

In Article 126a, paragraphs 2 and 3 are replaced by the following: 

‘2.  When a Member State avails itself of this possibility, it shall adopt the necessary 
measures in order to ensure that the requirements of this Directive are complied with, in 
particular  those  referred  to  in  Title  V,  with  the  exception  of  Article  63(1)  and  (2),  and 
Titles VI, VIII, IX and XI. 

3. 
Before granting such an authorization a Member State shall notify the marketing 
authorization  holder,  in  the  Member  State  in  which  the  medicinal  product  concerned  is 
authorised, of the proposal to grant an authorization under this  Article in respect of the 
product concerned.’ 

28. 

Article 127a is replaced by the following: 

EN 

48 

   EN 

“Article 127a 

When  a  medicinal  product  is  to  be  authorised  in  accordance  with  Regulation  (EC)  No 
726/2004, and the Scientific Committee in its opinion refers to recommended conditions 
or  restrictions  as  provided  for  in  points  (c),  (ca)  or  (cb)  of  Article  9(4)  thereof,  the 
Commission  may  adopt  a  decision  addressed to the Member States, in accordance with 
Articles  33  and  34  of  this  Directive,  for  the  implementation  of  those  conditions  or 
restrictions.” 

1. 

2. 

3. 

1. 

Article 2 
Transitional provisions 

With regard to 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 this Directive, the Member States shall ensure that the requirement applies to 
a  marketing  authorisation  granted  before  the  date  set  out  in  the  second 
subparagraph of Article 3(1) of this Directive from renewal of that authorisation 
or from the expiry of a period of three years starting from that date, whichever is 
the earliest. 

With  regard  to  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  this  Directive,  the  Member 
States  shall  ensure  that  that  requirement  applies  to  marketing  authorisations 
granted before the date set out in the second subparagraph of Article 3(1) of this 
Directive or from the expiry of a period of three years starting from that date 

The Member States shall ensure that the procedure under Articles 107n to 107r 
of  Directive  2001/83/EC  as  amended  by  this  Directive  applies  only  to  studies 
which  have  commenced  after  the  date  set  out  in  the  second  subparagraph  of 
Article 3(1) of this Directive. 

Article 3 
Transposition 

Member States shall adopt and publish, by [18 months from the entry into force] 
at  the  latest,  the  laws,  regulations  and  administrative  provisions  necessary  to 
comply  with  this  Directive.  They  shall  forthwith  communicate  to  the 
Commission  the  text  of  those  provisions  and  a  correlation  table  between  those 
provisions and this Directive. 

They shall apply those provisions from [18 months from the entry into force]. 

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When  Member  States  adopt  those  provisions,  they  shall  contain  a  reference  to 
this  Directive  or  be  accompanied  by  such  a  reference  on  the  occasion  of  their 
official publication. Member States shall determine how such reference is to be 
made. 

2. 

Member  States  shall  communicate  to  the  Commission  the  text  of  the  main 
provisions  of  national  law  which  they  adopt  in  the  field  covered  by  this 
Directive. 

Article 4 
Entry into force 

This Directive shall enter into force on the twentieth day after that of its publication in the 
Official Journal of the European Union. 

Article 5 
Addressees 

This Directive is addressed to the Member States. 

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. 

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51 

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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-
diff15 

NO 

YES 

NO 

No 1a0203 

Non-diff  NO 

YES 

NO 

No 1a0203 

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 

15 

Non-differentiated appropriations hereafter referred to as NDA. 

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52 

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Commission services. Taken together these problems mean that the safety of EU citizens 
is  not  optimally  protected  so  that  there  is  an  opportunity  to  reduce  the  public  health 
burden ADRs by improving EU pharmacovigilance.  

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: 

– 

– 

– 

– 

– 

– 

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: 

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53 

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⌧ 

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

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 

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54 

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consulted.  Concurrently  comments  of  the  Commission  services  raised  during  the  inter-
service steering group meetings were fully taken into consideration. 

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”16, 
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  the  adverse  effects  of  pharmaceutical  products  and  to 
put forward recommendations to make the system more robust.  

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. 

16

EN 

http://ec.europa.eu/enterprise/pharmaceuticals/pharmacovigilance_acs/docs/acs_consultat

ion_final.pdf 

55 

   EN 

                                                 
 
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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56 

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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  company17  (€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. 

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).  

17 

Wolters Kluwer Health 

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57 

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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  comprises  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 would 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 below 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: 
2008 
Year 

2009 

2012 

2010 

2011 

2013 

1.3 

1.4 

1.0 

1.5 

1.7 

1.0 

Total 
for 
period 
8.0 

12.6 

11.9 

13.1 

13.1 

12.8 

10.4 

74.1 

Pharmacovigilance 
database costs (€ 
millions to one 
decimal place) 
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 

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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,  including  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.  

Analysed options (revised if 
applicable) 

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

EMEA 

FTE 

EMEA 

EMEA 

Payments 
to 
rapporteurs 

Income 
Fees 

One-off 

 1,000,000

Salaries 
annually 

4

3

 646,832

 485,124

Annually  Annually  Annually 

 728,000 

 1,456,000

915,000  1,830,000

Eudravigilance development 

 2,871,000*

Pharmacovigilance data-processing 

Literature screening by the EMEA 

PSUR Assessment Worksharing 

Risk Management System assessment 

10

 1,617,080

3

3

 485,124

1,066,667

 485,124

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 

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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