Commission staff working document  - Accompanying document to the :#Proposal for a Regulation of the European Parliament and of the Council amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency and the : #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 #Summary of the impact assessment {COM(2008) 664 final} {COM(2008) 665 final} {SEC(2008) 2670}
Date: 2008-10-21
Institutions: European Commission
Subjects: European Medicines Agency, drug surveillance, marketing, medicinal product

EN 

EN 

   EN 

 
COMMISSION OF THE EUROPEAN COMMUNITIES 

Brussels, 10.12.2008 
SEC(2008) 2671 

COMMISSION STAFF WORKING DOCUMENT 

Accompanying document to the 

Proposal for a 

REGULATION OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL  

amending, as regards pharmacovigilance of medicinal products for human use, 
Regulation (EC) No 726/2004 laying down Community procedures for the authorisation 
and supervision of medicinal products for human and veterinary use and establishing a 
European Medicines Agency 

and the 

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 

SUMMARY OF THE IMPACT ASSESSMENT 

{COM(2008) 664 final} 
{COM(2008) 665 final} 
{SEC(2008) 2670} 

EN 

   EN 

 
 
 
 
 
 
 
 
 
 
 
1. 

INTRODUCTION 

Medicines  contribute  considerably  to  the  health  of  EU  citizens.  The  discovery, 
development  and  effective  use  of  drugs  have  improved  many  people's  quality  of  life, 
reduced the length of time spent in hospital and saved many lives. Consumption of drugs 
is increasing, with pharmaceutical market value reaching €141 billion in 2006. 

Medicines  can,  however,  also  have  adverse  (negative)  effects.  Adverse  drug  reactions 
(ADRs  –  a  response  to  a  medicine  which  is  noxious  and  unintended)  present  a  major 
public health burden in the EU. It is estimated that 5% of all hospital admissions are due 
to  an  ADR,  5%  of  all  hospital  patients  suffer  an  ADR  and  ADRs  are  the  5th  most 
common cause of hospital death. It is estimated that 197,000 deaths per year in the EU 
are caused by ADRs and that the total societal cost of ADRs in the EU is €79 billion. 

Medicines regulation and particularly the system of authorising medicines are critical for 
ensuring that only high quality, efficacious medicines of acceptable safety are allowed on 
the  EU  market.  However,  the  established  limitations  of  drug  development,  particularly 
the limitations of clinical trials in terms of their size, duration and controlled conditions 
means that some side effects will only be detected after a medicine has been authorised 
and entered the market.  

Pharmacovigilance  is  the  science  and  activities  relating  to  the  detection,  assessment, 
understanding and prevention of adverse effects of drugs and comprises: collecting and 
managing data on the safety of medicines, scrutinising at the data to detect ‘signals’ (any 
new or changing safety issues), evaluating the data and making decisions with regard to 
safety  issues,  acting  to  protect  public  health  (including  regulatory  action),  and, 
communicating with stakeholders about the safety of medicines.  

Key stakeholders involved in pharmacovigilance are:  

•  patients  as  the  users  of  medicines  and  families  and  carers  as  advisers  and  carers  of 

patients,  

•  all healthcare professionals but particularly: 

–  doctors (to advise patients, prescribe medicines and report ADRs) 

–  pharmacists (to advise patients, dispense medicines and report ADRs) 

–  nurses (to advise patients, administer medicines and report ADRs) 

–  academia (to conduct studies into the safety of medicines) 

•  medicines  regulators  including  Member  States  National  Competent  Authorities 
(including  regional  centres),  the  European  Medicines  Agency  (EMEA)  and  the 
European Commission,  

•  Healthcare service providers and governments and social insurance schemes, 

EN 

   EN 

 
•  Pharmaceutical  industry,  including  Marketing  Authorisation  Holders  (innovative, 
generic  and  over-the-counter  medicines  sectors),  manufacturers  and  distributers  of 
medicines (comprising a wide range of company sizes including a high proportion of 
small and medium-sized enterprises -SMEs). 

Of  these  stakeholders  the  current  EU  regulatory  framework,  made  up  principally  of 
provisions  in  Regulation  (EC)  No  726/2004  and  Directive  2001/83/EC  (supported  by 
implementing  guidelines),  place  direct  obligations  on  medicines  regulators  and  the 
industry  only.  However,  the  impact  of  these  provisions  can  affect  indirectly  all  those 
listed above, particularly in terms of the public health burden of ADRs. 

2. 

PROBLEM DEFINITION 

Significant  weaknesses  of  the  current  EU  system  of  pharmacovigilance  have  been 
identified  through  an  independent  Commission  sponsored  study,  extensive  public 
consultation  (in  2006  and  again  in  2007)  and  through  detailed  analysis  by  the 
Commission services. These weaknesses include: 

•  A lack of clear roles and responsibilities for the key responsible parties and a lack of 
clear  obligations  against  which  they  perform  their  roles  (resulting  in  poor 
compliance); 

•  Slow EU decision-making on drug safety issues particularly for nationally authorised 

products and frequent disharmony in action taken by the Member States; 

•  Low  levels  of  transparency  relating  to  pharmacovigilance  and  relatively  limited  EU 
coordination of  communication  about the safety of  medicines, plus complex product 
information with poor penetration of key warnings; 

•  Cumbersome oversight of companies' pharmacovigilance systems by the authorities; 

•  A lack of proactive and proportionate monitoring including a lack of risk management 
and  structured  data  collection  in  the  form  of  post  authorisation  safety  studies  and 
duplicative  reporting  rules  for  the  industry  and  authorities  relating  to  both  15-day, 
literature and periodic (PSUR) reporting of ADRs;  

•  Lack  of  inclusiveness  of  stakeholders  including  a  lack  of  direct  patient  reporting  of 

ADRs and their virtual absence from decision-making. 

Overall these weaknesses mean that limited resources are diverted to meet complex and 
duplicative administrative requirements, there is an over-reliance on poor quality reactive 
data,  decision-making  is  slow  and  measures  to  reduce  risk  to  patients  are  not  only 
sometimes  late  but  frequently  of  limited  effectiveness.  Taken  together  these  problems 
mean  that  the  safety  of  EU  citizens  is  not  optimally  protected  so  that  there  is  an 
opportunity 
improving  EU 
pharmacovigilance.  In  addition,  the  diversity  of  Member  State  pharmacovigilance 
requirements  and  the  disparate  Member  State  action  on  safety  issues  for  nationally 
authorised  products  means  that  the  single  market  in  pharmaceuticals  is  not  fully 
achieved. 

the  public  health  burden  ADRs  by 

reduce 

to 

EN 

   EN 

 
3. 

OBJECTIVES 

The  specific  objective  of  the  proposals  is  to  improve  the  health  of  EU  citizens  by 
strengthening and rationalising pharmacovigilance.  

The operational objectives of the proposals can be summarised as:  

(1)  Providing  for  clear  roles  and  responsibilities  for  the  key  responsible 
parties and clear obligations against which they perform their roles; 

(2)  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 of preventing unnecessary patient 
exposure to risks; 

(3)  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; 

(4)  Strengthen companies' pharmacovigilance systems, allowing companies to 

improve their systems constantly while reducing administrative burden; 

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

(6) 

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

4. 

POLICY OPTIONS 

Four basic policy-options were developed for the impact assessment:  

(1) 

No policy-change;  

(2) 

Deregulation;  

(3) 

Self-regulation, and;  

(4) 

Amendment to the existing European Community legislation.  

Enhanced implementation and enforcement work within the current legal framework (i.e. 
option 1) will improve pharmacovigilance and EU public health protection and it is for 
this  reason  that  work  to  improve  implementation  of  the  current  EU  pharmacovigilance 
system is an integral part of the Commission "Strategy to Better Protect Public Health by 
Strengthening  and  Rationalising  EU  Pharmacovigilance"  announced  in  February  2007. 
However, the impact overall of improvements of the current EU system will be limited 
and the step change improvement in public health protection can only be realised with a 

EN 

   EN 

 
change to EU legislation. On this basis only option 4 proved a realistic way of meeting 
the objectives proposed. 

A  large  number  of  potential  policy  options  were  highlighted  by  the  independent  study 
and by stakeholders during the first public consultation. The specific policy options were 
selected  and  modified  based  on  an  iterative  process  of  problem  investigation,  process 
understanding,  expert  dialogue  and  stakeholder  consultation  with  options  being  fine-
tuned while others were excluded during the process. Fifteen specific policy options were 
selected  on  the  basis  that  they  provided  the  best  sum  of  the  impacts  and  an  overall 
coherence of the EU regulatory system. These fifteen were included in the legal proposal.  

These are:  

•  Clarification and codification of the tasks and responsibilities of involved parties and 

establish standards; 

•  Establishment of a clear EMEA committee structure for pharmacovigilance scientific 
assessment and decision making coordinating activities and making recommendations 
on the safety of medicines at the EU level; 

•  Rationalising the EU pharmacovigilance referral procedures; 

•  Increasing drug safety transparency; 

•  Improved  EU  coordination  of  communication  about  major  new  or  changing  safety 

issues and establishment of an EU portal on the safety of medicines;  

•  Introduction of a new section in the Summary of Product Characteristics and Patient 
Information Leaflet on ‘key information' with a transitional implementation period; 

•  Introduction  of  a  "Pharmacovigilance  System  Master  File"  to  ensure  robust  but  un-

bureaucratic oversight of companies pharmacovigilance systems; 

•  Provision  of  a  clearer  legal  basis  for  risk management  plans  for  new  and  authorised 

products with safety concerns, including post-authorisation safety studies; 

•  Codification of guiding principles and oversight for the conduct of non-interventional 

post-authorisation safety studies;  

•  Simplification  of  ADR  reporting  using  the  EU  Eudravigilance  database  as  a  central 

tool; 

•  Scanning of the scientific literature by the EMEA with a clearly defined in scope;  

•  Exchange  of  data  on  medication  errors  that  result  in  an  adverse  reaction  including 

between the competent authorities for medicines and those for patient safety;  

•  Removal of the current routine requirement for industry periodic reports (PSURs) for 

low risk, old and established products; 

EN 

   EN 

 
•  Provision  of  the  legal  basis  for  the  new  EMEA  pharmacovigilance  committee 
structure  to  require  submission  and  coordinate  assessment  of  PSURs  and  make 
consequent recommendations for product labelling; 

•  Provision of the legal basis for patients to report suspected adverse drug reactions. 

5. 

ANALYSIS OF IMPACTS 

The  chosen  policy  options  were  found  to  be  coherent  with  existing  international 
harmonisation  in  pharmacovigilance  and  will  lead  to  further  convergence  with  the 
systems in place or being introduced in the United States, Canada and Japan.  

The  chosen  policy  options  were  not  found  to  have  a  significant  environmental  impact. 
However, the increased use of information technology will reduce the need for duplicate 
paper  reporting  and  the  increase  in  transparency  will  allow  pharmacovigilance 
assessments to be widely available though the internet. 

With regard to impact on public health (the key social impact) none of the chosen policy 
options have a negative impact and those with the greatest positive impact were found to 
be:  codified  roles,  responsibilities  and  standards;  fast  robust  EU  decision-making; 
transparency  and  EU  coordination  of  drug  safety  communications;  improved  product 
information; improved risk management including high quality post-authorisation safety 
studies,  data  sharing  on  medication  errors  and  work-sharing  on  the  assessment  of 
periodic reports (PSURs).  

Overall the most conservative estimate of the saving to society of the proposals is €237 
Million per year across the EU with a maximum estimate of €2.4 Billion per year. The 
most  conservative  estimate  of  the  public  health  impact  of  the  proposals  suggested  591 
lives  saved  across  the  EU  per  year  with  a  maximum  estimate  of  5910  lives  saved  per 
year. 

Currently  the  EU  pharmaceutical  industry  sector  spends  an  estimated  €833  Million 
annually  on  meeting  the  EU  regulatory  requirements  for  pharmacovigilance  and  the 
policy  options  proposed  would  redirect  the  industry  spend  from  duplicative  ADR, 
periodic, literature and system reporting to proactive monitoring, with higher quality data 
collection through risk management planning and post-authorisation studies. Overall, and 
including this redirection of spending, the package of proposals will save the EU industry 
sector  an  estimated  €145  Million  per  year 
representing  17.4%  of  their  current  EU 
spending on pharmacovigilance. 

In 2004 the EU medicines regulators employed 317 staff in pharmacovigilance activities 
and  staff  numbers  have  increased  slightly  over  time.  The  proposals  will  lead  to  costs 
incurred  by  the  regulators  with  estimated  one-off  implementation  costs  of  €3,9  Million 
for  the  EMEA  and  €3.0  Million  across  the  EEA  National  Competent  Authorities  and 
ongoing annual running costs of €10.1 Million for the EMEA  and €4.6 Million across the 
EEA  National  Competent  Authorities.  The  proposals  explicitly  foresee  industry  fees  to 
cover  these  pharmacovigilance  costs  and  these  fees  are  included  in  the  calculations  of 
industry  costs  which  revealed  17.4%  overall  industry  savings.  It  should  be  noted  that 
these figures will not necessarily result in direct fee increases as, at least for the EMEA, 
fee income is currently in surplus. 

EN 

   EN 

 
6. 

CONCLUSION 

This  impact  assessment  has  shown  that  increasing  the  clarity,  efficiency  and  quality  of 
the  EU  system  of  pharmacovigilance,  through  amendments  to  the  existing  EU  legal 
framework,  presents  a  win  win  situation  with  major  public  health  improvements  of  at 
least  591  lives  and  €237  Million  of  public  health  burden  saved  per  year  across  the  EU 
and overall cost savings of €145 Million  per year to the EU industry sector. 

EN 

   EN