EN   EN 
 
 
 EUROPEAN  
COMMISSION   
Brussels, 26.4.2023  
COM(2023) 192 final  
2023/0132 (COD)  
 
Proposal for a  
DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL  
on the Union code relating to medicinal products for human use, and repealing Directive 
2001/83/EC and Directive 2009/35/EC  
(Text with EEA relevance)  
{SEC(2023)  390 final}  - {SWD(2023)  191 final}  - {SWD(2023)  192 final}  -
 {SWD(2023)  193 final}   EN 1  EN EXPLANATORY MEMORANDUM  
1. CONTEXT  OF THE  PROPOSAL  
• Reasons for and objectives of the proposal  
EU pharmaceutical legislation has enabled the authorisation of safe, effica cious and 
high-quality medicinal products . Howe ver, patient access to medicinal products  
across the EU and security of supply are growing concerns , mirrored by recent 
Council conclusi ons1 and resolutions of the European Parliament2. There is also a 
growing problem of shortages of medicinal products for many EU/EEA countries. 
Consequences of such shortages include decreased quality of treatment received by 
patients and increased burden on health systems and on healthcare professionals, 
who need to identify and provide alternative treatments. While the pharmaceutical 
legislation  creates regulatory i ncentives for innovation  and regulatory tools to 
support timely authorisation of innovative and promising therapies , these medicinal 
products d o not always reach the pati ent, and patients in the EU  have differing levels 
of access.  
Moreover, innovation  is not always  focused on unmet medical needs, and there are 
market failures, especially in the development of priority antimicrobials that can help 
address antimicrobial resistance. Scientific and technological developments and 
digitalisation are not fully exp loited, whil e the environmental impact of medicinal 
products  needs attention. In addition, t he authorisation system c ould be  simplifi ed to 
keep up with global regulatory competition. The pharmaceutical s trategy for Europe3 
is a holistic answer to the current challenges of the pharmaceutical policy with  
legislative and non -legislative actions interacting together to achieve its overall goal 
of ensuring E U’s supply of safe and affordable medicinal products  and supporting 
the EU pharmaceutical industry ’s innovation efforts4. Reviewing  the pharmaceutical 
legislation is key to achieving these objectives . However,  innovation, access and 
affordability are also influenced by factors outside the  scope  of th is legislation, such 
as glo bal research and innovation activities or national pricing and reimbursement 
decisions. Hence, not  all problems can be addressed by the re form  of the legislation 
alone . Despite this, EU  pharmaceutical  legislation can be an enabling  and connecting  
factor  for innovation, access, affordability and environmental protection.  
The proposed revision of the EU pharmaceutical legislation  builds on the high level 
of public health protection and harmonisation already achieved for the authorisation 
of medicin al product s. The overarching aim of the reform  is to ensure that patients 
across the EU have timely and equitable access  to medicines . Another  objective of 
the proposal is to enhance security of supply and address shortages through specific 
measures , including stronger obligations on marketing authorisation holders to notify 
                                                 
1 Council conclusions on strengthening the balance in the pharmaceutical systems in the EU and its 
Member States (OJ C 269, 23.07.2016, p. 31).  Council conclusions on access to medicines and medical 
devices fo r a stronger and resilient EU, 2021/C 269 I/02 (OJ C 269I, 7.7.2021, p. 3) .  
2 European Parliament resolution of 2 March 2017 on EU options for improving access to medicine 
(2016/2057(INI) , European Parliament resolution of 17 September 2020 on the shortage of medicines – 
how to address an emerging pro blem ( 2020/2071(INI) . 
3 Communication from the Commission, Pharmaceutical Strategy for Europe  (COM/2020/761 final), 
https://health.ec.europa.eu/medicinal -products/pharmaceutical -strategy -europe_en . 
4 Mission letter of the President of the  European  Commission to Stella Kyriakides , 
 Commissioner  for Health and Food Safety , mission -letter -stella -kyriakides_en.pdf (europa.eu) . EN 2  EN potential or actual shortages and marketing withdrawals, cessations and suspensions 
in advance of a foreseen interruption to continued supply of a medicinal product to 
the market.  To support t he sector’s global competitiveness and innovative power , 
right  balance needs to be struck between giving incentives for innovation, with more 
focus on  unmet medical needs, and measures on access and affordability . 
The framework needs to be sim plified, adapted to scientific and technological 
changes , and contribute to reducing the environmental impact of medicin al products . 
This proposed re form  is comprehensive but targeted and focuses on provisions 
relevant to achiev ing its specific objectives;  therefore it covers all provisions apart 
from those concerning advertising, falsified medicin al products , and homeopathic 
and traditional herbal medicinal products.  
Therefore, the objectives of the proposal are the following:  
General objectives  
– guarantee a high level of public health by ensuring the quality, safety and 
efficacy of medicinal products for EU patients;  
– harmonise the internal market  for the supervision and control of medicinal 
products and the rights and duties incumbent upon the competent aut horities of 
the Member States.  
Specific objectives  
– make sure all patients across the EU have timely and equitable access to safe, 
effective, and affordable medicines.  
– enhance security of supply and ensure medicines are always available to 
patients, regardless of where they live in the EU.  
– offer an attractive , innovation -and competitiveness friendly environment for 
research, development , and production of medicines  in Europe . 
– make medicines more environmentally sustainable . 
All the general and specific objectives set out above are also relevant for the areas of 
medicinal products for rare diseases and for children.  
• Consistency  with  existing  provisions  in the policy  area  
The current  EU pharmaceutical  legislation  includes  both general  and specific  
legislation.  Directive  2001/83/EC  of the European  Parliament  and of the Council5 
and Regulation  (EC)  No 726/2004  of the European  Parliament  and of the Council6 
(together  ‘general pharmaceutical  legislation’)  lay down  provisions  related  to 
medicinal  products  authorisation  and post-authorisation  requirements,  pre-
authorisation  support  schemes,  regulatory  incentives  in terms  of data and market  
protection,  manufacturing  and supply , and the European  Medicines  Agency  (EMA).  
The general  pharmaceutical  legislation  is complemented  by specific  legislation  on 
medicinal  products  for rare diseases  (Regulation  (EC)  No 141/2000,  the ‘Orphan  
                                                 
5 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 us e (OJ L 311, 28.11.2001, p. 67).  
6 Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying 
down Community procedures for t he authorisation and supervision of medicinal products for human 
and veterinary use and establishing a European Medicines Age ncy (OJ L 136, 30.4.2004, p. 1).  EN 3  EN Regulation’7), medicinal  products  for children  (Regu lation  (EC)  No 1901/2006,  the 
‘Paediatric  Regulation’8) and advanced  therapy  medicinal  products  (Regulation  (EC)  
No 1394/2007,  the ‘ATMP  Regulation’9).The proposed  revision  of the 
pharmaceutical  legislation  will consist  of two legislative  proposals:  
– a new directive,  repealing  and replacing  Directive  2001/83/EC  and Directive  
2009/35/EC  of the European  Parliament  and of the Council10 and incorporating  
relevant  parts  of the Paediatric  Regulation  (Regulation  (EC)  No 1901/2006 ); 
– a new regulation,  repealing  and replacing  Regulation (EC) No 726/2004 , 
repealing  and replacing  the Orphan  Regulation (Regulation (EC)  No 141/2000) 
and repealing and incorporating  relevant  parts  of the Paediatric  Regulation  
(Regulation  (EC)  No 1901/2006) .  
The merger of the Orphan Regulation and the P aediatric Regulation  with the 
legislation applicable to all medicinal products will allow for simplification and 
increased coherence.  
Medicin al products  for rare diseases and for children will continue to fall under  the 
same provisions as any other medicinal product concerning their quality, safety and 
efficacy, for example concern ing the marketing authorisation procedures, 
pharmacovigilance and quality requirements. However, specific requirements will 
also continue to apply to these typ es of medicinal products  in order to support their 
development . This is because market forces alone have proven insufficient to 
stimulate adequate research and development of medicinal products for children and 
patients suffering from a rare disease. Such requirements, which are currently laid 
down in separate legislati ve acts , should be integrated in to the regulation and this 
directive  in order to ensure clarity and coherenc e of all the measures applicable to 
these medicinal products.  
• Consistency with other Union policies  
The EU pharmaceutical  legislation  described  above  has close  links  with several  other  
related  pieces  of EU legislation.  The ‘Clinical  Trials  Regulation ’ (Regulation  (EU)  
No 536/2014)11 allows  for more  efficient  approval  of clinical  trials in the EU. 
Regulation  (EU)  2022/12312 strengthens  the role of the European  Medicines  Agency  
in order  to facilitate  a coordinated  EU-level  response  to health  crises.  The EMA  fees 
                                                 
7 Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on  
orphan medicinal products  (OJ L 18, 22.1.2000, p. 1 ). 
8 Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 
2001/20/EC,  Directive 2001/83/EC and Regulation (EC) No 726/2004  (OJ L 378, 27.12.2006, p. 1).  
9 Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 
on advanced therapy medicinal products and amending Directive 2001/83/EC an d Regulation (EC) No 
726/2004  (OJ L 324, 10.12.2007, p. 121).  
10 Directive 2009/35/EC of the European Parliament and of the Council of 23 April 2009 on the colouring 
matters which may be added to medicinal products (OJ L 109, 30.4.2009, p. 10).  
11 Regulation  (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on 
clinical trials on medicinal products for human use, and repealing Directive 2001/2 0/EC (OJ L 158, 
27.5.2014, p. 1).  
12 Regulation (EU) 2022/123 of the European Parliament a nd of the Council of 25 January 2022 on a 
reinforced role for the European Medicines Agency in crisis preparedness and management for 
medicinal products and medical devices  (OJ L 20, 31.1.2022, p. 1).  EN 4  EN legislation13 contributes  to providing  adequate  financing  for the EMA's  activi ties, 
including  respective  remuneration  to national  competent  authorities  for their 
contribution  to completing  the EMA’s  tasks.  
There  are also links  with EU regulatory  frameworks  for other  health  products.  EU 
legislation  on blood,  tissues  and cells (BTC)14 is relevant,  as some  substances  of 
human  origin  are starting  materials  for medicinal  products.  The EU regulatory  
framework  for medical  devices15 is also relevant,  as there  are products  that combine  
medicinal  products  and medical  devices.  
Futhermore,  the objectives  of the proposed  reform  of the pharmaceutical  legislation  
are consistent  with those  of a number  of broader  EU policy  agendas  and initiatives.  
In terms  of promoting  innovation,  Horizon  Europe16, a key funding  programme  for 
EU research  and innovation , and Beating  Cancer  Plan17 both support  research  and 
development  of new medicinal  products.  In addition,  innovation  in the 
pharmaceutical  sector  is promoted  by the intellectual  property  frameworks,  on 
patents  under  the national  patent  laws,  the European  Patent  Convention  and the 
Trade -Related  Aspects  of Intellectual  Property  Rights  (TRIPS)  agreement , and on 
supplementary  protection  certificates  under  the EU SPC Regulation18. The 
intellectual  property  action plan19 under  the Industrial  Strategy  includes  modernising  
the system  of supplementary  protection  certificates  (SPCs) . SPCs  extend  certain  
patent  rights  to protect  innovation  and compensate  for lengthy  clinical  trials  and 
marketing  authorisation  procedu res. With  regard  to addressing  unmet  medical  needs  
in the area of antimicrobial  resistance,  the proposed  reform  of the pharmaceutical  
legislation  will contribute  to the objectives  of the European  one health  action  plan 
against  antimicrobial  resistance  (AMR )20. 
                                                 
13 Council Regulation (EC) No 297/95 of 10 February 1995  on fees payable to the European Agency for 
the Evaluation of Medicinal Products , and Regulation (EU) No 658/2014 of the European Parliament 
and of the Council on fees payable to the European Medicines Agency for the conduct of 
pharmacovigilance activities  in respect of medicinal products for human use  (OJ L 35, 15.2.1995, p. 1) . 
14 Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting 
standards of quality and safety for the collection, testing, processing, storage and  distribution of human 
blood and blood components and amending Directive 2001/83/EC , and Directive 2004/23/EC of the 
European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for 
the donation, procurement, testing, processing, preservation, storage and distribution of human tissues 
and cells  (OJ L 033, 8.2.2003, p. 30).  
15 Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical 
devices, amending Directive 2001/83/EC, Regulatio n (EC) No 178/2002 and Regulation (EC) No 
1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC  (OJ L 117, 5.5.2017, p. 1) and 
Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro 
diagnostic medic al devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU  
(OJ L 117, 5.5.2017, p. 176).  
16 Regulation (EU) 2021/695 of the European Parliament and of the Council of 28 April 2021 establishing 
Horizon Europe – the Framework Programme fo r Research and Innovation, laying down its rules for 
participation and dissemination, and repealing Regulations (EU) No 1 290/2013 and (EU) No 1291/2013 
(OJ L 170, 12.5.2021, p. 1 ). 
17 Communication from the Commission , Europe's Beating Cancer Plan  (COM/2021 /44 final) . 
18 Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 
concerning the supplementary protection certificate for medicinal products  (OJ L 152, 16.6.2009, p. 1 ). 
19 Communication from the Commission, Making the mo st of the EU’s innovative potential. An 
intellectual property action plan to support the EU’s recovery and resilience  (COM/2020/760 final ). 
20 Communication from the Commission, A European One Health Action Plan against Antimicrobial 
Resistance (AMR) , https://ec.europa.eu/health/system/files/2020 -01/amr_2017_action -plan_0.pdf . EN 5  EN Concerning  access  to medicinal  products , in addition  to the pharmaceutical  
legislation,  the intellectual  property  frameworks,  the Health  Technology  Assessment  
(HTA)  Regulation  (Regulation  (EU)  2021/2282 , the ‘HTA  Regulation’ )21 and the 
Transparency  Directive  (Directive  89/105/EEC)22 also play a role. In addition  to 
extending  certain  patent  rights  to protect  innovation,  SPCs  impact  the effect  of 
regulatory  protection  periods  provided  by the pharmaceutical  legislation  and 
therefore  the entry  of generic  and biosimilar  medicinal  products  and ultimately  
patient  access  to medicinal  products  and affordability.  Under  the HTA  Regulation,  
national  HTA  bodies  will conduct  joint clinical  assessments  that compare  new 
medicinal  products  to existing ones.  Such  joint clinical  assessments  will help 
Member  States  take more  timely  and evidence -based  decisions  on pricing  and 
reimbursement.  Finally,  the Transparency  Directive  regulates  procedural  aspects  of 
the Member  States’  pricing  and reimbursement  decisions  but does not effect  the level  
of price.  
In order  to enhance  security  of supply  of medicinal  products , the proposed re form  of 
the pharmaceutical legislation aims  to address  systemic  shortages  and supply  chain  
challenges.  The proposed  reform  theref ore complements and further develops the 
roles of the Member States and competent authorities of the Member States as set out 
in the extension of the EMA mandate (Regulation (EU) 2022/123), and is aimed at 
ensuring access to and continued supply of critica l medicinal products during health 
crises. It also complements the mission of the Health Emergency Preparedness and 
Response Authority (HERA) to ensure availability of medical countermeasures in 
preparation for and during health crises. The proposed re form  of the pharmaceutical 
legislation is therefore consistent with the package of legislative initiatives related to 
health security under the European Health Union23. 
To address  environmental  challenges,  the proposed  reform  of the pharmaceutical  
legislation  will support  initiatives  under  the European  Green  Deal24. These  include  
the EU action  plan ‘Towards  Zero  Pollution  for Air, Water  and Soil’  and the revision  
of: (i) the Urban  Waste  Water  Treatment  Directive25, (ii) the Industrial  Emissions  
Directive26 and (iii) the list of surface  and groundwater  pollutants  under  the Water  
Framework  Directive27. The proposal  is also well aligned  with the Strategic  
Approach  to Pharmaceuticals  in the Environment28. 
                                                 
21 Regulation (EU) 2021/2282 of the European Parliament and of the Council of 15 December 2021 on 
health technology assessment and amending Directive 2011/24/EU  (OJ L 458, 22.12.2021, p. 1 ). 
22 Council Directive 89/105/EEC of 21 December 1988 relating to the transparency of measures 
regulating the prices of medicinal products for human use and t heir inclusion in the scope of national 
health insurance systems  (OJ L 40, 11.2.1989, p. 8 ). 
23 European Health Union - Protecting the health of Europeans and collectively responding to cross -border 
health crises,  
 https://commission.europa.eu/strategy -and-policy/priorities -2019 -2024/promoting -our-european -way-
life/european -health -union_en . 
24 Communication from the C ommission , The European Green Deal  (COM /2019 /640 final ). 
25 Council Directive 91/271/EEC of 21 May 1991 concerning urban waste -water treatment (OJ L 135, 
30.5.1991, p. 40).  
26 Directive 2010/75/EU of the European Parliament and of the Council of 24 November 2010 on 
industrial emissions (integrated pollution prevention and control) (OJ L 334 17.12.2010, p. 17) . 
27 Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a 
framework for Community action in the field of w ater policy  (OJ L 327, 22.12.2000, p. 1 ) and Directive 
2013/39/EU of the European Parliament and of the Council of 12 August 2013 amending Directives 
 EN 6  EN Finally,  on the use of health  data, the European  Health  Data  Space29 will provide  a 
common  framework  across  Member  States  for access  to high-quality  real world  
health  data.  This will promote  progress  in research  and development  of medicinal  
products  and provide  new tools  for pharmacovigi lance  and comparative  clinical  
assessments.  By facilitating  access  to and use of health  data,  the two initiatives  
together  will support  the competitiveness  and innovation  capacity  of the EU’s  
pharmaceutical  industry.  
2. LEGAL  BASIS,  SUBSIDIARITY  AND  PROPORTIONALITY  
• Legal  basis  
The proposal is based on Articles 114(1) and 168(4) , point (c) of the Treaty on the 
Functioning of the European Union (TFEU). This is consistent with the legal basis of 
existing EU pharmaceutical legislation. Article 114(1) has as its object the 
establishment and functioning of the internal market, while Article 168(4) , point (c) 
relates to the setting of high standards for the  quality and safety of medicinal 
products.  
• Subsidiarity  (for non-exclusive  competence)   
Common standards of quality, safety and efficacy  for the authorisation of medicin al 
products  constitute a cross -border public health issue that affects all Member States 
and thus can be regulated effectively only at EU level.  EU action relies also on the 
single market to achieve a stronger impact as regards access to safe, effective and 
affordable medicin al products , and with regard to  the security of supply across the 
EU. Uncoordinated measures by Member States may result in distortions of 
competition and barrie rs to intra -EU trade  for medicinal products that are relevant for 
the entire EU, and would also likely  increase administrative burden fo r 
pharmaceutical companies, which often operate in mor e than one Member State.  
A harmonised approach at EU level also pr ovides greater potential for incentives to 
support innovation and for concerted act ion to develop medicinal products  in areas of 
unmet medical needs. Moreover, s implification and streamlining of processes under 
the proposed re form  are expected to reduce ad ministrative burden for companies and 
authorities and hence improve the efficiency and at tractiveness of the EU system. 
The reform  will also have a positive influence on the competitive functioning of the 
market through targeted  incentives and other measur es that facilitate early market 
entry of generic and biosimilar medicin al products,  contributing to patient access and 
affordability.  Nevertheless, the proposed re form  of the pharmaceutical legislation  
respects Member States’ exclusive competence in the pr ovision of health services, 
including pricing and reimbursement policies and decisions.  
                                                                                                                                                         
2000/60/EC and 2008/105/EC as regards priority substances in the field of water policy Text with EEA 
relev ance (OJ L 226, 24.8.2013, p. 1 ). 
28 Strategic Approach to Pharmaceuticals in the Environmen t, 
  https://ec.europa.eu/environment/water/water -dangersub/pharmaceuticals.htm . 
29 Comm unication from the Commission, A European Health Data Space: harnessing the power of health 
data for people, patients and innovation  (COM/2022/196 final).  EN 7  EN • Proportionality  
The initiative does not go beyond what is necessary to achieve the objectives of the 
reform . It does so in a way that is conducive to national action,  which would 
otherwise not be sufficient to achieve those objectives in a satisfactory way.  
The principle of proportionality has been reflected in the comparison of different 
options evaluated in the impact assessment . For example , trade -offs are inherent 
between the objective of innovation  (promoting the development of new medicinal 
products)  and the objective of affordability (which is often achieved by 
generic/biosimilar competition ). The re form  maintains the incentives as a key 
element for innovation, but they are adapted to better encourage and reward product 
development in areas of unmet medical needs and to better address  timely  patient 
access  to medicinal products  in all Member States.   
• Choice  of the instrument  
The proposed  directive  introduces  a large  number  of amendments  to Directive  
2001/83/EC  and incorporates  part of the current  provisions  and amendments  to 
Regulation  (EC)  No 1901/2006.  A new directive  repealing  Directive  2001/83/EC  
(rather  than an amending  directive)  is therefore  considered  the appropriate  legal  
instrument.  A directive  remains  the best choice  of legal  instrument  to avoid  
fragmentation  of national  legislation  on medicinal  products  for human  use, given  that 
the legislation  is based  on a system  of national  and EU marketing  authorisations.  
National  authorisations  are granted  and managed  on the basis  of national  laws 
implementing  the EU law. The evaluation  of the general  pharmaceutical  legislation  
has not found  that the choice  of legal  instrument  has caused  specific  problems  or 
reduced  the level  of harmonisation . In addition,  a REFIT  Platform  opinion30  from  
2019  showed  that there  was no support  among  the Member  States  to turn Directive  
2001/83/EC  into a regulation.  
3. RESULTS  OF EX-POST  EVALUATIONS,  STAKEHOLDER  
CONSULTATIONS  AND  IMPACT  ASSESSMENTS  
• Ex-post evaluations/fitness  checks  of existing  legislation  
For the re form  of the general pharmaceutical legislation, stakeholder consultation 
activities were carried out as part of  ‘back -to-back’  evaluati ons and impact  
assessment s of the general  pharmaceutical  legislation  and of the Orphan  and 
Paediatric  Regulations31. 
For medicinal products for rare diseases and for children a joint evaluation on the 
functioning of the two pieces of legislation was carried out and published in 202032. 
For the general pharmaceutical legislation the evaluation of the legislation showed 
that the legislation continues to be relevant for the dual overarching objectives of 
protecti ng public health and harmonis ing the intern al market for medicin al products  
in the EU. The legislation delivered on the objectives of the 2004 revision , albeit not 
                                                 
30 The EU's efforts to simplify legislation – 2019 Annual Burden survey,  
 https://commission.europa.eu/system/files/2020 -08/annual_burden_survey_2019_4_digital.pdf . 
31 Commission staff working document , Impact Assessment , Annex 5: Evaluation.   
32 Evaluation of the medicines for  rare diseases and children legislation,  
  https://health.ec.europa.eu/medicinal -products/medicines -children/ev aluation -medicines -rare-diseases -
and-children -legislation_en . EN 8  EN to the same extent for all . The objective of ensur ing quality, safety and efficacy of 
medicinal products  was achieved to the largest extent, while patient access to 
medicin al products  in all Member States was achieved only to a limited extent. As to 
ensuring the competitive functioning of the internal market and attractiveness in a 
global context, the legisl ation has performed to a moderate extent. The evaluation 
found that the achievements or shortcomings of the 2004 revision vis -a-vis its 
objectives depend on many external factors outside the remit of the legislation . These 
include  R&D  activities and intern ational location of R&D clusters, national pricing 
and reimbursement decisions, business decisions and market size. The 
pharmaceutical sector and  the development of medicin al products  are global ; 
research and clinical trials conducted on one continent will  support development and 
authorisation in other continents; global are also the supply chains and manufacturing 
of medicin al products . International cooperation to harmonise requirements to 
support authorisation exist s, e.g. the International Council for H armonisation of 
Technical Requirements for Pharmaceuticals for Human Use33. 
The evaluation identified the main shortcomings  that the pharmaceutical legislation 
has not adequately addressed, while recognising that these also depend on factors 
outside its rem it. These main shortcomings are as follows:  
– Medical needs of patients are not sufficiently met . 
– Affordability of medicinal products  is a challenge for health systems . 
– Patients have u nequal access to medicin al products  across the EU . 
– Shortages of medicin al products are an increasing problem in the EU.  
– The medicinal product lifecycle can have negative impacts on the  environment . 
– The regulatory system does not sufficiently cater for i nnovation and in some 
instances creates unnecessary administrative burden . 
Concerning medicinal products for rare diseases and for children, the evaluation 
showed that overall the two specific pieces of legislation have achieved positive 
results by allowing more medicinal products to be developed for these two 
population groups. Ho wever, it also identified important shortcomings, which are 
similar to the ones identified for the general pharmaceutical legislation : 
– Medical needs of patients with rare diseases and of children are not sufficiently 
met. 
– Affordability of medicin al products  is a growing challenge for health systems . 
– Patients have u nequ al access to medicinal products  across the EU . 
– The regulatory system does not sufficiently cater for innovation and in some 
instances creates unnecessary administrative burden.  
• Stakeholder  consultations  
For the re form  of the gene ral pharmaceutical legislation, s takeholder consultation 
activities were carried out as part of the ‘back -to-back’ evaluation and impact 
assessment34. A single consultation strategy was prepared for this exercise, including 
                                                 
33 ICH – harmonisation for better health, https://www.ich.org/ .  
34 Commission staff working document , Impact Assessment , Annex 2: Stakeholder Consultation 
(Synopsis Report).  EN 9  EN consultation activities looking backward and forward. It aimed to collect inputs and 
perspectives of all stakeholder groups both on the evaluation of the legislation and 
for the imp act assessment of  different possible policy options for the re form . 
The following key stakeholder groups were identified as priority groups in the 
consultation strategy:  the public ; organisations representing patients, consumers and 
civil society active in  public health and social issues ( ‘CSOs ’); healthcare 
professionals and healthcare providers; researchers, academia and learned societies 
(academics); environmental organisations; the pharmaceutical industry and their 
representatives.  
As part of the intern al policy work process supporting the revision, the Commission 
collaborated with the European Medicines Agen cy (EMA) and the competent 
authorities of the Member States (NCAs) dealing with the regulation of medicinal 
products . Both actors play a pivotal rol e in implement ing the pharmaceutical 
legislation.  
Information was collected through consultations that took place between 30 March 
2021 and 25 April 2022 . These  consisted of:  
– feedback on the Commission ’s combined evaluation roadmap/inception impact 
assess ment (30 March -27 April 2021);  
– Commission online public consultation (28 September  - 21 December 2021);  
– targeted stakeholder surveys  with public authorities, the pharmaceutical 
industry  including SMEs , academia, civil society representatives  and 
healthcare providers  (survey) (16 November 2021 -14 January 2022);  
– interviews (2 December 2021 -31 January 2022);  
– a validation workshop on the evaluation findings (workshop  1) on 19 January 
2022;  
– a validation workshop on the impact assessment findings (works hop 2) on 25 
April 2022.  
There was broad consensus among stakeholders that the current pharmaceutical 
system guarantees a high level of patient safety on which the revision can build  to 
address new challenges and improve supply of sa fe and affordable medic inal 
products, patient access  and innovation , especially in areas where the medical needs 
of patients are not met . The public , patients and civil society organisations expressed 
their expectation of  equitable access to innovative therapies  across the EU , including 
for unmet medical needs, and continuous supply  of their medicinal products . Public  
authorities and patient organisations opt ed for a variable duration for the current 
main ince ntives, as reflected in the preferred option. The p harmaceutical indust ry 
argued against any introduction of variable incentives or the shortening of existing 
ones and favour ed the introduction of additional or novel incentive s. Industry also 
highlighted the need for stability in the current legal framework and  predictability for 
incentives . The e lements on the environment, regulatory support for non -commercial 
entities and repurposing of medicin al products  included in the preferred option were 
supported by key stakeholders such as healthcare providers, academia  and 
environmental organisations.  
Concerning the revision of the legislation on medicin al products  for children and for 
rare diseases, specific consultation activities were carried out in the context of the 
impact assessment procedure: a public consultatio n ran from 7 May to 30 July 2021 . EN 10  EN Furthermore, targeted surveys, including  a costing survey both for pharmaceutical 
companies and public authorities, were conducted from 21 June to 30 July 2021 (late 
responses were accepted until the end of September 2021,  due to the summer break ). 
An interview program me with all relevant stakeholder groups  (public authorities, 
pharmaceutical industry incl uding  SMEs, academia, civil society representatives and 
healthcare providers ) was conducted at the end of June 2021 , whi le focus groups met 
on 23 February 2022 to discuss some of the main issue of the re form .  
There was broad consensus among stakeholders that  the two pieces of legislation 
have had a positive effect on the development of medicinal products for children and 
the treatment of rare diseases. However, concerning the Paediatric Regulation, all the 
current structure of the paediatric investigation pla n and of the condition allowing the 
waiver of the obligation to draw up such a plan  were considered as possible obstacles 
to the development of certain innovative products. All stakeholders highlighted that 
for both the medicinal products for rare diseases  and the medicinal products for 
children , medicinal products addressing unmet medical needs of patients should be 
better supported. Public  authorities supported  a variable duration for market 
exclusivity  for medicinal products  for rare diseases  as a tool t o better focus 
development in areas where treatments are not available. The p harmaceutical 
industry argued against any introduction of variable incentives or the shortening of 
existing ones  and favoured the introduction of additional or novel incentives. As for 
the revision of the general pharmaceutical legislation, i ndustry also highlighted the 
need for stability in the current legal framework and predictability for incentives . 
• Collection  and use of expertise   
In addition  to the extensive  stakeholder  consultation  described  in previous  sections,  
the following  external  studies  were  conducted  to support  the ‘back -to-back’  
evaluation  and impact  assessment  of the general  pharmaceutical  legislation  and the 
evaluation  and impact  assessment  of the orphan  and paediatric  legislation : 
– Study  supporting  the Evaluation  and Impact  Assessment  of the general  
pharmaceutical  legislation.  Evaluation  Report , Technopolis  Group  (2022).  
– Study  supporting  the Evaluation  and Impact  Assessm ent of the general  
pharmaceutical  legislation.  Impact  Assessment  Report , Technopolis  Group  
(2022).  
– Future -proofing  pharmaceutical  legislation  - Study  on medicine  shortages , 
Technopolis  Group  (2021) . 
– Study  to support  the evaluation  of the EU Orphan  Regulation , Technopolis  
Group  and Ecorys  (2019) . 
– Study  on the economic  impact  of supplementary  protection  certificates,  
pharmaceutical  incentives  and rewards  in Europe , Copenhagen  Economics  
(2018) . 
– Study  on the economic  impact  of the Paediatric  Regulation,  including  its 
rewards  and incentives , Technopolis  Group  and Ecorys  (2016).  
• Impact  assessments  
General pharmaceutical legislation  EN 11  EN The impact assessment for the revision of the general pharmaceutical legislation35 
analysed three policy options (A, B and C).  
– Option A builds on the status quo and achieves the objectives mainly through 
new incentives . 
– Option B reaches the objectives through more obligations and oversight . 
– Option C adopts a ‘quid pro quo’ approach in the sense that positive behaviour 
is rewarded and obligations are only used when there are no alternatives.  
Option A maintains the current system of regulatory protection for innovative 
medicinal products and adds additional conditional periods of protecti on. Priority 
antimicrobials benefit from a transferable exclusivity voucher. Current requirements 
on security of supply are retained (notification of withdrawal at least two months in 
advance). The existing requirements on the environmental risk assessment  continue 
with additional information obligations.  
Option B provides for a variable duration of regulatory data protection periods  (split 
into standard and conditional periods) . Companies must either have an antimicrobial 
in their portfolio or pay into a f und to finance the development of new ones. 
Companies are obliged to launch medicin al products  with an EU -wide authorisation 
in the majority of Member States (small markets included) and to provide 
information  on public funding received. Current requirements on security of supply 
are retained and companies are obliged to offer their marketing authorisation for 
transfer to another company before withdrawal.  The environmental risk assessment 
results in  additional responsibilities for companies.  
Option C provides for a variable duration of regulatory data protection  (split into 
standard and conditional periods), striking  a balance between providing attractive 
incentives for innovation and supporting timely patient access to medicinal products  
across t he EU.  Priority antimicrobials can benefit from a transferable exclusivity 
voucher subject to strict eligibility criteria and conditions for use of the voucher, 
while prudent -use measures further contribute to addressing antimicrobial resistance . 
Marketing  authorisation holders are required to  ensure  transparency on public 
funding for clinical trials. Reporting of shortages  is harmonised and only critical 
shortages  are brought to the attention of authorities at  the EU  level . Marketing 
authorisation holders  are obliged to notify possible shortages earlier and to offer their 
marketing authorisation for transfer to another company before withdrawal. 
Requirements on the environmental risk assessment and conditions of use are 
strengthened.  
All options are complemented by a set of common elements  aimed at simplifying and 
streamlining regulatory procedures and future -proofing the legislation with a view to 
accommodating novel technologies.  
The preferred option  is based on option C and also inc ludes the common elements 
mentioned above. The preferred option was considered to be the best policy choice , 
taking into account the specific objectives of the revision and the economic, social 
and environmental impacts  of the proposed measures.  
The prefer red option and its introduction of variable incentives  is a cost -effective 
way of achieving the objectives of improved access, addressing unmet medical need 
                                                 
35 Commission staff working document , Impact Assessment.  EN 12  EN and affordability for health systems. It is expected to provide 15% increased access, 
meaning 67 million more people residing in the EU  who can potentially benefit from 
a new medicinal product, and more medicinal products addressing unmet medical 
needs  at the same cost for the public payers as today . In addition, savings are 
expected for companies and r egulatory authorities through the cross -cutting measures 
that would allow for better coordination, simplification and accelerated regulatory 
processes.  
Measures to incentivise the development of priority antimicrobials are estimated to 
entail costs for pu blic payers and the generic industry but could be effective against 
antimicrobial resistance if applied under strict conditions and with tight measures for 
prudent use. These costs must also be seen in the context of the threat of resistant 
bacteria and cu rrent costs incurred from antimicrobial resistance including deaths, 
healthcare costs and productivity losses.  
The originator companies would have additional costs and benefits from the 
incentives and the market launch conditionality, and overall they wou ld see an 
increase in their sales.  Some  increased  costs will be associated with the reporting on 
shortages. Regulatory authorities will incur costs to perform additional tasks in the 
areas of shortage management , strengthened environmental risk assessment and 
enhanced pre-authorisation scientific and regulatory support.  
Orphan and paediatric legislation  
The impact assessment on the revision of the orphan  and paediatric  legislation also 
analysed three policy options (A, B and C) per legislative act. The different policy 
options vary as to the incentives or rewards to which medicinal products for rare 
diseases and for children would be entitled. In addition, the revision will include a 
series of common elements present in all options . 
For medicinal pro ducts for rare diseases , option A keeps the 10 years of market 
exclusivity and adds - as an additional incentive - a transferable regulatory protection 
voucher for products addressing a high unmet medical need ( HUMN ) of patients. 
Such a voucher allows for a one -year extension in the length of regulatory protection 
or can be sold to another company and used for a product in that company’s 
portfolio . 
Option B  abolishes the current market exclusivity of 10 years for all orphan 
medicin al products . 
Option C  provides for a variable duration of market exclusivity of 10, 9 and 5 years, 
based on the type of orphan medicinal product ( for HUMN, new active substances 
and well -established use applications respectively ). A ‘bonus’ market exclusivity 
extension of one year can be granted, based on patient accessibility in all relevant 
Member States, but only for HUMN products and new active substances.  
All options are complemented by a set of common elements aimed at simplif ying and 
streamlining regulatory procedures and fut ure-proofing the legislation . 
Option C  was considered to be the best policy choice, taking into account the specific 
objectives and the economic and social impacts of the proposed measures.  This 
option is expected to provide a balanced positive outcome con tributing to the 
achievement of the four objectives of the revision. It will aim to  refocus investments  
and boost innovation, in particular  in products addressing HUMN, without 
undermining the development of other medicin al products  for rare diseases.  The 
measures provided for under this option are also expected to  improve the EN 13  EN competitiveness of EU pharmaceutical industry , including of SMEs , and will lead to 
the best results in terms of patient access  (due to: (i) the possibility for generics and 
biosimilar s to enter the market earlier than they do today; and (ii) the proposed 
access conditionality for exten ding the market exclusivity ). Furthermore, more 
flexible criteria to better define an orphan condition will make the legislation  more 
‘fit’ to accommodate new technologies and reduce administrative burdens.  
The total balance of yearly costs and benefit calculated per interested stakeholder 
group for this preferred option compared to the baseline are: EUR 662 million  cost 
savings  for public payers from accelerated generic entry and a EUR 88 million  profit 
gain for the generic industry . The public will benefit from  an additional one or two 
HUMN medicinal products and overall broader and faster access for patients . 
Originators will see  an estimated  EUR 640 million  gross profit loss f rom earlier 
generic entry, but  savings are expected for companies through the cross -cutting 
measures in the general pharma ceutical  legislation that would allow for better 
coordination, simplification and acc elerated regulatory processes.  
For medicinal products for children , in o ption A the six month supplementary 
protection certificate ( SPC) extension is kept as a reward for all medicinal products 
completing a paediatric investigation plan ( ‘PIP’). Furthermore, an extra reward 
benefiting products addressing unmet medical needs  of children is added. This will 
consist of either 12 extra months of SPC extension or a regulatory protection voucher 
(duration one year) , which could be transferred to anot her product (possibly of 
another company) against payment, allowing the receiving product to benefit from 
extended regulatory data protection (+ one year). In option B , the reward for 
completi ng a PIP is abolished. Developers of every new medicinal product  would 
continue to be obliged to agree with the EMA  and conduct a PIP , but the extra costs 
incurred would not be rewarded. In option C, like today , the six month SPC 
extension remains the main reward for completing a PIP. All options are 
complemented by a s et of common elements aimed at simplif ying and streamlining 
regulatory procedures and future -proofing the legislation . 
Option C was considered the best policy choice, taking into account the proposed 
measures’ specific objectives and economic s and social i mpacts . Option C is 
expected to yield to an increased number of medicinal products , in particular in areas 
of unmet medical needs of children , which are expected to reach children faster than 
today . It would also  ensur e a fair re turn of investment for medicinal products  
developers who fulfil the legal obligation to study medicin al products  in children, as 
well as reduced administrative costs linked to the procedures that follow from the 
obligation.  
New simplification measures and obligations (for examp le those linked to medicinal 
product’s mechanism of action) are expected to cut time to access to children’s 
versions of medicinal products by 2 -3 years and to bring three more new medicinal 
products for children yearly compared to the baseline, which in t urn results in 
additional rewards for developers. These new medicinal products for children will 
result, on a yearly basis, in costs for the public estimated EUR 151 million, while 
originator companies would gain EUR 103 million in gross profits to compens ate 
their efforts. Thanks to simplification of the rewards scheme linked to the study of 
medicinal products for use in children, generic companies will find it easier to 
predict when they will be able to enter the market.  EN 14  EN • Regulatory  fitness  and simplifi cation  
The proposed  revisions  aim to simplify  the regulatory  framework  and improv e its 
effectiveness  and efficiency,  thereby  reducing  the administrative  costs  borne  by 
companies  and competent  authorities.  Most  of the envisaged  measures  will act on 
core procedures  for the authorisation  and lifecycle  management  of medicinal  
products.  
Administrative  costs  will fall for competent  authorities,  business  and other  relevant  
entities,  for two overarching  reasons.  Firstly,  procedures  will be streamlin ed and 
accele rated, for example  in connection  with the renewal  of marketing  authorisations  
and the submission  of variations  or the transfer  of the responsibility  for orphan  
designations  from  the Commission  to the EMA.  Secondly,  there  will be enhanced  
coordination  of the European  medicines  regulatory  network , for example  in terms  of 
the work  of different  EMA  committees  and interactions  with related  regulatory  
frameworks.  Further  contributions  to cost reductions  for business  and administrations  
are expected  to come  from  adaptations  to accommodate  new concepts  such as 
adaptive  clinical  trials,  a medicinal  product’s  mechanism  of action,  use of real world  
evidence,  and new uses of health  data within  the regulatory  framework . 
Enhanced  digitisation  will facilitate  the integration  of regulatory  systems  and 
platforms  across  the EU and support  for the re-use of data, and is expected  to reduce  
costs  for administrations  over time (although  it may induce  initial  one-off costs ). For 
example,  electronic  submissions  by industry  to the European  Medicines  Agency  and 
competent  authorities  of the Member  States  will deliver  cost savings  to industry.  
Moreover,  the envisaged  use of the electronic  product  information  (as opposed  to 
paper  leaflets ) should  also lead to administrative  cost reductions.  
SMEs  and non-commercial  entities  involved  in the develop ment  of medicinal  
products  are expected  to benefit  in particular  from  the envisaged  simplification  of 
procedures,  wider  use of electronic  processes  and reduction  of administrative  burden.  
The proposal  also aims  at optimis ing the regulatory  support  (e.g. scientific  advice)  to 
SMEs  and non-commercial  organisations , resulting  in additional  reductions  of 
adminis trative  costs  for these  parties.  
Overall,  the envisaged  measures  for simplification  and burden  reduction  are expected  
to reduce  costs  for businesses,  supporting  the ‘one in one out’ approach.  In 
particular,  the proposed  streamlining  procedures  and enhanced  support  are expected  
to yield  cost savings  for EU pharmaceutical  industry.  
• Fundamental  rights  
The proposal contributes to achieving a high level of human health protection  and is 
therefore consistent with Article 35 of the Charter of Fundamental Rights  of the 
European Union .  
4. BUDGETARY  IMPLICATIONS  
The financial  impact  is shown  in the Legal  Financial  Statement  attached  to the 
proposal  for a Regulation  of the European  Parliament  and of the Council,  laying  
down  Union  procedures  for the authorisation  and supervision  of medicinal  products  
for human  use and establishing  rules  governing  the European  Medicines  Agency,  
amending  Regulation  (EC)  No 1394/2007  and Regulation  (EU)  No 536/2014  and 
repealing  Regulation  (EC)  No 726/2004,  Regulation  (EC)  No 141/2000  and 
Regulation  (EC)  No 1901/2006.  EN 15  EN 5. OTHER  ELEMENTS  
• Implementation  plans  and monitoring,  evaluation  and reporting  arrangements  
The developmen t of new medicinal products  can be a long process that can take up to 
10-15 years. Incentives and rewards therefore have an influence  many years after the 
marketing authorisation date. The benefit for patients also needs to be measured over 
a period of at least 5 -10 years after a medicinal product  is authorised. The 
Commission intends to monitor relevant parameters that enable assessmen t of 
progress of the proposed measures  with a view to reaching their objectives. The 
majority of indicators are already collected at  the EMA level. Furthermore, the 
Pharmaceutical Committee36 will provide a forum for discussing issues related to  the 
transpo sition and monitoring progress. The Commission will report on the 
monitoring periodically. A meaningful evaluation of the results of the revised 
legislation can only be envisaged after at least 15 years from the deadline for its 
transpos ition. 
• Explanator y documents  (for directives)  
Following the ruling of the European Court of Justice in Commission vs Belgium 
(Case C -543/17), Member States must accompany their notifications of national 
transposition measures with sufficiently clear and precise information, indicating 
which provisions of national law transpose which provisions of a directive. This must 
be provided for each obligation, not only at article level. If Member States comply 
with this obligation, they would not need, in principle, to se nd explanatory 
documents on the transposition to the Commission.  
• Detailed  explanation  of the specific  provisions  of the proposal  
The proposed revision of the pharmaceutical legislation consists of a proposal for a 
new directive and a proposal for a new r egulation (see previous section ‘Consistency 
with existing provisions in the policy area’), which will also cover orphan and 
paediatric medicinal products. Provisions for orphan medicinal products have been 
integrated in the proposed regulation. While procedural  requirements appl icable  to 
paediatric  medicinal products are primarily integrated in the new regulation , the 
general framework for the authorisation and rewarding of these products ha ve been 
included in the new directive . The main areas of the revis ion under the proposed new 
regulation are covered by the explanatory memorandum of the accompanying 
proposal for  a regulation.  
Annex II to the directive contains the existing text of Annex I. Annex II will be 
updated by delegated act. The delegated act wil l be adopted and applied before the  
deadline for the transposition of the directive.  
The proposed directive includes the following main areas of revision:  
Promoting innovation and access to affordable medicinal products - creating a 
balanced pharmaceutical  ecosystem  
To enable innovation and promote the competitiveness of the EU pharmaceutical 
industry, in particular SMEs, the provisions of the proposed directive work in 
synergy with those of the proposed regulation. In this respect, a balanced system of 
incentives is proposed . The system  rewards innovation, especially in areas of unmet 
                                                 
36 Council Decision of 20 May 1975 setting up a pharmaceutical committee (75/320/EEC) . EN 16  EN medical needs , and innovation reaches patients and improves access across the EU. 
To make the regulatory system more efficient and innovation -friendly, measures are 
proposed t o simplify and streamline procedures and to create an agile and future -
proof framework (see also measures under ‘Reducing regulatory burden and 
providing a flexible regulatory framework to support innovation and 
competitiveness’ below and in the proposed r egulation).  
Introduction of variable incentives related to regulatory data protection  and 
rewarding  of innovation in areas of unmet medical needs  
The current standard period of regulatory data protection will be reduced from eight 
years to six years. Nevertheless, this remains competitive given what other regions 
offer. Furthermore, marketing authorisation holders will benefit from additional 
periods of data protection (beyond the standard six years) if they launch the 
medicinal products in all Member States covered by the marketing authorisation 
(+two years), if they address unmet medical needs (+ six months) , if they conduct 
comparative clinical trials (+six months ) or for an additional therapeutic indication (+ 
one year).  
Prolongation of data p rotection for the market launch will be granted if the medicinal 
product is supplied in accordance with the needs of the Member States concerned 
within two years from the marketing authorisation (or within three  years in the case 
of SMEs, not-for-profit en tities  or companies with limited experience in the EU 
system ). Member States have the possibility to waive the condition of launch in their 
territory for the purpose of the prolongation. This is expected to be the case 
particularly in situations where laun ch in a particular Member State is materially 
impossible or because there are special reasons why a Member State wishes that 
launch take s place later. Such a waiver does not mean that a Member State is not 
interested in the medicinal product altogether.  
Prolongation of data protection for addressing unmet medical need will be granted if 
the medicinal product is for a life -threatening or seriously debilitating disease with 
remaining high morbidity or mortality, and the use of the medicinal product results in 
a meaningful reduction in disease morbidity or mortality. The various elements of 
this criterion -based definition of unmet medical need (e.g. “remaining high morbidity 
or mortality”) will be further specified in implementing acts, taking into account 
scientific input by the EMA, to ensure that the concept of unmet medical need 
reflects scientific and technological developments and current knowledge in 
underserved diseases.  
The period of regulatory data protection is  followed by a period of market protect ion 
(two years), which remains unchanged under the proposed directive  as compared to 
the existing rules . 
With the additional conditional protection periods, the period of regulatory protection 
(data and market protection) can add up to 12 years  for innovat ive medicines (if a 
new therapeutic indication is added after the initial marketing authorisation).  
In addition, f or a medicinal product addressing  an unmet medical need , a company 
will benefit from an enhanced scientific and regulatory support scheme (‘PRIME’)  
and from accelerated assessment mechanisms . The PRIME support scheme will 
boost innovation in areas of unmet medical needs, allow pharmaceutical companies 
to speed up the development process and allow earlier patient access . The various 
elements of this criterion -based definition of unmet medical need (e.g “remaining EN 17  EN high morbidity or mortality”) will be further specified in implementing acts, taking 
into account scientific input by the EMA, to ensure that the concept of unmet 
medical need reflect s scientific and technological developments and current 
knowledge in underserved diseas es. 
Increased competition from earlier market entry of generic and biosimilar medicinal 
products  
The ‘Bolar exemption’ (under which studies can be carried out for subseq uent 
regulatory approval of generics and biosimilars during the patent  or supplemen tary 
protection certificate protection of the reference medicinal product), will be 
broadened in scope and its harmonised application in all Member States ensured. In 
additi on, procedures for the authorisation of generics and biosimilars will be 
simplified: as a general rule, risk management plans will no longer be required for 
generic and biosimilar medicinal products, considering that the reference medicinal 
product already  has such a plan. The interchangeability of biosimilars with their 
refere nce medicinal  products is also better recognised based on accumulated 
scientific experience with s uch medicinal  products. In addition, the act provides an 
incentive for repurposing off -patent, added value medicinal products. This supports 
innovation, resulting in a new therapeutic indication that offers significant clinical 
benefit in comparison with existing thera pies. Taken together, these measures will 
facilitate earlier market entry of generics and biosimilars, thus increasing competition 
and contributing to the objectives of promoting affordability of medicinal products 
and patient access.  
Increased transparency on the contribution of public funding to research & 
development costs  
Marketing authorisation holders will be required to publish a report listing all direct 
financial support received from any public authority or publicly funded body for the 
research and development of the medicinal product, whether successful or not 
successful . Such information will be easily accessible to the public on a dedicated 
webpage of the marketing authorisation holder and in the database of all medicinal 
products for  human use authorised in the EU. Greater transparency around public 
funding for medicinal products development is expected to help maintain or improve 
access to affordable medicinal products.  
Reducing the environmental impac t of medicinal product s  
Strengt hening the requirements for the environmental risk assessment (ERA) in the 
market authorisation of medicinal products will drive pharmaceutical companies to 
evaluate and limit potential adverse effects to the environment and public health. The 
scope of the  ERA is extended to cover new protection goals such as the risks of 
antimicrobial resistance.  
Reducing the regulatory burden and providing a flexible regulatory framework to 
support innovation and competitiveness  
Reduction of the regulatory burden will be ensured by measures simplify ing 
regulatory procedures and improv ing digitisation. These include provisions on 
electronic submission of applications and electronic product information (ePI) on 
authorised medicinal products, the latter being an option that M ember States can opt 
for based on their particular readiness to replace the paper leaflet. Measures to reduce 
regulatory bu rden also include  abolishing the renewal and the sunset clause. The 
reduction of administrative burden through simplification and digitisation measures EN 18  EN will benefit in particular to SMEs and not -for-profit entities involved in developing 
medicinal products. The various measures to reduce the regulatory burden will 
strengthen the competitiveness of the pharm aceutical sector.  
Adapted frameworks with specific regulatory requirements tailored to the 
characteristics or methods inherent to certain, especially novel, medicinal products 
will ensure an agile and future -proof regulatory environment while keeping the 
existing high standards of quality, safety and efficacy. Such adapted frameworks 
could draw on the results of the regulatory sandboxes established in the proposed 
regulation.  
The proposed directive provides rules for products which combine a medicinal 
produ ct and a medical device and specifies the interplay with the medical devices 
legal framework. These provisions improve legal certainty in order to accommodate 
increasing innovation in this field. In addition, the interplay with the legislation on 
substance s of human origin (‘SoHO’  as defined in the ‘SoHO Regulation’) is further 
clarified with a new definition of ‘SoHO -derived medicinal product’ and the 
possibility for the EMA to make a scientific recommendation on a medicinal 
product’s regulatory status, un der the classification mechanism proposed in the 
regulation, in consultation with the relevant SoHO regulatory body. The proposed 
directive also introduces measures to improve the application of hospital exemptions 
for advanced therapy medicinal products.  
Specific provisions for new platform technologies37 will facilitate the development 
and authorisation of such types of innovation for the benefit of patients.  
Specific measures related to quality and manufacturing  
The advent of new therapeutic approaches t hat have features such as very short shelf -
lives, and which may be highly personalised, enable decentralised manufacture and 
use of patient -specific medicinal products. These paradigms of decentralised or 
personalised manufacturing require a shift away fro m existing regulatory frameworks 
that are designed to meet the regulatory expectations for large -scale centralised 
manufacture. The new legal framework incorporates a risk -based and flexible 
approach that will enable the manufacture or testing of a wide ra nge of medicinal 
products in close proximity to the  patient.  
                                                 
37 When a certain process/method is used to manufacture specific individualised treatments, i.e. 
adjustments to the medicine are made based on the characteristics of the patient or the causing 
pathogen.  EN 19  EN 2023/0132 (COD)  
Proposal for a  
DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL  
on the Union code relating to medicinal products for human use, and repealing Directive 
2001/83/EC and Directive 2009/35/EC  
(Text with EEA relevance)  
THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN UNION,  
Having regard to the Treaty on the Functioning of the European Union, and in partic ular 
Articles 114(1) and 168(4)(c)  thereof,  
Having regard to the proposal from the European Commission,  
After transmission of the draft legislative act to the national parliaments,  
Having regard to the opinion of the European Economic and Social Committee,  
Having regard to the opinion of the Committee of the Regions,  
Acting in accordance with the ordinary legislative procedure,  
Whereas:  
(1) The Union  general pharmaceutical legislation was established in 1965 with the dual 
objective of safeguarding public health and harmonising the internal market for 
medicines. It has developed considerably since then, but these overarching objectives 
have guided all revisions. The legislation governs the granting of marketing 
authorisations for all medicines for human use by defining conditions and procedures 
to enter and remain on the market. A fundamental principle is that a marketing 
authorisation is granted only t o medicines with a positive benefit -risk balance after 
assessment of their quality, safety and efficacy.  
(2) The most recent comprehensive revision took place between 2001 and 2004 while 
targeted revisions on post -authorisation monitoring (pharmacovigilanc e) and on 
falsified medicines were adopted subsequently. In the almost 20 years since the last 
comprehensive revision, the pharmaceutical sector has changed and has become more 
globalised, both in terms of development and manufacture. Moreover, science and  
technology have evolved at a rapid pace. However, there continues to be unmet 
medical needs, i.e. diseases without or only with suboptimal treatments. Moreover, 
some patients may not benefit from innovation because medicines may be 
unaffordable or not pla ced on the market in the Member State concerned. There is also 
a greater awareness of the environmental impact of medicines. More recently, the 
COVID -19 pandemic has stress tested the framework.  
(3) This revision is part of the implementation of the Pharma ceutical strategy for Europe 
and aims to promote innovation, in particular for unmet medical needs, while reducing 
regulatory burden and the environmental impact of medicines; ensure access to 
innovative and established medicines for patients, with special  attention to enhancing 
security of supply and addressing risks of shortages, taking into account the challenges EN 20  EN of the smaller markets of the Union ; and create a balanced and competitive system that 
keeps medicines affordable for health systems while rewa rding innovation.  
(4) This revision focuses on provisions relevant to achieve its specific objectives; 
therefore it covers all but provisions concerning falsified medicines, homeopathic and 
traditional herbal medicines. Nevertheless, for the sake of clarit y, it is necessary to 
replace Directive 2001/83/EC of the European Parliament and of the Council1 with a 
new Directive. The provisions on falsified medicines, homeopathic medicines and 
traditional herbal medicines are therefore maintained in this Directive  without 
changing their substance compared to previous harmonisations. However, in view of 
the changes in the governance of the Agency, the Herbal Committee is replaced by a 
working group .  
(5) The essential aim of any rules governing the authorisation, ma nufacturing, 
supervision, distribution and use of medicinal products must be to safeguard public 
health. Such rules should also ensure the free movement of medicinal products and the 
elimination of obstacles to trade in medicinal products to all patients i n the Union.   
(6) The regulatory framework for medicinal products use should also take into account the 
needs of the undertakings in the pharmaceutical sector and trade in medicinal products 
within the Union, without jeopardising the quality, safety and ef ficacy of medicinal 
products.  
(7) The EU and all its Member States as parties to the U nited Nations  Convention on the 
Rights of Persons with Disabilities are bound by its provisions to the extent of their 
competences. This includes the right to access inf ormation as set out in Article 21 and 
the right to the enjoyment of the highest attainable standard of health without 
discrimination on the basis of disability as set in Article 25.  
(8) This revision maintains the level of harmonisation that has been achieved. Where 
necessary and appropriate, it further reduces the remaining disparities, by laying down 
rules on the supervision and control of medicinal products and the rights and duties 
incumbent upon the competent authorities of the Member States with a view to 
ensuring compliance with legal requirements. In the light of experience gained on the 
application of the Union pharmaceutical legislation and the  evaluation of its 
functioning , the regulatory framework need to be adapted to scientific and 
technol ogical progress, the current market conditions and economic reality within the 
Union. Scientific and technological developments induce innovation and development 
of medicinal products, including for therapeutic areas where there is still unmet 
medical need . To harness these developments, the Union pharmaceutical framework 
should be adapted to meet scientific developments such as genomics, accommodate 
cutting edge medicinal products, e.g. personalised medicinal products and 
technological transformation such as data analytics , digital tools  and the use of 
artificial intelligence . These adaptations also contribute to competitiveness of the 
Union pharmaceutical industry.  
(9) Medicinal products for rare diseases and for children, should be subject to the same 
conditions as any other medicinal product concerning their quality, safety and 
efficacy, for example for what concerns the marketing authorisation procedures, 
quality and the pharmacovigilance requirements. However, specific requirements also 
                                                 
1 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the 
Community code  relating to medicinal products for human use (OJ L 311, 28.11.2001, p. 67).  EN 21  EN apply to them co nsidering their unique characteristics. Such requirements, which are 
currently defined in separate legislations, should be integrated in general 
pharmaceutical legal framework in order to ensure clarity and coherency of all the 
measures applicable to these  medicinal products. Furthermore, as some medicinal 
products authorised for use in children are authorised by the Member States, specific 
provisions should be integrated  in this Directive.  
(10) The system of a d irective and regulation for the general pharm aceutical legislation 
should be maintained to avoid fragmentation of national legislation on medicinal 
products for human use, given that the legislation is based on a system of national 
Member States and Union marketing authorisations. Member States natio nal 
marketing authorisations are granted and managed on the basis of national law 
implementing the Union pharmaceutical law. The evaluation of the general 
pharmaceutical legislation has not shown that the choice of legal instrument has 
caused specific prob lems or created disharmonisation. In addition, a REFIT Platform2 
opinion in 2019 showed that there was not support among the Member States to turn 
Directive 2001/83/EC into a Regulation.  
(11) The Directive should work in synergy with the Regulation to enab le innovation and 
promote competitiveness of the Union  pharmaceutical industry, in particular SME s. In 
this respect a balanced system of incentives is proposed that rewards innovation 
especially in areas of unmet medical need and innovation that reaches pa tients and 
improves access across the Union . To make the regulatory system more efficient and 
innovation -friendly the Directive also aims at reducing administrative burden and 
simplifying procedures for undertakings.  
(12) The definitions and scope of Directive 2001/83/EC should be clarified in order to 
achieve high standards for the quality, safety and efficacy of medicinal products and to 
address potential regulatory gaps, without changing the overall scope, due to scientific 
and technological develop ments, e.g. low -volume products, bedside -manufacturing or 
personalised medicinal products that do not involve an industrial manufacturing 
process.  
(13) To avoid the duplication of requirements for medicinal products in this Directive and 
in the Regulation,  the general standards in regards to quality, safety and efficacy of 
medicinal products laid down in this Directive shall be applicable to medicinal 
products covered by national marketing authorisation and also to medicinal products 
covered by centralised marketing authorisation . Therefore, the requirements for an 
application for medicinal product are valid for both, also the rules on prescription 
status, product information, regulatory protection and rules  on manufacturing, supply, 
advertising, supervision  and other national requirements shall be applicable to 
medicinal products covered by centralised marketing authorisation.  
(14) The determination of whether a product falls within the definition of a medicinal 
product must be made on a case -by-case basis t aking into account the factors set out in 
this Directive, such as the product’s presentation or pharmacological, immunological 
or metabolic properties.  
(15) In order to take account both of the emergence of new therapies and of the growing 
number of so -called ‘borderline’ products between the medicinal product sector and 
                                                 
2 The EU's efforts to simplify legislation – 2019 Annual Burden survey,     
 https://commission.europa.eu/system/files/2020 -08/annual_burden_survey_2019_4_digital.pdf . EN 22  EN other sectors, certain definitions and derogations should be modified, so as to avoid 
any doubt as to the applicable legislation. With the same objective of clarifying 
situations when a pro duct fully falls within the definition of a medicinal product  and 
also meet the definition of other regulated products , the rules for medicinal products 
under this Directive apply. Furthermore, to ensure the clarity of applicable rules, it is 
also appropri ate to improve the consistency of the terminology of the pharmaceutical 
legislation and clearly indicate the products excluded from the scope of this Directive.  
(16) The new definition for a substance of human origin (SOHO) by the [SoHO 
Regulation]  covers any substance collected from the human body in whatever manner, 
whether it contains cells or not and regardless of whether it meets the definition of 
‘blood’, ‘tissue’ or ‘cell’, for example human breast milk, intestinal microbiota and 
any other SoHO that may be applied to humans in the future. Such substances of 
human origin, other than tissues and cells, may become SoHO derived medicinal 
products, other than ATMPs, when the SoHO is subject to an industrial process 
involving systematisation, reproducibilit y and operations performed on a routine basis 
or batch -wise resulting in a product of standardised consistency. When a process 
concerns extraction of an active ingredient from the SoHO, other than tissues and 
cells, or a transformation of a SoHO, other tha n tissues and cells, by changing its 
inherent properties, this should also be considered a SoHO derived medicinal product.  
When a process concerns concentrating, separating or isolating elements in the 
preparation of blood components, this should not be co nsidered as changing their 
inherent properties . 
(17) For avoidance of doubt, the safety and quality of human organs intended for 
transplantation are regulated only by Directive 2010/53/EU  of the European 
Parliament and of the Council3, and the safety and q uality of substances of human 
origin intended for medically assisted reproduction are regulated only by [SoHO 
Regulation or if not in force, Directive 2004/23/EC].  
(18) Advanced therapy medicinal products that are prepared on a non -routine basis 
according to specific quality standards, and used within the same Member State in a 
hospital under the exclusive professional responsibility of a medical practitioner, in 
order to comply with an individual medical prescription for a custom -made product for 
an indivi dual patient, should be excluded from the scope of this Directive whilst at the 
same time ensuring that relevant Union rules related to quality and safety are not 
undermined (‘hospital exemption’). Experience has shown that there are great 
differences in t he application of hospital exemption among Member States. To 
improve the application of hospital exemption this Directive introduces measures for 
collection, reporting of data as well as review of these data yearly by the competent 
authorities and their pu blication by the Agency in a repository. Furthermore, the 
Agency should provide a report on the implementation of hospital exemption on the 
basis of contributions from Member States in order to examine whether an adapted 
framework should be established for  certain less complex ATMPs that have been 
developed and used under the hospital exemption. When an authorisation for the 
manufacturing and use of an ATMP under hospital exemption is revoked because of 
safety concerns, the relevant competent authorities sh all inform the competent 
authorities of other Member States.   
                                                 
3 Directive 2010/45/EU of the European Parliament and of the Council of 7 July 2010 on standards of 
quality and safety of human organs intended for transplantation (OJ L 207, 6.8.2010, p. 14).  EN 23  EN (19) This Directive should be without prejudice to the provisions of Council Directive 
2013/59/Euratom4, including with respect to justification and optimisation of 
protection of patients and ot her individuals subject to medical exposure to ionising 
radiation. In the case of radiopharmaceuticals used for therapy, marketing 
authorisations, posology and administration rules have to notably respect that 
Directive’s requirements that exposures of tar get volumes are to be individually 
planned, and their delivery appropriately verified taking into account that doses to 
non-target volumes and tissues are to be as low as reasonably achievable and 
consistent with the intended therap eutic purpose of the exp osure.  
(20) In the interest of public health, a medicinal product should only be allowed to be 
placed on the market in the Union when the marketing authorisation has been granted 
to the medicinal product, and its quality, safety and efficacy have been dem onstrated.  
However, exemption should be provided from this requirement in situations 
characterised by an urgent need to administer a medicinal product to address the 
specific needs of a patient, or confirmed spread of pathogenic agents, toxins, chemical 
agents or nuc lear radiation that could cause harm. In particular, to fulfil special needs, 
Member States should be allowed to exclude from the provisions of this Directive 
medicinal products supplied in response to a bona fide unsolicited order, formulated in 
accordanc e with the specifications of an authorised healthcare professional and for use 
by an individual patient under their direct personal responsibility. Member States 
should be also allowed to temporarily authorise the distribution of an unauthorised 
medicinal product in response to a suspected or confirmed spread of pathogenic 
agents, toxins, chemical agents or nuclear radiation any of which could cause harm.   
(21) Marketing authorisation decisions should be taken on the basis of the objective 
scientific criter ia of quality, safety and efficacy of the medicinal product concerned, to 
the exclusion of economic or any other considerations. However, Member States 
should be able exceptionally to prohibit the use in their territory of medicinal products.  
(22) The particulars and documentations that are to accompany an application for 
marketing authorisation for a medicinal product demonstrate that the therapeutic 
efficacy of the product overweight potential risks. The benefit -risk balance of all 
medicinal products will be assessed when they are placed on the market, and at any 
other time the competent authority deems appropriate.  
(23) As market forces alone have proven insufficient to stimulate adequate research into, 
and the development and authorisation of, medici nal products for the paediatric 
population, a system of both obligations and rewards and incentives has been put in 
place.  
(24) It is therefore necessary to introduce a requirement for new medicinal products or 
when developing paediatric indications of al ready authorised products covered by a 
patent or a supplementary protection certificate to present either the results of studies 
in the paediatric population in accordance with an agreed paediatric investigation plan 
or proof of having obtained a waiver or  deferral, at the time of filing a marketing 
authorisation application or an application for a new therapeutic indication, new 
pharmaceutical form or new route of administration.  However, in order to avoid 
                                                 
4 Council Directive 2013/59/Euratom of 5 December 2013 laying down basic safety standards for 
protection against the dangers  arising from exposure to ionising radiation, and repealing Directives 
89/618/Euratom, 90/641/Euratom, 96/29/Euratom, 97/43/Euratom and 2003/122/Euratom ( OJ L 13, 
17.1.2014, p. 1).  EN 24  EN exposing children to unnecessary clinical trials or due to the nature of the medicinal  
products, that requirement should not apply to generics or similar biological medicinal 
products and medicinal products authorised through the well -established med icinal use 
procedure, nor to homeopathic medicinal products and traditional herbal medicinal 
products authorised  through the simplified registration procedures  of this Directive . 
(25) In order to ensure that the data supporting the marketing authorisation concerning the 
use of a product in children to be authorised under this regulation have been correctly 
developed, the competent authorities should check compliance with the agreed 
paediatric investigation plan and any waivers and deferrals at the validatio n step for 
marketing authorisation applications.  
(26) In order to reward the compliance with all the measures included in the agreed 
paediatric investigation plan, for products covered by a supplementary protection 
certificate, if relevant information on t he results of the studies conducted is included in 
the product information, a reward should be granted in the form of a six month 
extension of the supplementary protection certificate created by [Regulation (EC) No 
469/2009 of the European Parliament and o f the Council5- OP please replace reference 
by new instrument when adopted ]. 
(27) Certain particulars and documentation that are normally to be submitted with an 
application for a marketing authorisation should not be required if a medicinal product 
is a generic medicinal product or a similar biological medicinal product (biosimilar) 
that is authorised or has been authorised in the Union. Both generic and biosimilar 
medicinal products are important to ensure access of medicinal products to a wider 
patient population and create a competitive internal market. In a joint statement 
authoriti es of the Member States confirmed that the experience with approved 
biosimilar medicinal products over the past 15 years has shown that in terms of 
efficacy, safety and immunogenicity they are comparable to their reference medicinal 
product and are therefo re interchangeable and can be used instead of its reference 
product (or vice versa) or replaced by another biosimilar of the same reference 
product . 
(28) Experience has shown that it is advisable to stipulate precisely the cases in which the 
results of tox icological and pharmacological tests or clinical studies  do not have to be 
provided with a view to obtaining authorisation for a medicinal product that is 
essentially similar to an authorised product, while ensuring that innovative 
undertakings are not pla ced at a disadvantage. For these specified  categories of 
medicinal products an abridged procedure  allow s applicant s to rely on data submitted 
by previous applicants and therefore to submit only some specific documentation.  
(29) For generic medicinal produc ts only the  equivalence of the generic medicinal product 
with the reference medicinal product has to be demonstrated.  For biological medicinal 
products, only the results of comparability tests and studies are provided to the 
competent authorities. For hybr id medicinal products i.e. i n cases where the medicinal 
product does not fall within the definition of a generic medicinal product or has 
changes in strength, pharmaceutical form, route of administration or therapeutic 
indications, compared to the referenc e medicinal product, the results of the appropriate 
non-clinical tests or clinical studies shall be provided to the extent necessary to 
                                                 
5 Regulation (EC) No 469/2009 of the European Parliament and of the Council  of 6 May 2009 
concerning the supplementary protection cert ificate for medicinal products (OJ L 152, 16.6.2009, p. 
10). EN 25  EN establish a scientific bridge to the data relied upon in the marketing authorisation for 
the reference medicinal product . The same applies  to bio -hybrid s i.e. in cases where a 
biosimilar medicinal product has changes in strength, pharmaceutical form, route of 
administration or therapeutic indications, compared to the reference biological 
medicinal product . In the latter two  situations, t he scientific bridge establish es that the 
active substance of the hybrid does not differ significantly in properties with regard to 
safety or efficacy. Where it differs significantly in respect of those properties, the 
applicant needs to subm it a full application.   
(30) Regulatory decision -making on the development, authorisation and supervision of 
medicines may be supported by access and analysis of health data, including real 
world data i.e. health data generated outside of clinical studies,  where appropriate. The 
competent authorities should be able to use such data, including via the European 
Health Data Space interoperable infrastructure . 
(31) Directive 2010/63/EU of the European Parliament and of the Council6 lays down 
provisions on the p rotection of animals used for scientific purposes based on the 
principles of replacement, reduction and refinement. Any study involving the use of 
animals, which provides essential information on the quality, safety and efficacy of a 
medicinal product, sho uld take into account those principles of replacement, reduction 
and refinement, where they concern the care and use of live animals for scientific 
purposes, and should be optimised in order to provide the most satisfactory results 
whilst using the minimum  number of animals. The procedures of such testing should 
be designed to avoid causing pain, suffering , distress or lasting harm  to animals and 
should follow the available EMA and ICH guidelines. In particular, the marketing 
authorisation applicant  and the marketing authorisation holder should take into 
account the principles laid down in Directive 2010/63/EU, including , where possible, 
use new approach methodologies in place of animal testing. These can include but are 
not limited to: in vitro model s, such as microphysiological systems including organ -
on-chips, (2D and 3D -) cell culture models, organoids and human stem cells -based 
models; in silico tools or read -across models.  
(32) Procedures should be in place to facilitate joint animal testing, whe rever possible, in 
order t o avoid unnecessary duplication of testing using live animals  covered by 
Directive 2010/63/EU . Marketing authorisation applicants and marketing authorisation 
holder s should make all efforts to reuse animal study results and make the results 
obtained from animal studies publicly available . For abridged applications marketing 
authorisation applicants should refer to the relevant studies conducted for the reference 
medicinal product.  
(33) With respect to clinical trials, in particular  those conducted outside the Union, on 
medicinal products destined to be authorised within the Union, it should be verified, at 
the time of the evaluation of the marketing authorisation application, that these trials 
were conducted in accordance with the p rinciples of good clinical practice and the 
ethical requirements equivalent to the provisions of Regulation (EU) 536/2014  of the 
European Parliament and of the Council7. 
                                                 
6 Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the 
protection of animals used for scientif ic purposes  (OJ L 276, 20.10.2010, p. 33 ). 
7 Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on 
clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (OJ L 158, 
27.5.2014, p. 1).  EN 26  EN (34) There is the possibility under certain circumstances for marketing authorisations to be 
granted, subject to specific obligations or conditions, on a conditional basis or under 
exceptional circumstances. The legislation should allow under similar circumstan ces 
for medicinal products with a standard marketing authorisation for new therapeutic 
indications to be authorised on a conditional basis or under exceptional circumstances. 
The products authorised on a conditional basis or under exceptional circumstances  
should in principle satisfy the requirements for a standard marketing authorisation 
with the exception of the specific derogations or conditions outlined in the relevant 
conditional or exceptional marketing authorisation and shall  be subject to specific 
review of the fulfilment of the imposed specific conditions or obligations. The grounds 
for refusal of a marketing authorisation should apply mutatis mutandis  for such cases.  
(35) With the exception of those medicinal products that are subject to the centra lised 
authorisation procedure established by [revised Regulation (EU) No. 726/2004], a 
marketing authorisation for a medicinal product should be granted by a competent 
authority in one Member State. In order to avoid unnecessary administrative and 
financia l burdens for applicants and competent authorities, a full in -depth assessment 
of an application for the authorisation of a medicinal product should be carried out 
only once. It is appropriate therefore to lay down special procedures for the mutual 
recogni tion of national authorisations. Moreover, it should be possible to submit the 
same application in parallel in several Member States for the purpose of a common 
assessment under the lead of one of the Member States concerned.  
(36) Moreover, rules should be  established under those procedures to resolve any 
disagreements between competent authorities in a coordination group for mutual 
recognition and decentralised procedures medicinal products (‘the coordination 
group’) without undue delay. In the event of a disagreement between Member States 
about the quality, the safety or the efficacy of a medicinal product, a scientific 
evaluation of the matter should be undertaken according to a Union standard, leading 
to a single decision on the area of disagreement bind ing on the Member States 
concerned. Whereas this decision should be adopted by a rapid procedure ensuring 
close cooperation between the Commission and the Member States.  
(37) In certain cases of major disagreement that cannot be solved, the case should be 
escalated and be subject to a scientific opinion of the Agency, which is then 
implemented through a Commission Decision.  
(38) In order to better protect public health and avoid any unnecessary duplication of effort 
during the examination of application for  a marketing authorisation for medicinal 
products, Member States should systematically prepare assessment reports in respect 
of each medicinal product that is authorised by them, and exchange the reports upon 
request. Furthermore, a Member State should be able to suspend the examination of an 
application for authorisation to place a medicinal product on the market that is 
currently under active consideration in another Member State with a view to 
recognising the decision reached by the latter Member State.  
(39) In the interest of as broad as possible access to medicinal products, a Member State 
that has an interest in receiving access to a particular medicinal product undergoing 
authorisation through the decentralised and mutual recognition procedures should  be 
able to opt -into that procedure.  
(40) In order to increase availability of medicinal products, in particular on smaller 
markets, it should, in cases where an applicant does not apply for an authorisation for 
a medicinal product in the context of the mu tual-recognition procedure in a given EN 27  EN Member State, be possible for that Member State, for justified public health reasons, to 
authorise the placing on the market of the medicinal product.  
(41) In the case of generic medicinal products of which the referen ce medicinal product has 
been granted a marketing authorisation under the centralised procedure, applicants 
seeking marketing authorisation should be able to choose either of the two procedures, 
on certain conditions. Similarly, the mutual -recognition or d ecentralised procedure 
should remain  available as an option for certain medicinal products , even if they  
represent a therapeutic innovation or are of benefit to society or to patients. Since 
generic medicines account for a major part of the market in medic inal products, their 
access to the Union market should be facilitated in the light of the experience 
acquired, therefore, the procedures to include other Member States concerned to such 
procedure should be further simplified.  
(42) The simplification of procedures  should not have an impact on standards or the quality 
of scientific evaluation of medicinal products to guarantee the quality, safety and 
efficacy  and t herefore, the scientific evaluation period should remain . However, the 
reduction of overall period for marketing authorisation procedure from 210 days to 
180 days  is foreseen . 
(43) Member States should ensure adequate funding of competent authorities to carry out 
their tasks under this Directive and [revised Regulation (EU) 726/2004]. In addition,  
Member States should ensure adequate resources are assigned by the competent 
authorities for the purpose of their contributions to the work of the Agency, taking into 
account the cost -based remuneration they receive from the Agency.  
(44) As regards acces s to medicinal products, previous amendments to the Union 
pharmaceutical legislation have addressed this issue by providing for accelerated 
assessment of marketing authorisation applications or by allowing conditional 
marketing authorisation for medicinal products for unmet medical need. While these 
measures accelerated the authorisation of innovative and promising therapies, these 
medicinal products do not always reach the patient and patients in the Union still have 
different levels of access to medicinal  products. Patient access to medicinal products 
depends on many factors. Marketing authorisation holders are not obliged to market a 
medicinal product in all Member States; they may decide not to market their medicinal 
products in, or withdraw them from, o ne or more Member States. National pricing and 
reimbursement policies, the size of the population, the organisation of health systems 
and national administrative procedures are other factors influencing market launch and 
patient access.  
(45) Addressing unequal patient access  and affordability of medicinal products has become 
a key priority of the Pharmaceutical Strategy for Europe, as also highlighted  by 
Council conclusions8 and a resolution of the European Parliament9. Member States 
called for revised mec hanisms and incentives for development of medicinal products 
tailored to the level of unmet medical need, while ensuring health system 
sustainability, patient access and availability of affordable medicinal products in all 
Member States.  
                                                 
8 Council conclusions on strengthening the balance in the pharmaceutical systems in the EU and its 
Member States, (OJ C, C/269, 23.07.2016, p. 31). Council Conclusions on Access to medicines and 
medical devices for a Stronger and Resilient EU, (2021/C 269 I/02).  
9 European Parliament resolution of 2 March 2017 on EU options for improving access to medicine 
(2016/2057(INI)) Shortages of medicines, 2020/2071(INI).  EN 28  EN (46) Access also comprise affordability. In this regard, the Union pharmaceutical 
legislation respects the competence of the Member States in terms of pricing and 
reimbursement. In a complementary manner, it aims to have a positive impact on 
affordability and sustainabilit y of health systems with measures that support 
competition from generic and biosimilar medicinal products. The competition from 
generic and biosimilar medicinal products should also, in turn, increase patient access 
to medicinal products.  
(47) To ensure dialogue among all actors in the medicines lifecycle, discussions on policy 
issues related to the application of the rules related to prolongation of regulatory data 
protection for market launch shall take place in the Pharmaceutical Committee. T he 
Commission may invite bodies responsible for health technology assessment as 
referred to in Regulation (EU) 2021/2282 or national bodies responsible for pricing 
and reimbursement, as required, to participate in the deliberations of the 
Pharmaceutical Co mmittee.  
(48) While pricing and reimbursement decisions are a Member State competence, the 
Pharmaceutical Strategy for Europe announced actions to support cooperation of 
Member States to improve affordability. The Commission has transformed the group 
of Na tional Competent Authorities on Pricing and Reimbursement and public 
healthcare payers (NCAPR) from an ad -hoc forum to a continuous voluntary 
cooperation with the aim to exchange information and best practices on pricing, 
payment and procurement policies t o improve the affordability and cost -effectiveness 
of medicines and health system’s sustainability. The Commission is committed to 
stepping up this cooperation and further supporting information exchange among 
national authorities, including on public proc urement of medicines, while fully 
respecting the competences of Member States in this area. The Commission may also 
invite NCAPR members to participate in deliberations of the Pharmaceutical 
Committee on topics that may have an impact on pricing or reimbur sement policies, 
such as the market launch incentive.  
(49) Joint procurement, whether within a country or across countries, can improve access, 
affordability, and security of supply of medicines, in particular for smaller countries. 
Member States intereste d in joint procurement of medicines can make use of Directive 
2014/24/EU10, which sets out purchasing procedures for public buyers, the Joint 
Procurement Agreement11 and the proposed revised Financial Regulation12. Upon 
request from the Member States the Comm ission may support interested Member 
States by facilitating coordination to enable  access to medicines for patients in the 
Union  as well as information exchange , in particular for medicines for rare and 
chronic diseases . 
(50) The establishment of a criteri a-based definition of ‘unmet medical need’ is required to 
incentivise the development of medicinal products in therapeutic areas that are 
currently underserved.  To ensure that the concept of unmet medical need reflects  
scientific and technological developments  and current knowledge in underserved 
diseases , the Commission should  specify and update using  implementing acts , the 
criteria of satisfactory method of diagnosis, prevention or treatment, ‘remaining high 
                                                 
10 Directive 2014/24/EU of the European Parliament and of the Council of 26 February 2014 on publ ic 
procurement and repealing Directive 2004/18/EC (OJ L 94, 28.3.2014, p. 65).  
11 Regulation (EU) 2022/2371 of the European Parliament and of the Council of 23 November 2022 on 
serious cross -border threats to health and repealing Decision No 1082/2013/EU . 
12 COM/2022/223 final . EN 29  EN morbidity  or mortality’, ‘relevant patient population’ following scientific assessment 
by the Agency.  The Agency will seek input from a broad range of authorities or bodies 
active along the lifecycle of medicinal products in the framework of the consultation 
proces s established under the [revised Regulation (EC) No 726/2004]  and also take 
into account  scientific initiatives at EU level  or between Member States  related to analysing 
unmet medical needs, burden of disease and priority setting for research and developme nt. 
The criteria for ‘unmet medical need’ can be subsequently used by Member States to 
identify specific therapeutic areas of interest.   
(51) The inclusion of new therapeutic indications to an authorised medicinal products 
contributes to the access of patients to additional therapies and therefore should be 
incentivised.  
(52) For the initial marketing authorisation application for medicinal products containing a 
new active substance, the submission of clinical trials that include as a comparator an 
evidence-based existing treatment should be incentivised, in order to foster the 
generation of comparative clinical evidence that is relevant and can accordingly 
support subsequent health technology assessments and decisions on pricing and 
reimbursement by Mem ber States.  
(53) A marketing authorisation holder should ensure the appropriate and continuous supply 
of a medicinal product throughout its lifetime irrespective of whether that medicinal 
product is covered by a supply incentive or not.  
(54) Micro, small and medium -sized enterprises (‘SMEs’), not -for-profit entities  or entities 
with limited experience in the Union  system should benefit from additional time to 
market a medicinal product in the Member States where the marketing authorisation is 
valid for the purposes of receiving additional regulatory data protection.  
(55) When applying the provisions on market launch incentives, marketing authorisation 
holders and Member States should do their utmost to achieve a mutually agreed supply 
of medic inal products in accordance with the needs of the Member State concerned, 
without unduly delaying or hindering the other party from enjoying its rights under 
this Directive.  
(56) Member States have the possibility to waive the condition of launch in their  territory 
for the purpose of the prolongation  of data protection for market launch . This can be 
done through a statement of non -objection to prolong the period of regulatory data 
protection . This is expected to be the case particularly in situations where  launch in a 
particular Member State is materially impossible or because there are special reasons 
why a Member State wishes that launch take place later.  
(57) The issuing of documentation from the Member States as regards the prolongation of 
data protect ion for the purpose of supply of medicinal products in all Member States 
where a marketing authorisation is valid, in particular the waiver to the conditions for 
such prolongation, does not affect at any time the powers of the Member States as 
regards the supply, setting of prices for medicinal products or their inclusion in the 
scope of national health insurance schemes. Member States do not waive the 
possibility to request release or supply of the product concerned at any time before, 
during or after the prolongation of the data protection period.  
(58) An alternative way of demonstrating supply relates to the inclusion of medicinal 
products in a positive list of medicinal products covered by the national health 
insurance system in accordance with Directive  89/105/EEC. The related negotiations 
between companies and the Member State should be conducted in good faith.  EN 30  EN (59) A Member State that considers that the conditions of supply have not been met for its 
territory should provide a reasoned statement of non-compliance at the latest in the 
Standing Committee on Medicinal Products for Human Use procedure of the variation 
linked to the provision of the relevant incentive.  
(60) The Commission and Member States shall continuously monitor any data and 
learnings  from the application of the incentives system in order to improve, including 
through implementing acts, how these provisions are applied. The Commission shall 
establish a list of national contact points in this regard.  
(61) When a compulsory licenc e has b een granted  by a relevant  authority in the Union  to 
tackle a public health emergency , regulatory data protection may, if still in force, 
prevent the effective use of the compulsory licenc e as they impede  the authorisation  of 
generic medicinal products , and  thus access to the medicinal products needed to 
address the crisis . For this reason,  data and market protection should be suspended 
when a compulsory licenc e has been issued to tackle a  public health emergency. Such 
a suspension of the regulatory data pro tection should be allowed only in relation to the 
compul sory licenc e granted  and its beneficiary. The suspension shall comply with the 
objective,  the territorial  scope , the duration and the subject matter of the granted 
compulsory licence . 
(62) The suspens ion of the regulatory data protection should be granted only for the 
duration of the compulsory licenc e. A ‘suspension ‘ of data and market protection in 
cases of public health emergency shall mean that data and market protection shall 
produce no effect in relation to the particular licensee of the compulsory lice nce while 
that compulsory licenc e is in effect. When the comp ulsory licenc e ends, the data and 
market protection shall resume their effect . The suspension should not result in an 
extension  of the original duration.  
(63) It is currently possible for applicants for marketing authorisation of generic, 
biosimilar, hybr id and bio -hybrid medicinal products to conduct studies, trials and the 
subsequent practical requirements necessary to obtain regulatory approvals for those 
medicinal products during the term of protection of the patent or Supplementary 
Protection Certific ate (SPC) of the reference medicinal product, without this being 
considered patent or SPC infringement. The application of this limited  exemption  is 
however fragmented across the Union and it is considered necessary, in order to 
facilitate the market entry  of generic , biosimilar, hybrid and bio -hybrid  medicinal 
products  that rely on a reference medicinal product , to clarify its scope in order to 
ensure a harmonised application in all Member States, both in terms of beneficiaries 
and in terms of activities c overed. The exemption must be confined to conduct studies 
and trials and other activities needed for the regulatory approval process, health 
technology assessment and pricing reimbursement request, even though this may 
require substantial amounts of test p roduction to demonstrate reliable manufacturing. 
During the term of protection of the patent or SPC of the reference medicinal product, 
there can be no commercial use of the resulting  final medicinal products obtained for 
the purposes of the regulatory app roval process.  
(64) It will allow , inter alia , to conduct studies to support pricing and reimbursement as 
well as the manufacture or purchase of patent protected active substances for the 
purpose of seeking marketing authorisations during that period, contributing to the 
market entry of generics and biosimilars on day one of loss of the patent or SPC 
protection.  EN 31  EN (65) The competent authorities should  refuse the validation for an application for a 
marketing authorisation referring to data of a reference m edicinal product only on the 
basis of the grounds set out in this Directive. The same applies to any decision to 
grant, vary, suspend , restrict  or revoke the marketing authorisation. The competent 
authorities cannot base their decision on any other grounds . In particular , those 
decisions cannot be based on the  patent  or SPC  status of the reference medicinal 
product . 
(66) In order to address the challenge of antimicrobial resistance, antimicrobials  should be 
packaged in quantities that are appropriate for th e therapy cycle relevant for that 
product and national rules on antimicrobial subject to prescription ensure that they are 
dispensed in a way that corresponds to the quantities described by the prescription.  
(67) The provision of information to healthcare professionals and to patients on the 
appropriate use, storage and disposal of antimicrobials is a joint responsibility of 
marketing authorisation holders and of Member States who should ensure appropriate 
collection system for all medicinal products.  
(68) While this Directive restricts the use of antimicrobials by setting certain categories of 
antimicrobials under prescription status, due to the growing antimicrobial resistance in 
the Union, competent authorities of the Member States should consider further  
measures for example expanding the prescription status of antimicrobials or the 
mandatory use of diagnostic tests before prescription. Competent authorities of the 
Member States should consider such further measures according to the level of 
antimicrobial  resistance in their territory and the needs of patients.  
(69) The pollution of waters and soils with pharmaceutical residues is an emerging 
environmental problem, and there is scientific evidence that the presence of those 
substances in the environment fr om their manufacturing, use and disposal poses a risk 
to the environment and public health. The evaluation of the legislation showed that 
strengthening of existing measures to reduce the impact of medicinal products ' 
lifecycle  on the environment and public  health  is required. Measures under this 
Regulation complement the main environmental legislation, in particular the Water 
Framework Directive (2000/60/EC13), the Environmental Quality Standard Directive 
(2008/105/EC14) the Groundwater Directive (2006/118/EC15), the Urban Wastewater 
Treatment Directive (91/271/EEC16), the Drinking Water Directive (2020/218417) and 
the Industrial Emissions Directive (2010/75/EU18). 
(70) Marketing authorisation applications for medicinal products in the Union should 
include an Envi ronmental Risk Assessment (ERA) and risk mitigation measures. If the 
                                                 
13 Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a 
framework for Community action in the field of water policy (OJ L 327, 22.12.2000, p. 1).  
14 Directive 2008/105/EC of the European Pa rliament and of the Council of 16 December 2008 on 
environmental quality standards in the field of water policy, amending and subsequently repealing 
Council Directives 82/176/EEC, 83/513/EEC, 84/156/EEC, 84/491/EEC, 86/280/EEC and amending 
Directive 2000/6 0/EC of the European Parliament and of the Council (OJ L 348, 24.12.2008, p. 84).  
15 Directive 2006/118/EC of the European Parliament and of the Council of 12 December 2006 on the 
protection of groundwater against pollution and deterioration (OJ L 372, 27.1 2.2006, p. 19).  
16 Council Directive 91/271/EEC of 21 May 1991 concerning urban waste -water treatment (OJ L 135, 
30.5.1991, p. 40).  
17 Directive (EU) 2020/2184 of the European Parliament and of the Council of 16 December 2020 on the 
quality of water intended  for human consumption (recast) (OJ L 435, 23.12.2020, p. 1).  
18 Directive 2010/75/EU of the European Parliament and of the Council of 24 November 2010 on 
industrial emissions (integrated pollution prevention and control) (recast) (OJ L 334, 17.12.2010, p. 17). EN 32  EN applicant fails to submit a complete or sufficiently substantiated environmental risk 
assessment or they do not propose risk mitigation measures to sufficiently address the 
risks identifi ed in the environmental risk assessment,  the marketing authorisation 
should  be refused. The ERA should be updated when new data or knowledge about 
relevant risks become available.  
(71) Marketing authorisation applicants should take into account environment al risk 
assessment procedures of other EU legal frameworks that may apply to chemicals 
dependent on their use. Further to this Regulation, there are four main other 
frameworks: (i) Industrial chemicals (REACH, (Reg ulation  (EC) No 1907/2006); (ii) 
Biocides (Reg ulation  (EC) No 528/2012); (iii) Pesticides (Reg ulation  (EC) No 
1107/2009); and (iv) Veterinary medicines (Regulation (EU) 2019/6)). As a part of the 
Green Deal, the Commission has proposed a ‘one -substance one -assessment’ (OS -OA) 
approach for chemical s19, in order to increase the efficiency of the registration system, 
reduce costs and unnecessary animal testing.  
(72) The emissions and discharges of antimicrobials to the environment from 
manufacturing sites may lead to antimicrobial resistance (“AMR”), which is a global 
concern regardless where the emissions and discharges take place. Therefore, the ERA 
scope should be extended to cover the risk of AMR selection during the entire life 
cycle of antimicrobials, including manufacturing.  
(73) The proposal also includes provisions for a risk -based approach regarding the ERA 
obligations of marketing authorisation holders before October 2005 and the setting -up 
of an ERA monograph system for active substances. This ERA monograph system 
should be available to appl icants for use when conducting an ERA for a new 
application . 
(74) For medicinal products authorised prior to October 2005, without any  ERA, specific 
provisions should be introduced to set up a risk based prioritisation programme for the 
ERA submission or u pdate by the market authorisation holders.  
(75) Cyprus, Ireland, Malta and Northern Ireland have historically relied on the supply of 
medicinal products from or through parts of the United Kingdom other than Northern 
Ireland. Following the withdrawal of th e United Kingdom of Great Britain and 
Northern Ireland from the European Union and the European Atomic Energy 
Community, to prevent shortages of medicinal products and ultimately to ensure a 
high level of public health protection, specific derogations to t his Directive need to be 
included for medicinal products supplied to Cyprus, Ireland, Malta and Northern 
Ireland from or through parts of the United Kingdom other than Northern Ireland. In 
order to ensure uniform application of Union law in the Member Stat es, the 
derogations applicable in Cyprus, Ireland and Malta should be of a temporary nature 
only.  
(76) To ensure that all children in the Union have access to the products specifically 
authorised for paediatric use, when an agreed paediatric investigation plan has led to 
the authorisation of a paediatric indication for a product already marketed for other 
therapeutic indications, the marketing authorisation holder should be obliged to place 
                                                 
19 Communication from the Commission to the European Parliament, the European Council, the Council, 
the European Economic and Social Committee and the Committee of the Regions, The European Green 
Deal,  Brussels  (2019) , COM(2019) 640 final.  EN 33  EN the product in the same markets within two years of the date of app roval of the 
indication.  
(77) It is necessary in the interest of public health to ensure the continuing availability of 
safe and effective medicinal products authorised for paediatric indications. Therefore, 
if a marketing authorisation holder intends to w ithdraw such a medicinal product from 
the market then arrangements should be in place so that the paediatric population can 
continue to have access to the medicinal product in question. In order to help achieve 
this, the Agency should be informed in good t ime of any such intention and should 
make that intention publicly available . 
(78) To avoid unnecessary administrative and financial burdens both for the marketing 
authorisation holders and the competent authorities, certain streamlining measures 
should be introduced, in line with the digital by default principle. Electronic 
application for marketing authorisation and for variations to the terms of the marketing 
authorisation should be introduced.  
(79) As a general rule, risk management plans for generic and  biosimilar medicinal 
products should not be developed and submitted, considering that the reference 
medicinal product has such a plan, except in specific cases, where a risk management 
plan should be provided. Furthermore, as a general rule a marketing au thorisation 
should be granted for an unlimited period; exceptionally, one renewal may be decided 
only on justified grounds related to the safety of the medicinal product.  
(80) In the event of a risk to public health, the marketing authorisation holder or t he 
competent authorities should be able to make urgent safety or efficacy restrictions on 
their own initiative. In such case, when the referral procedure is launched, any 
duplication of assessment should be avoided.  
(81) To address patients’ needs, an incr easing number of innovative medicinal products 
derive from or are combined with other products that may be manufactured or tested 
and regulated under more than one Union legal framework. Similarly, the same sites 
are increasingly overseen by the authoritie s established under different Union legal 
frameworks. To ensure safe and efficient production and supervision of such products 
and to allow an appropriate delivery to patients, it is important to ensure coherence. 
The coherence and sufficient alignment can  only be ensured through appropriate 
cooperation in the development of the practices and principles applied under the 
different Union legal frameworks. An appropriate cooperation should therefore be 
embedded within several provisions of this Directive, suc h as those regarding 
classification advice, oversight, or the development of guidelines.  
(82) For products that combine a medicinal product and a medical device the applicability 
of the two respective regulatory frameworks should be specified and the appro priate 
interaction between the two applicable regulatory frameworks should be ensured. The 
same should apply to combinations of medical products and products other than 
medical devices.  
(83) To ensure that the competent authorities have all the information  needed for their 
assessment in the case of  integral combinations of a medicina l product with a medical 
device or  of combinations of a medicinal product  with a product  other than a medical 
device , the marketing authorisation applicant shall submit data est ablishing the safe 
and effective use of the integral combination of the medicinal product with the 
medical device or of the combination of a medicinal product with the other product. 
The competent authority should  assess the benefit -risk balance of the int egral EN 34  EN combination taking into account the suitability of the use of the medicinal product 
together with the medical device  or the other product.  
(84) To ensure that the competent authorities have all the information needed for their 
assessment of medicinal products in exclusive  use with a medical  device  (that is to say 
medicinal products that are presented in a package with a medical device or that are to 
be used with a medical device referenced in the summary of product characteristics) 
the marketing authorisation applicant  shall submit data establishing the safe and 
effective use of the medicinal product  taking into account its use with the medical 
device. The competent authority should  assess the benefit -risk balance of the 
medicinal product, also taking into account the use of the medicinal product with the 
medical device.  
(85) The Directive  also clarifies that a medical device that is part of an int egral 
combination has to comply with the general safety and performance requirements set 
out in Annex I of Regulation (EU) 2017/745  of the European Parliament and of the 
Council20. A medical device in exclusive  use with a medical  device  needs to meet all 
of the requirements of Regulation (EU) 2017/745.  A medicinal product in exclusive 
use with a medical device that is not ancillary to that of the medical device shall 
comply with the requirements of this Directive and of the [revised Regu lation (EC) No 
726/2004] taking into account its use with the medical device, without prejudice to the 
specific requirements of the Regulation (EU) 2017/745.  
(86) For all these products (integral combinations of a medicinal product and a medical 
device, me dicinal products in exclusive  use with medical  devices  and combinations of 
a medicinal product  with a product other than a medical device ) the competent 
authority should also be able to request the marketing authorisation applicant to 
transmit any addition al information needed  and the marketing authorisation applicant  
should be bound to submit  any such information requested . For medicinal product in 
exclusive use with a medical device that is not ancillary to that of the medical device, 
the marketing author isation applicant shall also, upon request from the competent 
authority, submit any additional information related to the medical device taking into 
account its use with the medicinal product and that is relevant for the post -
authorisation monitoring of th e medicinal product, without prejudice to the specific 
requirements of the [revised Regulation (EC) No 726/2004].  
(87) For integral combination of a medicinal product with a medical device and for 
combinations of a medicinal product with a product other than a medical device,  the 
marketing authorisation holder should also bear the overall responsibility f or the 
whole product in terms of compliance of the medicinal product with the requirements 
of this Directive and the [revised Regulation(EC) No 726/2004]  and should ensure 
coordination of the information flow between the sectors throughout the assessment 
procedure and the lifecycle of the medicinal product.  
(88) In order to ensure the quality, safety and efficacy of medicinal product at all stages of 
manuf acturing and distribution the marketing authorisation holder shall be responsible, 
when necessary to trace back an active substance, excipient or any other substance that 
used in the manufacturing of medicinal product and intended to be part of the 
                                                 
20 Regulation  (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical 
devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 
1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (OJ L 117 , 5.5.2017, p. 1).  EN 35  EN medicin al product or expected to be present in the medicinal product, for example 
impurities , degradation products or contaminants.  
(89) In the interests of public health marketing authorisation holders should be able to 
ensure the traceability of any substance t hat is used, intended or expected to be present 
in a medicinal product at all stages of manufacturing and distribution, and identify any 
natural or legal person from whom they have been supplied these substances. 
Therefore, procedures and systems should be  placed to provide that information in 
case it should be necessary with the view of quality, safety or efficacy of medicinal 
products.  
(90) It is recognised that the development of pharmaceuticals is an area where neither 
science, nor technology stand stil l. The last decades have seen new categories of 
medicinal products emerging from biological medicinal products to biosimilars or 
advanced therapy medicinal products or in the future phages therapies. Those 
categories of products may in some instances requi re adapted rules to fully take 
account of their specific characteristics. For that reason a forward looking legal 
framework should include provisions to enable such adapted frameworks subject to 
strict criteria and under a Commission empowerment guided by the scientific input of 
the European Medicines Agency.   
(91) The adaptations may entail adapted, enhanced, waived or deferred requirements 
compared to standard medicinal products. They could in particular include changes to 
the dossier requirements for such medicinal products, the way their quality, safety and 
efficacy is demonstrated by applicants or tailored manufacturing controls and good 
manufacturing practices requirements, as well as add itional control methods prior and 
during their administration and use. The adaptions should however not go beyond 
what is necessary for the attainment of the objective of adaptation to the specific 
characteristics.  
(92) In order to increase the preparednes s and responsiveness against health threats, in 
particular the emergence of antimicrobial resistance, adapted frameworks may be 
relevant to facilitate the rapid change of antimicrobials composition to maintain their 
efficacy. The use of established platfor ms would allow efficient and timely adaptation 
of those medicinal products to the clinical context .  
(93) To optimise the use of resources for both applicants for marketing authorisation and 
competent authorities an d avoid duplication of assessment  of chem ical active 
substances  of medicinal products , marketing authorisation applicants should be able to 
rely on  an active substance master file certificate or a monograph of the European 
Pharmacopeia , instead  of submitting the relevant data as  required in accor dance with 
Annex II . An active substance master file certificate may be granted by the Agency 
when the relevant data on the active substance concerned is not already covered by a 
monograph of the European Pharmacopeia or by another active substance master file 
certificate.  The Commission should be empowered to establish the procedure for the 
single assessment of an active substance master file. To further optimise the use of 
resources, the Commission should be empowered to allow use a  certification scheme 
also for  additional quality master files  i.e. for active substances other than chemical 
active substances, or for other substances present or used in the manufacture of a 
medicinal product, required in accordance with Annex II,  e.g. in case of novel 
excipi ents, adjuvants, radiopharmaceutical precursors and active substance 
intermediates, when the intermediate is a chemical active substance by itself or used in 
conjugation with a biological substance.  EN 36  EN (94) For reasons of public health and legal consistency, and with a view to reducing the 
administrative burden and strengthening predictability for economic operators, 
variations to all types of marketing authorisations should be subject to harmonised 
rules.  
(95) The terms of a marketing authorisation for a medi cinal product may be varied, after it 
has been granted. While the core elements of a variation are laid down in this 
Directive, the Commission should be empowered to complement these elements by 
laying down further necessary elements, to adapt the system t o scientific and 
technological progress, including digitalisation, and to ensure that unnecessary 
administrative burden is avoided for both the marketing authorisation holders and 
competent authorities.  
(96) Scientific and technological progresses in data analytics and data infrastructure 
provide valuable support to the development, authorisation and supervision of 
medicinal products. The digital transformation has affected regulatory decision -
making, making it more data -driven and multiplying the possibili ties for regulatory 
authorities to access evidence, across the lifecycle of a medicinal product. This 
Directive recognises the competent authorities of the Member States’ capacity to 
access and analyse data submitted independently from the marketing author isation 
applicant or marketing authorisation  holder. On this basis, competent authorities of the 
Member States should take initiative to update the summary of product characteristics 
in case new efficacy or safety data impacts the benefit -risk balance of a  medicinal 
product.  
(97) Access to individual patient data from clinical studies in structured format allowing for 
statistical analyses is valuable to assist regulators in understanding the submitted 
evidence and to inform regulatory decision -making on th e benefit -risk balance of a 
medicinal product. The introduction of such possibility in the legislation is important 
to further enable data -driven benefit -risk assessments at all stages of the lifecycle of a 
medicinal product. This Directive therefore empow ers competent authorities of 
Member States to request such data as part of the assessment of initial and post -
marketing authorisation applications.  Due to the sensitive nature of health data, the 
competent authorities  should  safeguard its processing operat ions and ensure that they 
respect the data protection principles of lawfulness, fairness and transparency, purpose 
limitation, data minimisation, accuracy, storage limitation, integrity and 
confidentiality. Where the processing of personal data is necessar y for the purposes of 
this Directive , such processing should be done in accordance with Union law on the 
protection of personal data. Any processing of personal data under this Directive  
should take place in accordance with Regulation (EU) 2016/67921 and Regulation 
(EU) 2018/172522 of the European Parliament and of the Council.   
(98) Pharmacovigilance rules are necessary for the protection of public health in order to 
prevent, detect and assess adverse reactions to medicinal products placed on the Unio n 
                                                 
21  Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the 
protection of natural persons with regard to the processing of personal data and on the free movement of 
such data, and repealing Directive  95/46/EC (General Data Protection Regulation) (OJ L 119, 4.5.2016, 
p. 1).  
22  Regulation (EU) 2018/1725 of the European Parliament and of the Council of 23 October 2018 on the 
protection of natural persons with regard to the processing of personal data by the Union institutions, 
bodies, offices and agencies and on the free movement of such data, and repealing Regulation (EC) No 
45/2001 and Decision No 1247/2002/EC (OJ L 295, 21.11.2018, p. 39).  EN 37  EN market, as the full safety profile of medicinal products can only be known after they 
have been placed on the market . 
(99) In order to ensure the continued safety of medicinal products in use, it is necessary to 
ensure that pharmacovigilance systems in t he Union are continually adapted to take 
account of scientific and technical progress.  
(100)  It is necessary to take account of changes arising as a result of international 
harmonisation of definitions, terminology and technological developments in the fie ld 
of pharmacovigilance.  
(101)  The increasing use of electronic networks for communication of information on 
adverse reactions to medicinal products marketed in the Union is intended to allow 
competent authorities to share the information at the same time.  
(102)  It is the interest of the Union to ensure that the pharmacovigilance systems for 
centrally authorised medicinal products and those authorised by other procedures are 
consistent.  
(103)  Marketing authorisation holders should be proactively responsible  for on -going 
pharmacovigilance of the medicinal products they place on the market.  
(104)  The use of colours in human and veterinary medicinal products is currently regulated 
by Directive 2009/35/EC of the European Parliament and of the Council23, and 
restricted to those authorised in accordance with Regulation (EC) No 1333/2008 of the 
European Parliament and of the Council  on food additives24, for which specifications 
are laid down in Commission Regulation (EU) No 231/201225. Uses of excipients 
other than col ours in medicinal products are subject to the Union rules on medicinal 
products and are evaluated as part of the overall benefit risk profile of a medicinal 
product.  
(105)  Experience has shown the need to maintain to a certain extent the principle of the u se 
in medicinal products of those colours authorised as food additives. However, it is also 
appropriate to foresee a specific assess ment for the use of the colour in medicines 
when a food additive is removed from Union list of food additives. Therefore, in  this 
specific case, EMA should carry out its own assessment for the use of the colour in 
medicines, taking into account the EFSA opinion and its underlying scientific 
evidence, as well as any additional scientific evidence and giving particular 
considerat ion to the use in medicines. EMA should also be responsible for following 
any scientific evidence for the colours retained for specific medicine use only. 
Directive 2009/35/EC should therefore be repealed.  
(106)  With regard to the supervision and inspections , manufacturing and import of starting 
materials or intermediate and also of  functional excipient shall be under surveillance 
due to their ancillary action to the active substance and to their possible impact to the 
quality, safety and efficacy to the medicinal products.  
                                                 
23 Directive 2009/35/EC of the European Parliament and of the Co uncil of 23 April 2009 on the colouring 
matters which may be added to medicinal products (OJ L 109, 30.4.2009, p. 10).  
24 Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on 
food additives (OJ L 354, 31.12.2008,  p. 16 ). 
25 Commission Regulation (EU) No 231/2012 of 9 March 2012 laying down specifications for food 
additives listed in Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and 
of the Council (OJ L 83, 22.3.2012, p. 1).  EN 38  EN (107)  The main purpose of any regulation on the manufacture and distribution of medicinal 
products should be to safeguard public health.  
(108)  It should be ensured that, in the Member States, the supervision and control of the 
manufacture and the distribution  of medicinal products is carried out by official 
representatives of the competent authority  who fulfils minimum conditions of 
qualification . 
(109)  There may be cases where manufacturing or testing steps of medicinal products need 
to take place in sites close to patients, for example advanced therapy medicinal 
products with short shelf -life. In such cases, these manufacturing or testing steps may 
need to be decentralised to multiple sites to reach patients across the Union . When the 
manufacturing or testing steps are decentralised, they should be carried out under the 
responsibility of the qualified person of an authorised central site. The dec entralised 
sites should not require a separate manufacturing authorisation from the one granted to 
the relevant central site but should be registered by the competent authority of the 
Member State in which the decentralised site is established. In the case  of medicinal 
products containing, consisting or derived from autologous SoHO, the decentralised 
sites have to be registered as a SoHO entity as defined in and pursuant to [SoHO 
Regulation] for the activities of donor review and eligibility assessment, don or testing 
and collection, or just for collection in the case of products manufactured for 
autologous use.  
(110)  The quality of medicinal products manufactured or available in the Union should be 
guaranteed by requiring that the active substances used in t heir composition comply 
with the principles of good manufacturing practice in relation to those medicinal 
products. It has proved necessary to reinforce the Union provisions on inspections and 
to compile a Union database  of the results of those inspections . 
(111)  Verification of compliance with the legal requirements of manufacturing, distribution 
and use of medicinal products by relevant entities through a system of supervision, is 
of fundamental importance to ensure that the objectives of this Directive a re 
effectively achieved. Therefore, the competent authorities of the Member States 
should have the power to perform on site or remote inspections, as part of the system 
of supervision at all stages of manufacturing, distribution and use of medicinal 
produc ts or active substances  and rely on the outcome of inspections conducted by 
trusted third countries competent authorities . To preserve the effectiveness of the 
inspections, the competent authorities should have the possibility to perform joint 
inspections and also, where necessary, unannounced inspections.  
(112)  The frequency of controls should be established by the competent authorities having 
regard to the risk and to the level of compliance expected in different situations. That 
approach should allow tho se competent authorities to allocate resources where the risk 
is the highest. In some cases, the system of supervision should be applied irrespective 
of the level of risk or suspected  non-compliance, for example prior to granting 
manufacturing authorisatio ns. 
(113)  Within the procedure for "Certification of Suitability to the monographs of the 
European Pharmacopoeia" the European Directorate for the Quality of Medicines and 
Healthcare  verifies by means of inspections whether the data submitted by the 
applicant established by the Council of Europe confirms the suitability of monographs 
to control the chemical purity, microbiological quality and TSE risk (if relevant). It 
also verifies w hether the manufacturing complies with good manufacturing practice 
for active substances. Depending of the outcome of the inspection, a certificate of EN 39  EN compliance or non -compliance of good manufacturing practice , is issued by the 
European Directorate for th e Quality of Medicines and Healthcare or by the Member 
State participating in the inspection . 
(114)  Each undertaking that manufactures or imports medicinal products should set up a 
mechanism to ensure that all information supplied about a medicinal product  conforms 
to the approved conditions of use.  
(115)  The conditions governing the supply of medicinal products to the public should be 
harmonised.  
(116)  In this connection persons moving around within the Union have the right to carry a 
reasonable quantity o f medicinal products lawfully obtained for their personal use. It 
should also be possible for a person established in one Member State to receive from 
another Member State a reasonable quantity of medicinal products intended for their 
personal use.  
(117)  By virtue of [revised Regulation (EC) No 726/2004], certain medicinal products are 
the subject of a Union marketing authorisation. In this context, the prescription status 
of medicinal products covered by a Union marketing authorisation needs to be 
establis hed. It is therefore important to set the criteria on the basis of which Union 
decisions will be taken.  
(118)  It is therefore appropriate to harmonise the basic principles applicable to the 
prescription status of medicinal products in the Union or in the M ember State 
concerned, while taking as a starting point the principles already established on this 
subject by the Council of Europe as well as the work of harmonisation completed 
within the framework of the United Nations, concerning psychotropic or narcot ic 
substances  - the United Nations Single Convention of 1961 on narcotic drugs and 
Convention on Psychotropic Substances of 1971 . 
(119)  Many operations involving the wholesale distribution of medicinal products may cover 
several Member States simultaneousl y. 
(120)  It is necessary to exercise control over the entire chain of distribution of medicinal 
products, from their manufacture or import into the Union through to supply to the 
public, so as to guarantee that such products are stored, transported and han dled in 
suitable conditions. The requirements that should be adopted for this purpose will 
considerably facilitate the withdrawal of defective products from the market and allow 
more effective efforts against counterfeit products.  
(121)  Any person involved  in the wholesale distribution of medicinal products should be in 
possession of a special authorisation. Pharmacists and persons authorised to supply 
medicinal products to the public, and who confine themselves to this activity, should 
be exempt from obtai ning this authorisation. It is however necessary, in order to 
control the complete chain of distribution of medicinal products, that pharmacists and 
persons authorised to supply medicinal products to the public keep records showing 
transactions in products  received.  
(122)  Marketing authorisation is to be subject to certain essential conditions and it is the 
responsibility of the Member State concerned to ensure that such conditions are met; 
whereas each Member State is to recognize authorisations granted by  other Member 
States.  
(123)  Certain Member States impose on wholesalers who supply medicinal products to 
pharmacists and on persons authorised to supply medicinal products to the public EN 40  EN certain public service obligations. Those Member States should be able  to continue to 
impose those obligations on wholesalers established within their territory. They should 
also be able to impose them on wholesalers in other Member States on condition that 
they do not impose any obligation more stringent than those that the y impose on their 
own wholesalers and provided that such obligations may be regarded as warranted on 
grounds of public health protection and are proportionate in relation to the objective of 
such protection.  
(124)  Rules should be laid down as to how the la belling and package leaflets are to be 
presented.  
(125)  The provisions governing the information supplied to users should provide a high 
degree of consumer protection, in order that medicinal products may be used correctly 
on the basis of full and comprehe nsible information.  
(126)  The marketing of medicinal products whose labelling and package leaflets comply 
with this Directive should not be prohibited or impeded on grounds connected with the 
labelling or package leaflet.  
(127)  The use of electronic and technological possibilities other than paper package leaflets 
can facilitate access to medicinal products, medicinal products distribution and should 
always guarantee equal or better quality of information to all patients compared to the 
paper form of prod uct information.  
(128)  Member States have varying levels of digital literacy and internet access. In addition, 
patient and healthcare professional needs may differ. It is therefore necessary that 
Member States have a discretion on the adoption of measures enabling the electronic 
provision of product information  while ensuring that no patient is left behind, taking 
into account the needs of different age categories and the different levels of digital 
literacy in the population, and making sure that product i nformation is easily 
accessible to all patients . Member States should progressively allow the possibility for 
electronic product information , while ensuring full compliance with the rules on 
protection of personal data , and adhere to harmonised standards d eveloped at EU 
level.  
(129)  Where Member States decide that the package leaflet should be made available in 
principle only electronically, they should also ensure that a paper  version of the 
package leaflet is to be made available on demand  and without add itonal cost to 
patients . They should also ensure that the information in digital format is easily 
accessible to all patients, for instance by including in the outer packaging of the 
product a digitally readable barcode, which would direct the patient to th e electronic 
version of the package leaflet.  
(130)  The use of multi -language packages can be a tool for access to medicinal products, in 
particular for small markets and in public health emergencies.  Where multi -language 
packages are used, Member States ma y allow the use on the labelling and package 
leaflet of an official language of the Union that is commonly understood in the 
Member States where the multi -language package is marketed.  
(131)  To ensure a high level of transparency of public support to the r esearch and 
development of medicinal products , the reporting of public contribution  for the 
development of a particular medicinal product should be a requirement for all 
medicines. Given however the practical difficulty to identify how indirect public 
funding instruments, such as tax advantages, have supported a particular product , the 
reporting obligation should only concern the direct  public financial support, such as EN 41  EN direct grants or contracts . Therefore, th e provisions of this  Directive ensure, without 
prejudice to the rules on the protection of confidential and personal data, transparency 
regarding any direct financial support  received from any public authority or public 
body to carry out  any activities for  the research and development of medicin al 
products . 
(132)  To ensure the accuracy of the information made publicly available by the marketing 
authorisation holder, the declared information has to be subject to audit by an 
independent auditor.  
(133)  In ord er to ensure a harmonised and consistent reporting of public contribution for the 
development of a particular medicinal products, the Commission should be able to 
adopt implementing  acts to clarify the principles and format that the marketing 
authorisation  holder should adhere to when report ing this information.   
(134)  This Directive is without prejudice to the application of measures adopted pursuant to 
Directive 2006/114/EC of the European Parliament and of the Council26 or pursuant to 
Directive 2005/29/EC  of the European Parliament and of the Council27. Therefore the 
provisions regarding the advertising of medicinal products of this Directive should 
therefore be considered, where relevant, as a lex specialis  with respect to Directive 
2005/29/EC . 
(135)  Adver tising, even of medicinal products not subject to a prescription, could affect 
public health and distort competition. Therefore, advertising of medicinal products 
should meet certain criteria. Persons qualified to prescribe, administer or supply 
medicinal products can properly evaluate the information available in advertising 
because of their knowledge, training and experience. The advertising of medicinal 
products to persons who cannot properly assess the risk associated with their use may 
lead to medicina l product misuse or overconsumption which is liable to harm public 
health. Therefore advertisement to the general public of medicinal products that are 
available only on medical prescription should be prohibited. Furthermore, distribution 
of samples free o f charge to the general public for promotional ends is to be 
prohibited , also teleshopping for medicinal products shall be prohibited pursuant to 
Directive 2010/13/EU of the European Parliament and of the Council28. It should be 
possible within certain rest rictive conditions to provide samples of medicinal products 
free of charge to persons qualified to prescribe or supply  them so that they can 
familiarise themselves with new products and acquire experience in dealing with them.  
(136)  Advertising of medicinal products should aim at dissemina ting objective and unbiased  
information about the medicinal product. For that purpose, it is expressly forbidden 
highlight negatively another medicinal product or to suggest that advertised medicinal 
product might be safer or more effective than another medicinal product. Comparison 
                                                 
26 Directi ve 2006/114/EC of the European Parliament and of the Council of 12 December 2006 
concerning misleading and comparative advertising (OJ L 376, 27.12.2006, p. 21).  
27 Directive 2005/29/EC of the European Parliament and of the Council of 11 May 2005 concerning  unfair 
business -to-consumer commercial practices in the internal market and amending Council Directive 
84/450/EEC, Directives 97/7/EC, 98/27/EC and 2002/65/EC of the European Parliament and of the 
Council and Regulation (EC) No 2006/2004 of the European P arliament and of the Council (‘Unfair 
Commercial Practices Directive’) (OJ L 149, 11.6.2005, p. 22) . 
28 Directive 2010/13/EU of the European Parliament and of the Council of 10 March 2010 on the 
coordination of certain provisions laid down by law, regulatio n or administrative action in Member 
States concerning the provision of audiovisual media services (Audiovisual Media Services Directive) 
(OJ L 095 15.4.2010, p. 1).  EN 42  EN of medicinal product s should only be allowed if such information is listed in the 
summary of product characteristics of the medicinal product  being advertised . This 
prohibition covers any medicinal product, also biosimilars , and therefore it would be 
misleading to refer in the advertising, that a biosimilar medicinal product would not be 
interchangeable with the original biological medicinal product or another biosimilar 
from the  same original biological medicinal product. Additional strict rules about 
negative and comparative advertising of competitor medicinal products will prohibit 
claims that can mislead persons qualified to prescribe, administer or supply them.   
(137)  The dis semination of information which encourages the purchase of medicinal 
products should be considered within the concept of advertising of medicinal products, 
even where that information does not refer to a specific medicinal product, but to 
unspecified medic inal products.  
(138)  Advertising of medicinal products should be subject to strict conditions and effective, 
adequate monitoring. Reference in this regard should be made to the monitoring 
mechanisms set up by Directive 2006/114/EC.  
(139)  Medical sales repr esentatives have an important role in the promotion of medicinal 
products. Therefore, certain obligations should be imposed upon them, in particular 
the obligation to supply the person visited with a summary of product characteristics.  
(140)  Innovative, ‘c ombination medicinal products’ and other developed medicinal products 
are complex in regards to their composition and administration. Therefore , in addition 
to persons qualified to prescribe  medicinal products, also  persons qualified to 
administer medicina l products need to be familiar with all characteristics of those 
medicinal products, especially with safe administration and use, including the 
comprehensive instructions to the patients. For that purpose information about 
medicinal products subject to med ical prescription is also clearly allowed to persons 
qualified to administer them.  
(141)  Persons qualified to prescribe, administer or supply medicinal products should have 
access to a neutral, objective source of information about products available on th e 
market. Whereas it is nevertheless for the Member States to take all measures 
necessary to this end, in the light of their own particular situation.  
(142)  In order to ensure that information on the use of the medicinal products in children are 
appropriat ely taken into account at the moment of marketing authorisation, it is 
therefore necessary to introduce a requirement for new medicinal products or when 
developing paediatric indications of already authorised products covered by a patent or 
a supplementary  protection certificate, to present either the results of studies in the 
paediatric population in accordance with an agreed paediatric investigation plan or 
proof of having obtained a waiver or deferral, at the time of filing a marketing 
authorisation appl ication or an application for a new therapeutic indication, new 
pharmaceutical form or new route of administration. In order to ensure that the data 
supporting the marketing authorisation concerning the use of a product in children, the 
competent authoriti es responsible for the authorisation of a medicinal product should 
check compliance with the agreed paediatric investigation plan and any waivers and 
deferrals at the validation step for marketing authorisation applications.  
(143)  To provide healthcare pro fessionals and patients with information on the safe and 
effective use of medicinal products in the paediatric population, the results of the 
studies conducted in accordance with a paediatric investigation plan, independently 
from the fact that they suppor t or not the use of the medicinal product in children, EN 43  EN appropriate information should be included in the summary of product characteristics 
and, if appropriate, in the package leaflet. Information on waivers should also be 
included in product information. When all the measures in the paediatric investigation 
plan have been complied with, that fact should be recorded in the marketing 
authorisation, and that should then be the basis upon which companies can obtain 
rewards.  
(144)  Relevant data and information collected through clinical studies conducted before the 
introduction in the  Union  of a paediatric medicines Regulation and received by the 
competent authorities should be assessed without undue delay and taken into 
consideration for eventual variation of e xisting marketing authorisations.  
(145)  In order to ensure uniform conditions for the implementation of this Regulation, 
implementing powers should be conferred on the Commission. Those powers should 
be exercised in accordance with Regulation (EU) No 182/2 011 of the European 
Parliament and of the Council29. 
(146)  Due to the need to reduce overall approval times for medicinal products, the time 
between the opinion of the Committee for Medicinal Products for Human Use 
(CHMP) and the final decision on any Commi ssion Decision concerning national 
marketing authoris tions , in particular for referrals, should be reduced to , in principle, 
46 days.  
(147)  On the basis of the opinion of the Agency, the Commission should adopt a decision on 
the referral  by means of implem enting acts. In justified cases, the Commission may 
return the opinion for further examination or deviate in its decision from the opinion of 
the Agency. Taking into account the need to make medicinal products swiftly 
available to patients, it should be ac knowledged that the chairperson of the Standing 
Committee for Medicines for Human Use will use the available mechanisms under 
Regulation 182/2011 and notably the possibility to obtain the committees opinion in 
written procedure and within expeditious deadl ines which, in principle, will not 
exceed 10 calendar days.  
(148)  The Commission should be empowered to adopt any necessary changes to Annex II in 
order to take into account scientific and technical progress.  
(149)  In order to supplement or amend certain non-essential elements of this Directive, the 
power to adopt acts in accordance with Article 290 TFEU should be delegated to the 
Commission in respect of specifying the procedure for examination of application of 
active substance master file certificate, t he publication of such certificates, the 
procedure for changes to the active substance master file and its certificate, access to 
the active substance master file and its assessment report; specifying additional quality 
master files to provide information on a constituent of a medicinal product, the 
procedure for examination of application of a quality master file certificate, the 
publication of such certificates, the procedure for changes to the quality master file 
and its certificate, and access to the qu ality master file and its assessment report; 
determining the situations in which post -authorisation efficacy studies may be 
required; specifying the categories of medicinal products to which a marketing 
authorisation subject to specific obligations could b e granted and specifying the 
                                                 
29 Regulation (EU) No 182/2011 of the European Parliament and of the Council of 16 February  2011 
laying down the rules and general principles concerning mechanisms for control by Member States of 
the Commission’s exercise of implementing powers (OJ L 55, 28.2.2011, p. 13).  EN 44  EN procedures and requirements for granting such a marketing authorisation and for its 
renewal; specifying exemptions to variation and the categories in which variations 
should be classified and establishing procedures for the exa mination of applications 
for variations to the terms of marketing authorisations as well as specifying conditions 
and procedures for cooperation with third countries and international organisations for 
examination of applications for such variations. It is  of particular importance that the 
Commission carry out appropriate consultations during its preparatory work, including 
at expert level, and that those consultations be conducted in accordance with the 
principles laid down in the Interinstitutional Agreem ent of 13 April 2016 on Better 
Law-Making30. In particular, to ensure equal participation in the preparation of 
delegated acts, the European Parliament and the Council receive all documents at the 
same time as Member States’ experts, and their experts syste matically have access to 
meetings of Commission expert groups dealing with the preparation of delegated acts.  
(150)  This Directive seeks to enable the right access to preventive healthcare and to benefit 
from medical treatment under the conditions establis hed by national laws and practices 
and to ensure a high level of human health protection in the definition and 
implementation of all the Union’s policies and activities as laid down in Article 35 of 
the Charter of Fundamental Rights of the European Union.  
(151)  Since the objectives of this Directive, namely to establish rules on medicinal products 
ensuring the protection of public health and the environment as well as the functioning 
of the internal market, cannot be sufficiently achieved by the Member Stat es as 
national rules would lead to disharmonisation, unequal patient access to medicinal 
products and barriers to the internal market, but can rather, by reason of its effects, be 
better achieved at Union level, the Union may adopt measures, in accordance with the 
principle of subsidiarity as set out in Article  5 of the Treaty on European Union. 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 those objec tives.  
(152)  In accordance with the Joint Political Declaration of 28 September 2011 of Member 
States and the Commission on explanatory documents31, Member States have 
undertaken to accompany, in justified cases, the notification of their transposition 
meas ures with one or more documents explaining the relationship between the 
components of a directive and the corresponding parts of national transposition 
instruments. With regard to this Directive, the legislator considers the transmission of 
such documents to be justified.  
HAVE ADOPTED THIS DIRECTIVE:  
Chapter I:  
Subject matter, scope and definitions  
Article 1   
Subject matter and scope  
1. This Directive lays down rules for the placing on the market, manufacturing, import, 
export, supply, distribution , pharmacovigilance, control and use of medicinal 
products for human use.  
                                                 
30 OJ L 123, 12.5.2016, p. 1.  
31 OJ C 369, 17.12.2011, p. 14.  EN 45  EN 2. This Directive shall apply to medicinal products for human use intended to be placed 
on the market.  
3. In addition to the products referred to in paragraph 2, Chapter XI shall also apply to 
starting material s, active substances,  excipients and intermediate products.  
4. In cases where, taking into account all its characteristics, a product fall s within the 
definition of a ‘medicinal product’ and within the definition of a product covered by 
other Union law and there is a conflict between this Directive and other Union law,  
the provisions of this Directive shall prevail . 
5. The Directive shall not  apply to:  
(a) medicinal product s prepared in a pharmacy in accordance with a medical 
prescription for an individual patient ( ‘magistral formula ’); 
(b) medicinal product prepared in a pharmacy in accordance with a pharmacopoeia 
and intended to be supplied directly to the patients served by the pharmacy in 
question ( ‘officinal formula ’); 
(c) investigational medicinal product as defined in Article 2, paragraph 5 , of 
Regulation (EU) No 536/2014.  
6. Medicinal products referred to in paragraph 5, point (a), may be prepared in duly 
justified cases in advance by a pharmacy serving a hospital, on the basis of the 
estimated medical prescriptions within that hospital for the following seven  days.  
7. Member  States shall take the necessary measures  to develop the pr oduction and use 
of medicinal products derived from substances of human  origin  coming from 
voluntary unpaid donations . 
8. This Directive and all Regulations referred to therein shall be without prejudice to 
the application of national legislation prohibiting or restricting the use of any specific 
type of substance of human origin or animal cells, or the sale, supply or use of  
medicinal products containing, consisting of or derived from these animal cells or 
substances of human origin , on grounds not dealt with in the aforementioned Union 
law. The Member States shall communicate the national legislation concerned to the 
Commiss ion. 
9. The provisions of this Directive shall not affect the powers of the Member States' 
authorities either as regards the setting of prices for medicinal products or their 
inclusion in the scope of national health insurance schemes, on the basis of heal th, 
economic and social conditions.  
10. This Directive shall not affect the application of national legislation prohibiting or 
restricting the following:  
(a) the sale, supply or use of medicinal products as contraceptives or 
abortifacients ; 
(b) the use of any specific type of substance of human origin or animal cells, on 
grounds not dealt with in the aforementioned Union law;  
(c) the sale, supply or use of medicinal products containing, consisting of or 
derived from these animal cells or substances of human  origin , on grounds not 
dealt with in Union law . EN 46  EN Article 2  
Advanced therapy medicinal products prepared under hospital exemption  
1. By way of derogation from Article 1(1) , only this Article  shall apply to  advanced 
therapy medicinal products prepared on a n on-routine basis in accordance with the 
requirements set in paragraph 3  and used within the same Member State in a hospital 
under the exclusive professional responsibility of a medical practitioner, in order to 
comply with an individual medical prescriptio n for a custom -made product for an 
individual patient (‘advanced therapy medicinal products prepared under hospital 
exemption’).  
2. The m anufacturing of an advanced therapy medicinal product prepared under 
hospital exemption shall require an approval  by the competent authority of the 
Member State (‘ hospital exemption approval ’). Member States shall notify any such 
approval , as well as subsequent changes , to the Agency.  
The application for a hospital exemption approval shall be submitted to the 
competent a uthority of the Member State where the hospital is located.  
3. Member States shall ensure that advanced therapy medicinal products prepared under 
hospital exemption comply with the requirements equivalent to the good 
manufacturing practices and traceabilit y for advanced therapy medicinal products 
referred to in Articles 5 and 15 of Regulation (EC) No 1394/2007 32 respectively, and 
with pharmacovigilance requirements equivalent to those provided for at Union level 
pursuant to [revised Regulation (EC) No 726/2004] . 
4. Member States shall ensure that data on the use, safety and the efficacy of advanced 
therapy medicinal products prepared under hospital exemption  is collected and 
reported by the hospital exemption approval holder  to the competent authority o f the 
Member State at least annually. The competent authority of the Member State shall 
review such data and shall verify the compliance  of advanced therapy medicinal 
products prepared under hospital exemption  with the requirements referred to in 
paragraph  3. 
5. If a hospital exemption approval is revoked due to safety or efficacy concerns the 
competent authority of the Member States that approved the hospital exemption shall 
inform the Agency and the competent authorities of the other Member States.  
6. The competent authority of the Member State shall transmit the data related to the 
use, safety and efficacy of an advanced therapy medicinal product prepared under the 
hospital exemption approval to the Agency annually. The Agency shall, in 
collaboration w ith the competent authorities of Member States and the Commission, 
set up and maintain a repository of th at data.  
7. The Commission shall adopt implementing acts to specify the following:  
(a) details of the application for the approval of hospital exemption referred to in 
paragraph 1, second subparagraph , including the evidence on quality, safety 
and efficacy of the advance therapy medicinal products prepared under hospital 
exemption for the approval and the subsequent changes;  
                                                 
32 Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 
on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 
726/2004 (OJ L 324, 10.12.2007, p. 1).  EN 47  EN (b) the format for collection and reporting of data referred to in paragraph  4; 
(c) the modalities for the exchange of knowledge between hospital exemption 
approval holders within the same Member State or different Member States ; 
(d) the modalities for preparation  and use of advanced therapy medicinal products 
under hospital exemption on a non -routine basis . 
Those implementing acts shall be adopted in accordance with the examination 
procedure referred to in Article 2 14(2). 
8. The Agency shall provide to the Commission a report on the experience acquired 
with the hospital exemption approval s on the basis of contributions from Member 
States and the data referred to in paragraph 4. The first report shall be provided three 
years after [OP please insert the date = 18 months after the date of entering into force 
of this Directive ] and then every five years thereafter.  
Article 3  
Exceptions  under  certain  circumstances  
1. A Member State may, in order  to fulfil special needs, exclude from the scope  of this 
Directive medicinal products supplied in response to a bona fide unsolicited order, 
prepared  in accordance with the specifications of an authorised healthcare 
professional and for use by an individual patient under their direct personal 
responsibility. However, in such case Member States shall encourage healthcare 
professionals and patients to re port data on the safety of the use of such products to 
the competent authority of the M ember State in accordance with Article 9 7. 
For allergen medicinal products supplied in accordance with this paragraph, the 
competent authorities of the Member State may request the submission of relevant 
information in accordance with Annex II.  
2. Without prejudice to Article 30 of [revised Regulation (EC) No 726/2004 ], Member 
States may temporarily authorise the use and  distribution of an unauthorised 
medicinal product i n response to a suspected or confirmed spread of pathogenic 
agents, toxins, chemical agents or nuclear radiation any of which could cause harm.  
3. Member States shall ensure that marketing authorisation holders, manufacturers and 
healthcare professionals a re not subject to civil or administrative liability for any 
consequences resulting from the use of a medicinal product otherwise than for the 
authorised therapeutic indications or from the use of an unauthorised medicinal 
product, whe re such use is recomme nded or required by a competent authority in 
response to the suspected or confirmed spread of pathogenic agents, toxins, chemical 
agents or nuclear radiation any of which could cause harm. Such provisions shall 
apply whether or not  a national or a centrali sed marketing  authorisation has been 
granted.  
4. Liability for defective products, as provided for by [Council Directive 85/374/EEC33 
– OP please replace  reference by new instrument COM(2022) 495 when adopted], 
shall not be affected by paragraph 3 . 
                                                 
33 Council Directive 85/374/EEC of 25 July 1985 on the approximation of the laws, regulations and 
administrative provisions of the Member States, concerning liability for defective products (OJ L 210, 
7.8.1985, p. 29).   EN 48  EN Article 4  
Definitions  
1. For the purposes of this Directive, the following definitions apply:  
(1) ‘medicinal product’ means any substance or combination of substances that 
fulfils at least one of the following conditions:  
(a) any substance or combination of substances that is  presented as having 
properties for treating or preventing disease in human beings; or  
(b) any substance or combination of substances that may be used in or 
administered to human beings with a view to either restoring, correcting 
or mo difying physiological functions by exerting a pharmacological, 
immunological or metabolic action, or to making a medical diagnosis;  
(2) ‘substance’ means any matter irrespective of origin, which may be:  
(a) human, e.g. tissues and cells , human blood, human  secretions and human 
blood products;  
(b) animal, e.g. whole animals, animal organs and parts thereof, animal 
tissues and cells, animal secretions, toxins, extracts, animal blood and 
animal  blood products;  
(c) vegetal, e.g. plants, including algae , parts o f plants, plant  secretions and 
exudates , extracts;  
(d) chemical, e.g. elements, naturally occurring chemical materials and 
chemical products obtained by chemical change or synthesis;  
(e) micro -organisms, e.g. bacteria, viruses and protozoa;   
(f) fungi, inc luding micro -fungi  (yeast) ; 
(3) ‘active substance’ means  any substance or mixture of substances intended to be 
used in the manufacture of a medicinal product and that, when used in its 
production, becomes an active ingredient of that product intended to ex ert a 
pharmacological, immunological or metabolic action with a view to restoring, 
correcting or modifying physiological functions or to make a medical 
diagnosis;  
(4) ‘starting material’ means any material from which an active substance is 
manufactured or extracted;  
(5) ‘excipient’ means any ingredient  of a medicinal product other than the active 
substance;  
(6) ‘functional excipient’ means an excipient that contributes to or enhances the 
performance of a medicinal product or performs an action ancillary to that of 
the active substance but does not have a therapeutic contribution on its own;  
(7) ‘advanced therapy medicinal product’ means  advanced therapy medicinal 
product  as defined in Article 2 (1), point (a),  of Regulation (EC) No 1394/2007;  
(8) ‘allergen product’ means any medicinal product that is intended to identify or 
induce a specific acquired alteration in the immunological response to an 
allergen;  EN 49  EN (9) ‘competent authorities’ means the Agency and the competent authorities of the 
Members States;  
(10) ‘Agency’ means the European Medicines Agency;  
(11) ‘non-clinical’ means a study or a test conducted in vitro, in silico, or in 
chemico, or a non -human in vivo test related to the investigation of the safety 
and efficacy of a medicinal product. Such test ma y include simple and complex 
human cell -based assays, microphysiological systems including organ -on-chip, 
computer modelling, other non -human or human biology -based test methods, 
and animal -based tests;  
(12) ‘reference medicinal product’ means  a medicinal product that is or has been  
authorised in the Union under Article 5, in accordance with Article 6;  
(13) ‘generic medicinal product’ means  a medicinal product that has the same 
qualitative and quantitative composition in active substances and the same 
pharm aceutical form as the reference medicinal product;  
(14) ‘biological medicinal product’ means a medicinal product, the active substance 
of which is produced by or extracted from a biological source and which due  to 
its complexity, its characterisation and t he determination of its quality may 
require a combination of physico -chemical -biological testing, together with its 
control strategy;  
(15) ‘letter of access’ means an original document, signed by the owner of the data 
or its representative, that states tha t the data may be used for the benefit of a 
third party by a competent authority or the Commission for the purposes of this 
Directive;  
(16) ‘fixed dose combination medicinal product’ means a medicinal product 
consisting of a combination of active substance s intended to be placed on the 
market as a single pharmaceutical form;  
(17) ‘multi -medicinal product package’ means  a package that contains more than 
one medicinal product under a single invented name and intended to be used in 
a medical treatment where th e individual medicinal products in the package are 
for medical purposes simultaneously or sequentially administered;  
(18) ‘radiopharmaceutical’ means any medicinal product that, when ready for use, 
contains one or more radionuclides (radioactive isotopes) included for a 
medicinal purpose;  
(19) ‘radionuclide generator’ means any system incorporating a fixed parent 
radionuclide from which is produced a daughter radionuclide which is to be 
obtained by elution or by any other method and used in a radiopharmaceu tical;  
(20) ‘kit’ means any preparation to be reconstituted or combined with radionuclides 
in the final radiopharmaceutical, usually prior to its administration;  
(21) ‘radionuclide precursor’ means any other radionuclide produced for the radio -
labelling of  another substance prior to administration;  
(22) ‘antimicrobial’ means any medicinal product with a direct action on micro -
organisms used for treatment or prevention of infections or infectious diseases, 
including antibiotics, antivirals and antifungals;   EN 50  EN (23) ‘integral combination of a medicinal product with a medical device’ means a 
combination of a medicinal product with a medical device, as defined by 
Regulation (EU) 2017/745, and where:  
(a) the two form an integral product and where the action of the m edicinal 
product is principal and not ancillary to that of the medical device, or  
(b) the medicinal product is intended to be administered by the medical 
device and the two are placed on the market in such a way that they form 
a single integral product that is intended exclusively for use in the given 
combination and where the medical device is not reusable.  
(24) ‘combined advanced therapy medicinal products’  means a  product as defined 
in Article 2 of Regulation (EC) No 1394/2007, including when a  gene t herapy 
medicinal product is part of the combined advanced therapy medicinal product;  
(25) ‘medicinal product in exclusive  use with a medical  device’  means a m edicinal 
product presented in a package with a medical device  or to be used with a 
specific medical device, as defined by Regulation (EU) 2017/745, and 
referenced in the summary of product characteristics;  
(26) ‘combination of a medicinal product with a product other than a medical 
device’ means a combination of a m edicinal product with a product other than 
a medical device (as defined by Regulation (EU) 2017/745) and where the two 
are intended for use in the given combination  in accordance with the summary 
of product characteristics;  
(27) ‘immunological medicinal pr oduct’ means:  
(a) any vaccine or allergen product, or  
(b) any medicinal product  consisting of toxins or serums used to produce 
passive immunity or to diagnose the state of immunity;  
(28) 'vaccine’ means any medicinal product that is intended to elicit an immune 
response for prevention, including post exposure prophylaxis, and for treatment 
of diseases caused by an infectious agent;  
(29) ‘gene therapy medicinal product’ means a medicinal product, except vaccines 
against infectious diseases, that contains or  consists of:  
(a) a substance or a combination of substances intended to edit the host 
genome in a sequence -specific manner or that contain or consists of cells 
subjected to such modification; or  
(b) a recombinant or synthetic nucleic acid used in or admin istered to human 
beings with a view to regulating, replacing or adding a genetic sequence 
that mediates its effect by transcription or translation of the transferred 
genetic materials or that contain or consists of cells subjected to these 
modifications;  
(30) ‘somatic cell therapy medicinal product’ means a biological medicinal product 
that has the following characteristics:  
(a) contains or consists of cells or tissues that have been subject to 
substantial manipulation so that biological characteristics, ph ysiological 
functions or structural properties relevant for the intended clinical use EN 51  EN have been altered, or of cells or tissues that are not intended to be used 
for the same essential function(s) in the recipient and the donor;  
(b) is presented as having p roperties for, or is used in or administered to 
human beings with a view to treating, preventing or diagnosing a disease 
through the pharmacological, immunological or metabolic action of its 
cells or tissues.  
For the purposes of point (a), the manipulation s listed in Annex I to Regulation 
(EC) No 1394/2007, in particular, shall not be considered as substantial 
manipulations.  
(31) ‘SoHO -derived medicinal product other than ATMPs’ means any medicinal 
product containing, consisting of or deriving from a substa nce of human origin 
(SoHO), as defined in Regulation [SoHO Regulation], other than tissues and 
cells, that is of standardised consistency and is prepared by:  
(a) a method involving an industrial process which includes pooling of 
donations; or  
(b) a process  that extracts an active ingredient from the substance of human 
origin or transforms the substance of human origin by changing its 
inherent properties;  
(32) ‘risk management plan’ means a detailed description of the risk management 
system;  
(33) ‘environmental risk assessment’ means the evaluation of the risks to the 
environment, or risks to public health, posed by the release of the medicinal 
product in the environment from the use and disposal of the medicinal product 
and the identification of r isk prevention, limitation and mitigation measures. 
For medicinal product with an antimicrobial mode of action, the ERA also 
encompasses an evaluation of the risk for antimicrobial resistance selection in 
the environment due to the manufacturing, use and d isposal of that medicinal 
product;  
(34) ‘antimicrobial resistance’ means the ability of a micro -organism to survive or 
to grow in the presence of a concentration of an antimicrobial agent that is 
usually sufficient to inhibit or kill that micro -organism;  
(35) ‘risks related to use of the medicinal product’ means any risk:  
(a) relating to the quality, safety or efficacy of the medicinal product as 
regards patients' health or public health;  
(b) of undesirable effects on the environment posed by the medicinal 
product ; 
(c) of undesirable effects on public health due to the release of the medicinal 
product in the environment including anti -microbial resistance;  
(36) ‘active substance master file’ means a document that contains a detailed 
description of the manufa cturing process, quality control during manufacture 
and process validation prepared in a separate document by the manufacturer of 
the active substance;  
(37) ‘paediatric investigation plan’ means a research and development programme 
aimed at ensuring that t he necessary data are generated determining the EN 52  EN conditions in which a medicinal product may be authorised to treat the 
paediatric population;  
(38) ‘paediatric population’ means that part of the population aged between birth 
and 18 years;  
(39) ‘medicinal prescription’ means any medicinal prescription issued by a 
professional person qualified to do so;  
(40) ‘abuse of medicinal products’ means persistent or sporadic, intentional 
excessive use of medicinal products that is accompanied by harmful physical 
or psychological effects;  
(41) ‘benefit -risk balance’ means an evaluation of the positive therapeutic effects of 
the medicinal product in relation to the risks referred to  in point (35), subpoint 
(a); 
(42) ‘marketing authorisation holder representative ’ means the person, commonly 
known as local representative, designated by the marketing authorisation 
holder to represent the marketing authorisation holder  in the Member State 
concerned;  
(43) ‘package leaflet’ means information for the user that accompanies the 
medicinal product;  
(44) ‘outer packaging’ means the packaging into which is placed the immediate 
packaging;  
(45) ‘immediate packaging’ means the container or other form of packaging 
immediately in contact with the medicinal product;  
(46) ‘labelling’ means i nformation on the immediate packaging  or the outer 
packaging;  
(47) ‘name of the medicinal product’ means the name, which may be either an 
invented name not liable to confusion with the common name, or a common or 
scientific name accompanied by a trademark or by the name of the marketing 
authorisation holder;  
(48) ‘common name’ means the international non -proprietary name recommended 
by the World Health Organization for an active substance ; 
(49) ‘strength of the medicinal product’ means the content of the active substances 
in a medicinal product, expressed quantitatively per dosage unit, per unit of 
volume or per unit of weight according to the dosage form ; 
(50) ‘falsified medicinal product’ means any medicinal product with a false 
representation of:  
(a) its identity, including its packaging and labelling, its name or its 
composition as regards any of the ingredients including excipients or the 
strength of those ingredients;  
(b) its source, including its manufacturer, its country of manufacturing, its 
countr y of origin or its marketing authorisation holder; or  
(c) its history, including the records and documents relating to the 
distribution channels used;  EN 53  EN This definition does not include unintentional quality defects and is without 
prejudice to infringements  of intellectual property rights.  
(51) ‘public health emergency’ means a public health emergency recognised at 
Union level by the Commission under Article 23(1) of Regulation (EU) 
2022/2371 of the European Parliament and of the Council34; 
(52) ‘entity not e ngaged in an economic activity’ means any legal or natural person 
that is not engaged in an economic activity and that:  
(a) is not an undertaking or controlled by an undertaking; and,  
(b) has not concluded any agreements with any undertaking concerning 
sponsorship or participation to the medicinal product development ;  
(53) ‘micro, small and medium -sized enterprises’ means micro, small and medium -
sized enterprises as defined in Article 2 of Commission Recommendation 
2003/361/EC35; 
(54) ‘variation’ or ‘variat ion of the terms of a marketing authorisation’ means any 
amendment to:  
(a) the contents of the particulars and documents referred to in Article 6(2), 
Articles  9 to 14 and Article 62, Annex I and Annex II thereto and Article 
6 of the [revised Regulation (EC) No 726/2004]; or  
(b) the terms of the decision granting the marketing authorisation for a 
medicinal product, including the summary of product characteristics and 
any conditions, obligations, or restrictions affecting the marketing 
authorisation, or changes to the labelling or the package leaflet related to 
changes to the summary of product characteristics;  
(55) ‘post -authorisation safety study’ means any study relati ng to 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;  
(56) ‘pharmac ovigilance system’ means a system used by the marketing 
authorisation holder and by Member States to fulfil the tasks and 
responsibilities set out in Chapter IX  and designed to monitor the safety of 
authorised medicinal products and detect any change to th eir benefit -risk 
balance;  
(57) ‘pharmacovigilance system master file’ means a detailed description of the 
pharmacovigilance system used by the marketing authorisation holder with 
respect to one or more authorised medicinal products;  
(58) ‘risk management system’ means 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 activities and interventions;  
                                                 
34 Regulation (EU) 2022/2371 of the European Parliament and of the Council of 23 November 2022 on 
serious cross -border threats to health and repealing Decision No 1082/2013/EU ( OJ L 314, 6.12.2022, 
p. 26).  
35 Commission Recommendation of 6 May 2003 concerning the definition of micro, small and medium -
sized enterprises (OJ L 124, 20.5.2003, p. 36).  EN 54  EN (59) ‘adverse reaction’ means a response to a medicinal product that is noxious and 
unintended;  
(60) ‘serious adverse reaction’ means an adverse reaction that results in death, is 
life-threatening, requires inpatient hospitalisation or prolongation of existing 
hospitalisation, results in persistent or significant disability or incapacity, or is 
a congenital anomaly or a birth defect;  
(61) ‘unexpected adverse reaction’ means an adverse reaction, the nature, severity 
or outcome of which is not consistent with the s ummary of product 
characteristics;  
(62) ‘homeopathic medicinal product’ means a medicinal product prepared from 
homeopathic stocks in accordance with a homeopathic manufacturing 
procedure described by the European Pharmacopoeia or, in the absence thereof, 
by the pharmacopoeias currently used officially in the Member States;  
(63) ‘traditional herbal medicinal product’ means a herbal medicinal product that 
fulfils the conditions laid down in Article 134(1) ; 
(64) ‘herbal medicinal product’ means any medicinal product, exclusively 
containing as active ingredients one or more herbal substances or one or more 
herbal preparations, or one or more such herbal substances in combination with 
one or more herbal preparations;  
(65) ‘herbal substances’ means all mainly who le, fragmented or cut plants, plant 
parts, algae, fungi, lichen in an unprocessed, usually dried or fresh form, and 
certain exudates that have not been subjected to a specific treatment are also 
considered to be herbal substances. Herbal substances are pre cisely defined by 
the plant part used and the botanical name according to the binomial system 
(genus, species, variety and author);  
(66) ‘herbal preparations’ means preparations obtained by subjecting herbal 
substances to treatments such as extraction, dis tillation, expression, 
fractionation, purification, concentration or fermentation including  
comminuted or powdered herbal substances, tinctures, extracts, essential oils, 
expressed juices and processed exudates;  
(67) ‘corresponding traditional herbal medic inal product’ means a traditonal herbal 
medicinal product with the same active substances, irrespective of the 
excipients used, the same or similar intended purpose, equivalent strength and 
posology and the same or similar route of administration as the tr aditional 
herbal medicinal product applied for;  
(68) ‘wholesale distribution of medicinal products’ means all activities, consisting 
of procuring, holding, supplying or exporting medicinal products,  whether for 
profit or not,  apart from supplying medicinal  products to the public. Such 
activities are carried out with manufacturers or their depositories, importers, 
other wholesale distributors or with pharmacists and persons authorised or 
entitled to supply medicinal products to the public in the Member State  
concerned;  
(69) ‘brokering of medicinal products’ means all activities in relation to the sale or 
purchase of medicinal products, except for wholesale distribution, that do not 
include physical handling and that consist of negotiating independently and on  
behalf of another legal or natural person;  EN 55  EN (70) ‘public service obligation’ means to  guarantee permanently an adequate range 
of medicinal products to meet the requirements of a specific geographical area 
and to deliver the supplies requested within a very  short time over the whole of 
the area in question . 
2. The Commission is empowered to adopt delegated acts in accordance with Article 
215 to amend the definitions in paragraph 1, points (2) to (6), (8), (14), (16) to (31), 
in the light of technical and sci entific progress and taking into account definitions 
agreed at Union and international level without extending the scope of the 
definitions.  
Chapter II   
Application requirements  for national and centralised marketing 
authorisations  
SECTION  1 
GENERAL PROVI SIONS  
Article 5 
Marketing  authorisation s  
1. A medicinal product shall be placed on the market of a Member State only when a 
marketing authorisation has been granted  by the competent authorities of a Member 
State in accordance with Chapter III (‘national marketing authorisation’)  or a 
marketing authorisation has been granted in accordance with [revised Regulation 
(EC) No 726/2004 ] (‘central ised marketing authorisation’) . 
2. When an initial marketing authorisation has been granted  in accordance with 
paragraph 1, any development concerning  the medicinal product covered by the 
authorisation such as additional therapeutic indication , strengths, pharmaceutical 
forms, administration routes, presentations, as well as any variations of the marketing 
authorisation  shall also be granted an authorisation in accordance with paragraph 1 or 
be included in the initial marketing authorisation . All those marketing authorisations 
shall be considered as belonging to the same global marketing authoris ation , in 
particular  for the purpose of the marketing authorisations applications under Articles 
9 to 12, including as regards  the expiry of the regulatory data protection period for  
application s using a reference medicinal product . 
Article 6 
General  requirements  for marketing  authorisation  application s 
1. In order to obtain a marketing authorisation, an electronic marketing authorisation 
application shall be submitted to the competent authority concerned in a common 
format. The Agency shall make available such format after consultation with the 
Member States.  
2. The marketing authorisation application shall include the particulars and 
documentation listed in Annex I, submitted in accordance with Annex II.  EN 56  EN 3. The documents and information concernin g the results of the pharmaceutical and 
non-clinical  tests and the clinical studies referred to in Annex I shall be accompanied 
by detailed summaries in accordance with Article 7 and supportive raw data.  
4. The risk management system referred to in Annex I shall be proportionate to the 
identified risks and the potential risks of the medicinal product, and the need for 
post-authorisation safety data.  
5. The marketing authorisation application for a medicinal product that is not authorised 
in the Union  at the time of entry into force of this Directive  and for new therapeutic 
indications, including paediatric indications, new pharmaceutical forms, new 
strengths and new routes of administration  of authorised medicinal products which 
are protected either by  a supplementary protection certificate under [Regulation (EC) 
No 469/2009 - OP please replace reference by new instrument when adopted ], or by 
a patent which qualifies for the granting of the supplementary protection certificate, 
shall include one of the following:  
(a) the results of all studies performed and details of all information collected in 
compliance with an agreed paediatric investigation plan;  
(b) a decision of the Agency granting a product -specific waiver pursuant to Article 
75(1) of [revised  Regulation No (EC) 726/2004] ; 
(c) a decision of the Agency granting a class waiver pursuant to Article 7 5(2) of 
[revised  Regulation No (EC) 726/2004] ; 
(d) a decision of the Agency granting a deferral pursuant to Article 81 of [revised  
Regulation No (EC) 726/2004] ; 
(e) a decision of the Agency taken in consultation with the Commission pursuant 
to Article 83 of [revised  Regulation  No (EC)  726/2004]  to temporarily 
derogate from the provision referred to in points (a) to (d) above in case of 
health emergencies.  
The documents submitted under points (a) to (d) shall, cumulatively, cover all 
subsets of the paediatric population.  
6. The provisions of p aragraph 5 shall not apply to medicinal products authorised under 
Articles 9, 11, 13, Articles 125 to 141 and medicinal products authorised under 
Article s 10 and 12  which are not protected either by a supplementary protection 
certificate under [Regulation (EC) No 469/2009  - OP please replace reference by 
new instrument when adopted ], or by a patent which qua lifies for the granting of the 
supplementary protection certificate . 
7. The marketing authorisation applicant shall demonstrate that the principle of 
replacement, reduction and refinement of animal testing for scientific purposes has 
been applied in compliance with Directive 2010/63/EU  with regard to any animal 
study conducted in support  of the application.   
The marketing authorisation applicant shall not carry out animal test ing in case 
scientifically satisfactory non-animal testing method s are avail able. 
Article 7 
Expert  verification  
1. The marketing authorisation applicant shall ensure that the detailed summaries 
referred to in Article 6 (3) have been drawn up and signed by experts with the EN 57  EN necessary technical or professional qualifications  before they are submitted to the 
competent authorities . The technical or professional qualifications  of the experts  
shall be set out in a brief curriculum vitae.  
2. The experts  referred to in paragraph 1 shall justify any use made of scientific 
literature under Article 13  in accordance with the requirements  set out in Annex II.  
Article 8 
Medicinal products manufactured outside the Union  
Member States shall take all appropriate measures to ensure that:  
(a) the competent authorities of the Member States verify that manufacturers and 
importers of medicinal products coming from third countries are able to carry out 
manufacture in compliance with the particulars supplied pursuant to Annex I, or to 
carry out controls according to the methods described in the particulars 
accompanying the application in accordance with Annex I;  
(b) the competent authorities of the Member States may allow manufacturers and 
importers of medicinal products coming from third countries, in justifiable cases, to 
have certain stages of manufacture  or certain of the controls referred to in point (a) 
carried out by third parties; in such cases, the verifications by the competent 
authorities of the Member States shall also be made in the establishment designated.  
SECTION  2 
SPECIFIC  REQUIREMENTS  FOR  ABRIDGED  APPLICATIONS  FOR  MARKETING  
AUTHORISATION  
Article 9  
Application s concerning  generic  medicinal  products  
1. By way of derogation from Article 6 (2), the applicant for a marketing authorisation 
for a generic medicinal product shall not be required to provide to the competent 
authorities the results of non-clinical  tests and of clinical studies  if equivalence of the 
generic medicinal product with th e reference medicinal product is demonstrated.  
2. For th e purpose  of demonstrating the equivalence as referred to in paragraph 1,  the 
applicant shall submit to the competent authorities equivalence studies, or a 
justification as to why such studies were n ot performed, and demonstrate that the 
generic medicinal product meets the relevant criteria set out  in the appropriate 
detailed guidelines.  
3. Paragraph 1 shall also apply if the reference medicinal product has not been  
authorised  in the Member State in which the application for the generic medicinal 
product is submitted. In this case, the applicant shall indicate in the application the 
name of the Member State in which the reference medicinal product is or has been 
authorised. At the request of the compe tent authority of the Member State in which 
the application is submitted, the competent authority of the other Member State shall 
transm it within a period of one month  a confirmation that the reference medicinal 
product is or has been authorised together w ith the full composition of the reference 
medicinal  product and if necessary, any other relevant documentation.  EN 58  EN The various immediate -release oral pharmaceutical forms shall be considered to be 
the same pharmaceutical form.  
4. The different salts, esters,  ethers, isomers, mixtures of isomers, complexes or 
derivatives of an active substance shall be considered to be the same active 
substance, unless they differ significantly in properties with regard to safety or 
efficacy.  In those cases, t he applicant shal l submit additional information to  
demonstrate  that the different salts, esters, ethers, isomers, mixtures of isomers, 
complexes or derivatives of an active substance do not differ significantly in respect 
of those properties.   
5. Where there is a significant  differ ence in properties as referred to in paragraph 4 , the 
applicant shall submit additional information in order to prove the safety or efficacy 
of the different salts, esters, ethers, isomers, mixtures of isomers, complexes or 
derivatives  of the authorised active substance of the reference medicinal product in 
an application under Article 10 . 
Article 10 
Application s concerning  hybrid  medicinal  products  
In cases where the medicinal product does not fall within the definition of a generic medicinal 
product or has changes in strength, pharmaceutical form, route of administration or 
therapeutic indications, compared to  the reference medicinal product, the re sults of the 
appropriate non-clinical  tests or clinical studies  shall be provided to the competent authorities 
to the extent necessary  to establish a scientific bridge to the data relied upon in the marketing 
authorisation for the reference medicinal produ ct, and to demonstrate the safety and efficacy 
profile of the hybrid medicinal product.  
Article 11  
Application s concerning  biosimilar  medicinal  products  
For a biological medicinal product that is similar to a reference biological medicinal product 
(‘biosimilar medicinal product’) , the results of appropriate comparability tests and studies 
shall be provided  to the competent authorities . The type and quantity of supplementary data to 
be provided must comply with the relevant criteria stated in Annex I I and the related detailed 
guidelines. The results of other tests and studies  from the reference medicinal product's 
dossier shall not be provided.  
Article  12  
Application s concerning  bio-hybrid  medicinal  products  
In cases where a biosimilar medicinal product has changes in strength, pharmaceutical form, 
route of administration or therapeutic indications, compared to the reference biological 
medicinal product  (‘bio -hybrid’) , the results of the appropriate non-clinic al tests or clinical 
studies shall be provided  to the competent authorities  to the extent necessary  to establish a 
scientific bridge to the data relied upon in the marketing authorisation for the reference 
biological medicinal product , and to demonstrate the safety or efficacy profile of the 
biosimilar medicinal product.  EN 59  EN Article 13   
Application s based  on bibliographic  data 
In cases where no reference medicinal product is or has been authorised for the active 
substance of the medicinal product concerned, the applicant shall , by way of derogation from 
Article 6(2) , not be required to provide the results of non-clinical  tests or clinical studies  if the 
applicant can demonstrate that the active substances of the medicinal product have been in 
well-established medicinal use within the Union for the same therapeutic use and route of 
administration and  for at least ten years, with rec ognised efficacy and an acceptable level of 
safety in terms of the conditions set out in Annex II. In that event, the test and trial results 
shall be replaced by appropriate bibliographic data  in the form of  scientific literature.  
Article 14   
Application s based  on consent  
Following the granting of a marketing authorisation, the marketing authorisation holder may, 
by letter of access,  allow use to be made of all documentation refer red to in Article 6 (2) with a 
view to examining subsequent applications relati ng to other medicinal products possessing the 
same qualitative and quantitative composition in terms of active substances and the same 
pharmaceutical form.  
SECTION  3 
SPECIFIC  REQUIREMENTS  FOR  APPLICATIONS  FOR  CERTAIN  CATEGORIES  OF 
MEDICINAL  PRODUCTS   
Artic le 15   
Fixed  dose combination  medicinal  product , platform technologies  and multi -medicinal  
product  packages  
1. Where justified for therapeutic purposes, a marketing authorisation may be granted 
for a fixed dose combination  medicinal product . 
2. Where justified for therapeutic purposes , a marketing authorisation may , in 
exceptional circumstances, be granted for a medicinal product comprised of a fixed 
component and a variable component that is pre -defined in order to, where 
appropriate, target different  variants of an infectious agent or , where necessary , to 
tailor the  medicinal  product to characteristics of an individual patient or a group of 
patients  (‘platform technology’) . 
An applicant that intends to submit a n application for a  marketing authorisation for 
such a medicinal product shall seek , in advance , the agreement  concerning the 
submission of such application by  the competent authority concerned . 
3. Where justified for public health reasons and when the active substances cann ot be 
combined within a fixed dose combination  medicinal  product , a marketing 
authorisation may , in exceptional circumstances, be granted to a multi -medicinal 
product package.  
An applicant that intends to submit a an application for a marketing authorisati on for 
such a medicinal product shall seek , in advance , the agreement concerning the 
submission of such application by the competent authority concerned.  EN 60  EN Article 16   
Radiopharmaceuticals   
1. A marketing  authorisation shall be required for radionuclide generators, kits, and 
radionuclide precursors, unless they are used as starting material , active substance or 
intermediate  of radiopharmaceuticals covered by a marketing authorisation under 
Article 5 (1). 
2. A marketing authorisation shall not be required f or a radiopharmaceutical prepared at 
the time of use by a person or by an establishment authorised, according to national 
legislation, to use such radiopharmaceutical  in an approved healthcare establishment 
exclusively from authorised radionuclide generato rs, kits or radionuclide precursors 
in accordance with the manufacturer's instructions.  
Article 17  
Antimicrobials  
1. Where the application  for a  marketing authorisation concerns an antimicrobial, the 
application shall , in addition to the information referred to in Article 6 , contain  the 
following : 
(a) an antimicrobial  stewardship plan as referred to  in Annex I;  
(b) a description of the special information requirements outlined in Article 69  and 
listed in Annex I.  
2. The competent authority may impose obligations on the marketing authorisation 
holder if it finds the risk mitigation measures contained in the antimicrobial 
stewardship plan unsatisfactory.  
3. The marketing authorisation holder shall ensure that the pack siz e of the 
antimicrobial  corresponds to the usual posology and duration of treatment.  
Article 18  
Integral combinations of medicinal products and medical devices  
1. For integral combinations of a medicinal product and a medical device  the marketing 
authorisation applicant  shall submit data establishing the safe and effective use of the 
integral combination of the medicinal product and the medical device.  
As part of the assessment, in accordance with Article 29 , of the integral combination 
of a medici nal product and a medical device  the competent authorit ies shall assess 
the benefit -risk balance of the integral combination of a medicinal product and a 
medical device, taking into account the suitability of the use of the medicinal product 
together with the medical device.  
2. The relevant general safety and performance requirements set out in Annex I of 
Regulation (EU) 2017/745 shall apply as far as the safety and performance of the 
medical device part of the integral combination of a medicinal product wi th a 
medical device are concerned.  
3. The application for a marketing authorisation for an integral combination of a 
medicinal product with a medical device shall include the documentation supporting 
the compliance of the medical device part with the gener al safety and performance EN 61  EN requirements as referred to in paragraph 2 in accordance with Annex II , including, 
where relevant, the conformity assessment report by a notified body . 
4. In its evaluation of the integral combination of a medicinal product with a  medical 
device concerned, the competent authorit ies shall recognise the  results of the  
assessment of compliance of the medical device part of that integral combination 
with the general  safety and performance requirements in accordance with Annex I of 
Regulation (EU) 2017/745  including , where relevant, the results of the assessment by 
a notified body . 
5. The marketing authorisation applicant shall, upon request from the competent 
authority , submit any additional information related to the medical device  and that is 
relevant for the benefit -risk balance assessment of the integral combination of a 
medicinal product with a medical device  referred to in paragraph 1 . 
Article 19   
Medicinal products in exclusive use with medical devices  
1. For medicinal products in exclusive use with a medical device the marketing 
authorisation applicant  shall submit data establishing the safe and effective use of the 
medicinal product  taking into account its use with the medical device.  
As part of the asse ssment, in accordance with Article 29 , of the medicinal product  
referred to in th e first sub paragraph , the competent authorit ies shall assess the 
benefit -risk balance of the medicinal product taking into account the use of the 
medicinal product together with the medical device.  
2. For medicinal product s in exclusive use with a medical device the medical device  
shall meet the requi rements set out in Regulation (EU) 2017/745.  
3. The application for a marketing authorisation for a medicinal product in exclusive 
use with a medical device shall include the documentation supporting the compliance 
of the medical device with the general s afety and performance requirements as 
referred to in paragraph 2 in accordance with Annex II, including, where relevant, 
the conformity assessment report by a notified body.  
4. In its evaluation of the medicinal product referred to  in paragraph 1 the competent 
authority shall recognise the results of the assessment of compliance of the medical 
device concerned with the general safety and performance requirements in 
accordance with Annex I of Regulation (EU) 2017/745 including, where relevant, the 
results of the assessment by a notified body.  
5. The marketing authorisation applicant shall, upon request from the competent 
authority , submit any additional information related to the medical device and that is 
relevant for the benefit -risk balance assessmen t of the medicinal product  referred to 
in paragraph 1 , taking into account the use of the medicinal product with the medical 
device.  
6. If the action of the medicinal product is not anci llary to that of the medical device, 
the medicinal product shall comply with the requirements of this Directive and of the 
[revised Regulation (EC) No 726/2004] , taking into account its use with the medical 
device, without prejudice to the specific requirements of the Regulation (EU) 
2017/745.  EN 62  EN In this case, the marketing authorisation applicant shall, upon request from the 
competent authorit ies, submit  any additional information related to the medical 
device , taking into account its use with the medicinal product an d that is relevant for 
the post -authorisation monitoring of the medicinal product, without prejudice to the 
specific requirements of the [revised Regulation (EC) No 726/2004].  
Article 20  
Combinations of medicinal products with products other than medical devices  
1. For combinations of a medicinal product  with a product  other than a medical device , 
the marketing authorisation applicant  shall submit data establishing the safe and 
effective use of the combination of the medicinal product and the other product.  
As part of the assessment, in accordance with Article 29, of the combination of a 
medicinal product with a product other than a medical device t he competent 
authority shall assess the benefit -risk balance of the combination  of a medicinal  
product  and a product  other  than a medical  device , taking into account the use of the 
medicinal product together with the other product.  
2. The marketing authorisation applicant shall, upon request from the competent 
authority submit any additional information related to the product  other than medical 
devices and that is relevant for the benefit -risk balance assessment of the 
combination of me dicinal products with the product other than medical devices, 
taking into account the suitability of the use of the medicinal product with the 
product  referred to in paragraph 1 . 
SECTION  4 
SPECIFIC  DOSSIER  REQUIREMENTS  
Article 21   
Risk management plan  
The applicant of a marketing authorisation for a medicinal product referred to in Articles 9 
and 11 shall not be required to submit a risk management plan and a summary thereof, 
provided that no additional risk minimisation measures exist for the reference medicinal 
product and provided that the marketing authorisation for the reference medicinal product has 
not been withdrawn prior to the submission of the application.  
Article 22  
Environmental  risk assessment  and other environmental information  
1. When preparing the environmental risk assessment ( ‘ERA’) to be submitted pursuant 
to Article 6(2), the applicant shall take into account the scientific guidelines  on the 
environmental risk assessment of medicinal products for human use  as referred to in 
paragra ph 6, or provide the reasons for any divergence from the scientific guidelines 
to the Agency or, as appropriate to the competent authority of the Member State 
concerned, in a timely manner . Where available, the applicant shall take into account  
existing ERAs performed under other Union legislation.  EN 63  EN 2. The E RA shall indicate whether the medicinal product or any of its ingredients or 
other constituents is one of the following substances according to the criteria of 
Annex I to the Regulation (EC) No 1272/200 8: 
(a) persistent, bioaccumulative and toxic (PBT);  
(b) very persistent and very bioaccumulative (vPvB);  
(c) persistent, mobile and toxic (PMT), very persistent and very mobile (vPvM);  
or are endocrine active agents.  
3. The applicant shall also include in the ERA risk mitigation measures to avoid or 
where it is not possible, limit  emissions to air, water and soil of pollutants listed in 
Directive 2000/60/EC, Directive 2006/118/EC , Directive 2008/105/EC  and Directive 
2010/75/EU.  The applicant shall provid e detailed explanation that the proposed 
mitigation measures are appropriate and sufficient to address the identified risks to 
the environment.  
4. The ERA for antimicrobials shall include an evaluation of the risk for antimicrobial 
resistance selection in the environment due to the entire manufacturing supply chain 
inside and outside the Union , use and disposal of the antimicrobial taking into 
accoun t, where relevant, the existing international standards that have established 
predicted no effect concentration (PNECs) specific for antibiotics.  
5. The Agency shall  draw up scientific guidelines in accordance with Article 1 38 of 
[revised Regulation No (EC) 726/2004] , to specify technical details regarding the 
ERA requirements for medicin al products for human use . Where appropriate, the 
Agency shall consult the European Chemical Agency (ECHA), the European Food 
Safety Authority (EFSA) and the European Environmental Agency (EEA) on the 
drafting of these scientific guidelines . 
6. The marketing authorisation holder shall update  the ERA with new information  
without undue delay to the relevant competent authorities, in accordance with Article 
90(2), if new i nformation pertaining to the assessment criteria referred to in Article 
29 becomes available and could lead to a change of the conclusions of the ERA. The 
update  shall include any relevant information from environmental monitoring, 
including monitoring und er Directive 2000/60/EC, from eco -toxicity studies, from 
new or updated risk assessments under other Union legislation , as referred to in 
paragraph 1,  and environmental exposure data . 
For an ERA conducted prior to  [OP please insert the date = 18 months after the date 
of entering into force of this Directive] , the competent authority shall request the 
marketing authorisation holder to update the ERA if missing information has been 
identified for medicinal products potentially harmful to the environment.   
7. For medicinal products referred to in Articles 9 to 12 , the applicant may refer to ERA 
studies conducted for the reference medicinal product when preparing the ERA.  
Article 23  
ERA of medicinal  products  authorised  before  30 October  2005  
1. By [OP please insert the date = 30 months  after the date of the entry into force of this 
Directive] the Agency  shall , after consultation with the competent authorities of the 
Member States , the European Chemical Agency (ECHA), the European Food Safety 
Authority (E FSA) and the European Environmental Agency (EEA) , establish a EN 64  EN programme for the ERA to be submitted in accordance with Art icle 22 of th e 
medicinal products authorised before 30 October 2005 that have not been subject to 
any ERA and that the Agency has identified as potentially harmful to the 
environment  in accordance with paragraph 2 . 
This programme  shall be made publicly available  by the Agency . 
2. The Agency shall set the scientific criteria for the identification of the medicinal 
products as potentially harmful to the  environment  and for the prioritisation of their 
ERA , using a risk based approach. For this task, t he Agency may request from 
marketing authorisation holders the submission of relevant data or information .  
3. The marketing author isation holders for medicinal products identified in the 
programme referred to in paragraph 1 shall submit the ERA to the Agency . The 
outcome of the assessment of the ERA including the data submitted by the marketing 
authorisation holder shall be made publ icly available by the Agency.  
4. Where there are several medicinal products identified in the programme referred to 
in paragraph 1 that contain the same active substance and  that are expected to pose 
the same risks to the environment, the competent authorities of the Member States or 
the Agency shall encourage the marketing authorisation holders to conduct joint 
studies for the ERA , to minimise unnecessary duplication of data and use of animals.  
Article 24  
System  of ERA monographs  of the ERA data of active  substances  
1. The Agency  shall , in collaboration with the competent authorities of the Member 
States , set-up an active substance based review  system of ERA data (‘ERA 
monographs ’) for authorised medicinal product s. An ERA  monograph shall include a 
comprehensive set of physiochemical  data, fate data and effect data based on an 
assessment of a competent authority.  
2. The setting -up of the system of ERA monographs shall be based on a risk -based 
prioritisation of active substa nces.  
3. In the preparation of the ERA monograph referred to in paragraph 1, the Agency may 
request information, studies and data from competent authorities of the Member 
States and from marketing authorisation holders . 
4. The Agency in cooperation with th e competent authorities of the Member States 
shall conduct a proof -of-concept pilot of ERA monographs to be completed within 
three years after entering into force  of this Directive . 
5. The Commission is empowered to adopt delegated acts in accordance with Article 
215 and based on the results of a proof -of-concept pilot referred to in paragraph 4, to 
supplement this Directive by specifying  the following : 
(a) the content and format of ERA monographs;  
(b) the procedures for adopting and updating the ERA monogr aphs;  
(c) the procedures for submission of information, studies and data  referred to in 
paragraph 3 ; 
(d) the risk-based prioritisation criteria for the selection and prioritisation referred 
to in paragraph 2 ; EN 65  EN (e) the use of ERA monographs in the context of  new marketing authorisation 
applications for medicinal products to support their  ERA . 
Article 25   
Active  substance  master  file certificate  
1. Marketing authorisation  applicants may , instea d of submitting  the relevant data on a 
chemical active substance of  a medicinal product required in accordance with Annex 
II, rely on an active substance master file , an active substance master file  certificate  
granted by the Agency in accordance with this Article  (‘active substance master file 
certificate’ ) or a certific ate confirming that the quality of the active substance 
concerned is su itably controlled by the relevant monograph of the European 
Pharmacopeia . 
Marketing authorisation applicants may only rely on an active substance master file 
if no certificate  exists on  the same active sub stance master file.  
2. An active substance master file certificate may be granted by the Agency  in cases 
where the relevant data on the active substance concerned is not already covered by a 
monograph of the European Pharmacopeia  or by an active substance master file  
certificate . 
In order to obtain  an active substance master file certificate , an application shall be 
submitted to the Agency. The applicant  for an active substance master file certificate 
shall demonstrate that the active substance concerned is not already covered  by a 
monograph of the European Pharmacopeia  or an  active substance master file  
certificate . The Agency shall examine the application and, in case of a positive 
outcome, shall grant the certificate that shall be valid throughout the Union.  In case 
of centralised marketing authorisations, the application for an active substance 
master file certificate may be submitted as part of the marketing authorisation 
application for the corresponding medicinal p roduct.  
The Agency shall establish a repositor y of active substance master files , their 
assessments reports  and their certificates  and ensure that personal data is protected. 
The Agency shall ensure that the competent authorities of the Member State have 
access to this repository . 
3. The active substance master file and the active substance master file  certificate shall 
cover all the information required in Annex II on the active substance.  
4. The active substance master file certificate holder shall be the  manufacturer of the 
active substance.  
5. The active substance master file certificate holder shall keep the active substance 
master file up to date with scientific and technological progress and introduce the 
changes required to ensure that the active substance is manufactured and controlled 
in accordance with  generally accepted scientific methods.  
6. If requested by the Agency, the manufacturer of the substance for  which an 
application for an active substance master file certificate has been submitted or the 
active substance master file certifica te holder shall undergo  an inspection to verify 
the information contained in  the application or the active substance master file or 
their compliance with good manufacturing practices for active substances  referred to 
in Article 160 . EN 66  EN If the  manufacturer of an active substance refuses to undergo  such an inspection, the 
Agency may suspend or terminate  the application for an active substance master file 
certificate.  
7. If the active substance master file certificate holder does not fulfil the obligations set 
out in the paragraphs 5 and 6, the Agency may suspend or withdraw the certificate 
and, the competent authorities of the Member States  may suspend or revoke the 
marketing authorisation of a medicinal product relying on that certificate or take 
measures to pro hibit the supply of the medicinal product relying on that certificate.  
8. The marketing authorisation holder of the medicinal product granted on the basis of 
an active substance master file certificate remains responsible and liable for th at 
medicinal prod uct. 
9. The Commission is empowered to adopt delegated acts in accordance with Article 
215 to supplement this  Directive by specifying, the following:  
(a) the rules governing the content and format of the application for an active 
substance master file certificate ; 
(b) the rules for the examination of an application for an active substance master 
file certificate and for the granting of the certificate;  
(c) the rules for making publicly available  of active substance master file 
certificates;  
(d) the rules for introducing changes to the active substance master file and the 
active substance master file certificate;  
(e) the rules on  access  for competent authorities of the Member States  to the active 
substance master file and its assessment report ; 
(f) the rules on access  for marketing authorisation applicants and marketing 
authorisation holders relying on an active substance master file  certificate to 
the active substance master file and to the  assessment report . 
Article 26   
Additional  quality  master  files  
1. Marketing authorisation applicants may, instead of submitting the relevant data on an 
active sub stance  other than a chemical  active substance,  or on  other substances 
present or used in the manufacture of a medicinal product , required in accordance 
with Annex II, rely on an  additional quality master file, an  additional quality master 
file certificate  granted by the Agency in accordance with this Article (‘additional 
quality master file certificate’),  or a certificate confirmin g that the quality of that 
substance  is suitably controlled by the relevant monograph of the European 
Pharmacopeia.  
Marketing authorisation applicants may  only rely on an additional quality master file 
certificate if no  certificate exists on the same addit ional quality master file . 
2. Article 25, paragraphs 1 to 5, 7 and 8 shall also apply mutadis mutandis  to additional 
quality master file certification.  
3. The Commission is empowered to adopt delegated acts in accordance with Article 
215 to supplement this  Directive by specifying:  EN 67  EN (a) the rules governing the content and format of the application for an active 
substance master file certificate;  
(b) additional quality master files for which a certificate may be used in order to 
provide specific information on  the quality of a substance  present or used in the 
manufacture  of a medicinal product;  
(c) the rules for the examination of applications for making publicly available  of 
additional quality master file certificates;  
(d) the rules for introducing changes to the additional quality master file and the 
certificate;  
(e) the rules  on access for competent authorities of the Member State to the 
additional quality master file and its assessment report;  
(f) the rules on access  for marketing authorisation applicants and marketing 
authorisation holders relying on an additional quality master file certificate to 
the additional quality master file and to the assessment report.  
4. If requested by th e Agency, the manufacturer of a  substance present or used in the 
manufacture  of a medicinal product for which an application for a n additional  quality 
master file certificate has been submitted or the additional quality master file 
certificate holder shall undergo  an inspection to verify t he information contained in 
the application or the quality master file.  
If the  manufacturer of this substance  refuses to undergo such an inspection, the 
Agency may suspend or terminate the application for the additional  quality master 
file certificate.  
Article 2 7  
Excipients  
1. The applicant shall provide information on the excipients used in a medicinal product 
in accordance with the requirements set out in Annex II.  
Excipients shall be  examined  by the competent authorities as part of the medicinal 
product.  
2. Colours shall be used in medicinal products only if they are  included in one of the 
following lists : 
(a) the Union list of authorised food additives in Table 1 in Part B of Annex II to 
Regu lation (EC) No 1333/2008 and comply with the purity criteria and 
specifications laid down in Commission Regulation (EU) No 231/2012 ; 
(b) the list established by the Commission pursuant to paragraph 3. 
3. The Commission may establish a list of colours permitted for use in medicinal 
products other than those included in the Union list of authorised food additives.  
The Comm ission shall , where applicable on the basis of an opinion of the Agency, 
adopt a decision whether the co lour concerned shall be added to list of colours 
permitted for use in medicinal products referred to in the first subparagraph.  
A colour may be added to the list of colours permitted for use in medicinal products 
only where the colour has been removed fro m the Union list of authorised food 
additives.  EN 68  EN Where relevant, the list of colours permitted for use in medicinal products shall 
include purity criteria, specifications or restrictions applicable to the colour s included 
in that list . 
The list of colours pe rmitted for use in medicinal products shall be established by 
way of implementing acts. Those implementing acts shall be adopted in accordance 
with the examination procedure referred to in  Article 214(2).  
4. If a colour used in medicinal product is removed  from the Union list of authorised 
food additives, on the basis of the scientific opinion of the European Food Safety 
Authority ( ‘EFSA ’), the Agency shall, on the request of the Commission or on its 
own initiative, without undue delay issue a scientific op inion as regards the use of the 
colour concerned in medicinal product, taking into account the opinion of the EFSA  
if relevant. The opinion of the Agency shall be adopted by the Committee for 
Medicinal Products for Human Use.  
The Agency without undue delay shall send to the Commission its scientific opinion 
on the use of the colour in medicinal product together with a report on the 
assessment.   
The Commission shall, on the basis of the Agency opinion, and without undue delay, 
decide wheth er the colour concerned can be used in medicinal products and, where 
applicable, include it in the list of colours permitted for use in medicinal products 
referred to in paragraph 3.  
5. If a colour has been removed from the Union list of authorised food ad ditives for 
reasons that do not require an EFSA opinion, the Commission shall decide on the use 
of the colour concerned in medicinal products and, where applicable, include it in the 
list of colours permitted for use in medicinal products referred to in pa ragraph 3. The 
Commission may, in such cases, request the opinion from the Agency . 
6. A colour that has been removed from the Union list of authorised food additives can 
still be used as a colour in medicinal products until the Commission takes the 
decisio n on whether to include the colour on the list of colours permitted for use in 
medicinal products  in accordance with  paragraph 3.  
7. Paragraphs 2 to 6 shall also apply  to colours used in veterinary medicinal products as 
defin ed in Article 4(1) of Regulation (EU) 2019/6  of the European Parliament and of 
the Council  36. 
SECTION  5 
ADAPTED  DOSSIER  REQUIREMENTS   
Article 28  
Adapted  frameworks  due to the characteristics  or methods  inherent  to the medicinal  product  
1. Medicinal products listed in Annex VII shall be subject to specific scientific or 
regulatory requirements  due to the characteristics or methods inherent to the 
medicinal product , when : 
                                                 
36 Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on 
veterinary medicinal products and repealing Directive 2001/82/EC . EN 69  EN (a) it is not possible to adequately assess  the medicinal product or category of 
medicinal products applying t he applicable requirements due to scientific or 
regulatory challenges arising from characteristics or methods inherent to the 
medicinal product; and  
(b) the characteristics or methods positively impact the quality, safety and efficacy 
of the medicinal product or category of medicinal product or provide a major 
contribution to patient access or patient care.  
2. The Commission is empowered to adopt delegated ac ts in accordance with  Article 
215 to amend Annex VI I in order to take account of scientific and technical progress.  
3. The Commission is empowered to adopt delegated acts in accordance with Article 
215 to supplement this Directive by laying down:  
(a) detai led rules for the marketing authorisation and supervision of the medicinal 
products referred to in paragraph 1;  
(b) the technical documentation to be submitted by applicants for marketing 
authorisations for medicinal products referred to in paragraph 1.  
4. The detailed rules referred to in paragraph 3, point (a) , shall be proportionate to the 
risk and impact involved. These may entail adapted, enhanced, waived or deferred 
requirements. Any waiver or deferral shall be limited to the extent strictly necessary , 
proportionate and duly justified by the characteristics or methods inherent to the 
medicinal product, and shall be regularly reviewed and evaluated. Apart from the 
detailed rules referred to in paragraph 3, point (a), all other rules laid out in this 
Directive shall apply.  
5. Until the adoption of detailed rules for specific medicinal products listed in Annex 
VII pursuant to paragraph 3, an application for a marketing authorisation for that 
medicinal product may be submitted in accordance with Article 6(2). 
6. When adopting delegated acts referred to in this Article, the Commission shall take 
into account any available information resulting from a regulatory sandbox 
established in accordance with Article 115 of the [ revised Regulation (EC) No 
726/2004 ]. 
Chapter III  
Procedures for national m arketing authorisation s 
SECTION  1  
GENERAL  PROVISIONS   
Article 29   
Examination  of marketing  authorisation  application  
1. In order to examine an application submitted in accordance with Articles 6 and 9 to 
14, the competent authority of the Member State:  
(a) shall verify whether the particulars and documentations  submitted in support of 
the application comply with Articles 6 and 9 to 14  (‘validation’) , and examine EN 70  EN whether the conditions for issuing a marketing autho risation set out in Articles 
43 to 45 are complied with;  
(b) may submit the medicinal product, its starting materials or ingredients  and, if 
need be, its intermediate products or other, for testing by an Official Medicines 
Control Laboratory or a laboratory that a Member State has designated for that 
purpose in order to ensure that the control methods employed by the 
manufacturer of me dicinal products and described in the particulars 
accompanying the application in accordance with Annex I are satisfactory;  
(c) may, where appropriate, require the applicant to supplement the particulars 
accompanying the application in respect of the items  listed in the Articles 6 and 
9 to 14; 
(d) may consider and decide upon additional evidence available, independently 
from the data submitted by the marketing authorisation applicant.  
2. Where the competent authority of the Member State avails itself of the  option  
referred to in the first subparagraph, point (c) , the time limits laid down in Article 30 
shall be suspended until such time as the supplementary information required has 
been provided or for the time allowed to the applicant for giving oral or wri tten 
explanations . 
3. Where the competent authority of the Member State considers that the marketing 
authorisation application is incomplete, or contains critical deficiencies that may 
prevent the evaluation of the medicinal product it shall inform the app licant 
accordingly and shall set a time limit for submitting the missing information and 
documentation. If the applicant fails to provide the missing information and 
documentation within the time limit set, the application shall be considered to have 
been withdrawn.  
4. In cases where on examination of an application for a marketing authorisation the 
competent authority of the Member State considers that the submitted data are not of 
sufficient quality or maturity for the completion of the examination of the  
application , the examination can be terminated within 90 days of the validation of the 
application.  
The competent authority of the Member State shall summarise the deficiencies in 
writing. On this basis, the competent authority of the Member State shall inform the 
applicant accordingly and set a time limit to address the deficiencies. The application 
shall be suspended until the applicant addresses the deficiencies. If the applicant fails 
to address those deficiencies within the time limit set by th e competent authority of 
the Member State , the application shall be considered as withdrawn.  
Article 30   
Duration  of examination  of marketing  authorisation  application  
Member States shall take all appropriate measures to ensure that the procedure for grant ing a 
marketing authorisation for medicinal products is completed within a maximum of 180 days 
after the submission of a valid application  from the date of validation of a marketing 
authorisation  application.  
Article 31   
Types of national marketing authorisation procedures  EN 71  EN National marketing authorisation s may be granted in accordance with the procedures laid 
down  in Article 32 (‘purely national  marketing authorisation  procedure ’), Article s 33 and  34 
(‘decentralised procedure for national marketing authorisation’ ) or Article s 35 and  36 
(‘mutual recognition procedure for national marketing authorisation ’). 
SECTION  2 
MARKETING  AUT HORISATIONS  VALID  IN A SINGLE  MEMBE R STATE  
Article 32  
Purely national marketing authorisation  procedure  
1. An application for marketing authorisation according to Article 6(2) under the purely 
national marketing authorisation procedure  shall be submitted to the competent 
authority in that Member State in which the marketing authorisation is applied.  
2. The competent authority  in the Member State concerned  shall examine the 
application in accordance with Article s 29 and 30 and grant a marketing 
authorisation in accordance with Articles 43 to 45 and applicable national provisions.  
3. A marketing authorisation granted under the purely national marketing authorisation 
procedure  shall be valid only in the Member State of the competent authority that 
granted it.  
SECTION  3  
MARKETING  AUT HORISATION S VALID  IN SEVERAL  MEMBER  STATE S 
Article 33  
Scope of decentralised procedure for national  marketing authorisation s  
1. An application for marketing authorisation under the decentralised procedure for 
national marketing authorisation  in several Member States in respect of the same 
medicinal product shall be submitted to the competent authorities in those Member 
States in which the marketing authorisation is applied.  
2. The competent authorit ies in the Member State concerned shall examine the 
application s in accordance with Articles 2 9, 30 and 34 and grant a marketing 
authorisation in accordance with Articles 43 to 45. 
3. Where a competent authority of the  Member State notes that another marketing 
authorisation application for the same medicinal product is being examined by the 
competent authorit y in another Member State, the competent authorities of the 
Member State s concerned shall decline to examine  the application and shall advise 
the applicant that the provisions referred to in Article s 35 and 36  apply.  
4. Where the competent authorities of the Member State s are informed that another 
Member State has authorised a medicinal product that is the subject of a marketing 
authorisation application in the Member State concerned, they shall reject the 
application unless it was submitted in compliance with the provisions referred to in 
Article s 35 and 36 . EN 72  EN 5. Marketing authorisations granted under decentralised procedure for national 
marketing authorisation shall be valid only in those Member States of the competent 
authority that granted it . 
Article 34   
Decentralised procedure for national  marketing authorisation s 
1. With a view to obtain  a national marketing authorisation for a medicinal product in 
several  Member State s in respect of the same medicinal product under the 
decentralised procedure for national  marketing authorisation , an applicant shall 
submit a marketing authorisation  application based on an identical dossier to the 
competent authorit y of the Member State chosen by the applicant , to prepare an 
assessment report on the medicinal product  in accordance with Article 43(5) and to 
act in accordance with this Section  (‘reference Member State  for the decentralised 
procedure ’), and to the competent authorities in the other Member States concerned . 
2. The application for marketing authorisation shall contain:  
(a) the particulars and documentations  referred to Articles 6, 9 to 14 and 62; 
(b) a list of Member States concerned by the application.  
3. The applicant shall inform all the competent authorities of all Member States of its 
application at the time of submission. The competent authorit y of a Member State 
may request for justified public health reasons to enter the procedure and shall 
inform the applicant and the competent authorit y of the reference Member State for 
the decentralised procedure  of its request within 30 days from the date of submission 
of the application. The applicant shall provide the competent authorities of those 
Member States entering the procedure with the application without undue delay . 
4. In cases where on examination of an application for a marketing authorisation the 
competent authorit y of the reference Member State for the decentralised procedure  
consider s that the submitted data are not of sufficient quality or maturity for the 
completion of the examination  of the application , the examination can be terminated 
within 90 days of the validation of the application . 
The competent authorit y of the reference Member State for the decentralised 
procedure shall summarise the deficiencies in writing. On this basis, the competent 
authority of the reference Member State for the decentralised procedure shall inform 
the applicant and the competent authorities of the Member States concerned 
accordingly and set a time limit to address the deficie ncies. The application shall be 
suspended until the applicant addresses the deficiencies. If the applicant fails to 
address those deficiencies within the time limit set by the competent authority of the 
reference Member State for the decentralised procedur e, the application shall be 
considered as withdrawn.  
The competent authorit y of the reference Member State for the decentralised 
procedure  shall inform the  competent authorities of the Member States concerned 
and the applicant accordingly.  
5. Within 120 days after validation of the application, the competent authorit y of the 
reference Member State for the decentralised procedure shall  prepare an assessment 
report, a summary of product characteristics , the labelling and the package leaflet 
and s hall send them to the Member States concerned and to the applicant.  EN 73  EN 6. Within 60 days of receipt of the assessment report , the competent authorit ies of the 
Member States concerned shall approve the assessment report, the summary of 
product characteristics and the labelling and package leaflet and shall inform the  
competent authorit y of the  reference Member State for the decentralised procedure  
accordingly. The competent authorit y of the  reference Member State  for the 
decentralised procedure  shall record the  agreement of all parties, close the procedure 
and inform the applicant accordingly.  
7. Within 30 days after acknowledgement of the agreement , the competent authorit ies 
of all Member States concerned  in which an application has been submitted in 
accordance with paragraph 1 shall adopt a decision according to Articles 43 to 45 
and in conformity with the approved assessment report, the summary of product 
characteristics and the labelling and package lea flet as approved.  
SECTION  4  
MUTUAL  RECOGNITION  OF NATIONAL  MARKETING  AUTHORISATION S 
Article  35  
Scope of mutual recognition procedure for  national marketing authorisation s 
An application for marketing authorisation for mutual recognition procedure for national 
marketing authorisation , granted under Articles 43 to 45 and in accordance with Article 32, 
shall be submitted  to the competent authorities of other Member States  in accordance with the 
procedure laid down in Article  36. 
Article 36 
Mutual recognition procedure for national  marketing authorisation s 
1. An application for mutual recognition of a marketing authorisation , granted under 
Articles 43 to 45 and in accordance with Article 32, in several  Member States in 
respect of the same medicinal product shall be submitted to the competent authority 
of the Member State  that granted the marketing authorisation  (‘reference Member 
State for the mutual recognition procedure’)  and to the competent authorit ies of the 
Member States  concerned  where the applicant seeks to obtain a national marketing 
authorisation . 
2. Application shall include a list of Member States concerned by the application . 
3. The competent authority  of the reference Member State for the mutual recognition 
procedure  shall reject an application for mutual recognition of marketing 
authorisation of medicinal product within a year from the granting of that marketing 
authorisation, unless the competent authority  of the Member State informs the 
competent authority of the reference Member State for the mutual recognition 
procedure  of its interest in this medicinal product.  
4. The applicant shall inform the competent authorities of all Member States of its 
application at the time of submission. The competent authorit y of a Member State 
may request for justified public health reasons to enter the procedure and shall 
inform the applicant and the competent authorit y of the reference Member State  for 
the mutual recognition procedure  of its request within 30 days from the date of 
submission of the application. The applicant shall provide the competent authorities EN 74  EN of those Member States entering the procedure with the application without undue 
delay.  
5. If the competent authorities of the Member States concerned so require, the 
marketing authorisation holder shall request the competent authorit y of the  reference 
Member State for the mutual recognition procedure  to update the assessment report 
drawn on the medicinal concerned by the appl ication . In that case, the reference 
Member State shall update the assessment report within 90 days after validation of 
the application . If the competent authorities of the Member States concerned do not 
require the update of the assessment report, the ref erence Member State shall provide 
the assessment report within 30 days.  
6. Within 60 days  of receipt of the assessment report , the competent authorities of the 
Member States concerned shall approve the assessment report, the summary of 
product characteristics , the labelling and package leaflet and shall inform the 
competent authorit y of the reference Member State accordingly.  
7. The competent authorit y of reference Member State for the mutual recognition 
procedure  shall record the agreement of a ll parties, close the procedure and inform 
the applicant accordingly. The assessment report together with the summary of 
product characteristics, labelling and package leaflet approved by the competent 
authorit y of the reference Member State  for the mutual  recognition procedure  shall 
be sent to the Member States concerned and to the applicant.  
8. Within 30 days after acknowledgement of the agreement , the competent authorities 
of all Member States concerned  in which an application has been submitted in 
accordance with paragraph 1 shall adopt a decision according to Articles 43 to 45 in 
conformity with the approved assessment report, the summary of product 
characteristics , the labelling and package leaflet as  approved.  
SECTION  5  
COORDINATION  OF NATIONAL  MARKETING  AUTHORISATION  
Article 37   
Coordination group for decentralised and mutual recognition procedures  
1. A coordination group for decentralised and mutual recognition procedures 
(‘coordination group’) shall be set up for the following purposes:  
(a) the examination of any question relating to a national  marketing authorisation 
of a medicinal product in two or more Member States in accordance with the 
procedures laid down in Sections 3 , 4 and  5 of this Ch apter, and Article  95; 
(b) the examination of questions related to the pharmacovigilance of medicinal 
products covered by national marketing authorisations , in accordance with 
Articles 10 8, 110, 112, 116  and 1 21; 
(c) the examination of questions relating t o variations of national  marketing 
authorisations , in accordance with Article 93(1). 
For the fulfilment of its pharmacovigilance tasks contemplated under first 
subparagraph, point (b), including approving risk management systems and 
monitoring their effectiveness, the coordination group shall rely on the scientific EN 75  EN assessment and the recommendations of the Pharmacovigilance Risk Assessment 
Committee referred to  in Article 14 9 of [revised Regulation (EC) No 726/2004].  
2. The coordination group shall be composed of one representative per Member State 
appointed for a renewable period of three  years. Member States may appoint an 
alternate for a renewable period of three  years. Members of the coordination group 
may arrange to be accompanied by experts.  
Members of the coordination group and experts shall, for the fulfilment of their tasks, 
rely on the scientific and regulatory resources available to competent authorities of  
the Member States. Each competent authority of the Member State shall monitor the 
level of expertise of the evaluations carried out and facilitate the activities of 
nominated coordination group members and experts.  
Article 147  of [revised Regulation (EC) No 726/2004] shall apply to the coordination 
group as regards transparency and the independence of its members.  
3. The Agency shall provide the secretariat of this coordination group. The coordination 
group shall draw up its own Rules of Procedure, which s hall enter into force after a 
favourable opinion has been given by the Commission. These Rules of Procedure 
shall be made publicly available . 
4. The Executive Director of the Agency or the representative of the Executive Director  
and representatives of 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 competent authorities 
of the Member  States, including the consultative bodies concerned with the 
marketing authorisation.  
6. Where otherwise provided for in this Directive, within the coordination group , all 
Member States representatives  shall use their best endeavours to reach a position b y 
consensus on the action to be taken. If such a consensus cannot be reached, the 
position of the majority of the Member States represented within the coordination 
group 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.  
Article 38   
Divergent position s of Member States in decentralised or mutual recognition procedure  
1. If, at the end of the period laid down  in Article s 34(6) or 36(6), there is disagreement 
between Member States on whether the marketing authorisation can be issued , on the 
grounds of potential serious risk to public health, the disagreeing Member State 
concerned shall give a detailed explanation  of the points of disagreement and  the 
reasons for its position to the reference Member State, to the other Member States 
concerned and to the applicant. The points of disagreement shall be referred to the 
coordination group without undue delay.  
2. Guidelines to be adopted by the Commission shall define a potential serious risk to 
public health.  EN 76  EN 3. Within the coordination group, all disagreeing  Member States concerned  shall use 
their best endeavours to reach agreement on the action to be taken. T hey shall allow 
the applicant the opportunity to make its point of view known orally or in writing. If, 
within 60 days of the communication of the points of disagreement, the Member 
States reach an agreement  by consensus , the reference Member State shall r ecord the 
agreement, close the procedure and inform the applicant accordingly . The procedure 
laid down in  Article s 34(7) or 36(8) shall apply.  
4. If within the 60 -day period laid down in paragraph 3, an agreement by consensus 
cannot be reached, the position of the majority of the Member States represented 
within the coordination group shall be forwarded to the Commission, which shall 
apply the procedure laid down in Articles 41 and 42. 
5. In the circ umstances referred to in paragraph 4, Member States that have approved 
the assessment report, the summary of product characteristics, the labelling and 
package leaflet  of the reference Member State  may, at the request of the applicant, 
authorise the medici nal product without waiting for the outcome of the procedure 
laid down in Article 41. In that event, the national  marketing  authorisation granted 
shall be without prejudice to the outcome of that procedure.  
Article 39  
Referral procedure of divergent decisions  of Member States  
If applications  for a national marketing authorisation  have been  submitted in accordance with  
Articles 6 and 9  to 14 for a particular medicinal product, and if Member States have adopted 
divergent decisions concerning the nationa l marketing  authorisation , its variation, suspension  
or revocation  or the summary of product characteristics , the competent authorit y of the 
Member State, the Commission or the marketing authorisation holder may refer the matter to 
the Committee for Medicinal Products for Human Use for the application of the procedure 
laid down in Articles 41 and 42. 
Article 40  
Harmonisation of summary of prod uct characteristics  
1. In order to promote the harmonisation of national  marketing  authorisations for 
medicinal products throughout  the Union, the competent authorities of  the Member 
States shall, each year, forward to the coordination group referred to in Article 37 a 
list of medicinal products for which a harmonised summary of product characteristics 
is to be drawn up.  
2. The coordination group shall lay down a list of medicinal products for which a 
harmonised summary of product characterist ics is to  be drawn up, taking into 
account the proposals from the competent authorities of  all Member States, and shall 
forward that list to the Commission.  
3. The Commission or the competent authority of  a Member State, in agreement with 
the Agency and ta king into account the views of interested parties, may refer the 
matter concerning the harmonisation of summary of products characteristics of those  
medicinal  products to the Committee for Medicinal Products for Human Use  for the 
application of the procedu re laid down in Articles 41 and 42 . EN 77  EN Article 41  
Scientific evaluation by the Committee for Medicinal Products for Human Use  in a referral 
procedure  
1. When reference is made to the procedure laid down in this Article, the Committee for 
Medicinal Products for Human Use  referred to in Article 148  of [revised Regulation 
(EC) No 726/2004] shall consider the matter concerned and shall issue a reasoned 
opinion within 60 days from  the date when  the matter was referred to it.  
However, in cases submitted to the Com mittee for Medicinal Products for Human 
Use in accordance with Articles 39, 40 and 95 , this period may be extended by the 
Committee for Medicinal Products for Human Use  for a further period of up to 90 
days.  
On a proposal from its chairperson, the Committe e for Medicinal Products for 
Human Use  may agree to a shorter deadline.  
2. In order to consider the matter, the Committee for Medicinal Products for Human 
Use shall appoint one of its members to act as rapporteur. The Committee may also 
appoint individual experts to advise it on specific questions. When appointing 
experts, the Committee for Medicinal Products for Human Use  shall define their 
tasks and specify the time  limit for the completion of these tasks.  
3. Before issuing its opinion, the Committee for Medicinal Products for Human Use  
shall provide the applicant or the marketing authorisation holder with an opportunity 
to present written or oral explanations within a time limit which it shall specify.  
The opinion of the Committee for Medicinal Products f or Human Use  shall be 
accompanied by a summary of product characteristics , the labelling and package 
leaflet . 
If necessary, the Committee for Medicinal Products for Human Use  may call upon 
any other person to provide information relating to the matter befo re it or consider a 
public hearing . 
The Agency shall, in consultation with the parties concerned, draw up Rules of 
Procedure on the organisation and conduct of public hearings, in accordance with 
Article 163 of [revised Regulation (EC) No 726/2004].  
The Co mmittee for Medicinal Products for Human Use  may suspend the time  limits 
referred to in paragraph 1 in order to allow the applicant or the marketing 
authorisation holder to prepare explanations.  
4. The Agency shall without undue delay inform the applicant or the marketing 
authorisation holder where the opinion of the Committee for Medicinal Products for 
Human Use  provides  that: 
(a) the application does not satisfy the criteria for a marketing  authorisation;  
(b) the summary of product characteristics propose d by the applicant or the 
marketing authorisation holder in accordance with Article 62 is to be amended;  
(c) the marketing authorisation is to be granted subject to certain conditions, that 
are considered essential for the safe and effective use of the medicinal product , 
including pharmacovigilance;  
(d) a marketing authorisation is to be suspended, varied or revoked ; EN 78  EN (e) the medicinal product satisfies the conditions set out in Article 83 regard ing 
medicinal products addressing an unmet medical need.  
Within 12 days after receipt of the opinion, the applicant or the marketing 
authorisation holder may notify the Agency in writing of its intention to request a re -
examination of the opinion. In that case, they shall forward to the Agency the 
detailed grounds for the request within 60 days after receipt of the opinion.  
Within 60 days following receipt of the grounds for the request, the Committee for 
Medicinal Products for Human Use  shall re -examine it s opinion in accordance with 
Article 12(2 ), third  subparagraph, of [revised Regulation (EC) No 726/2004]. The 
reasons for the conclusion reached further to its re -examination  shall be annexed to 
the assessment report referred to in Article 12(2), third sub paragraph, of [revised 
Regulation (EC) No 726/2004].  
5. Within 12 days after its adoption, the Agency shall forward the final opinion of the 
Committee for Medicinal Products for Human Use  to the competent authorities of  
the Member States, to the Commission  and to the applicant or the marketing 
authorisation holder, together with a report describing the assessment of the 
medicinal product and stating the reasons for its conclusions.  
In the event of an opinion in favour of granting or maintaining a marketing  
authorisation to place the medicinal product concerned on the market, the following 
documents shall be annexed to the final opinion:  
(a) a summary of product characteristics, as referred to in Article 62; 
(b) the details of  any conditions affecting the marketing  authorisation within the 
meaning of paragraph 4, first subparagraph, point (c);  
(c) the details of any recommended conditions or restrictions with regard to the 
safe and effective use of the medicinal product;  
(d) the labelling and package leaflet.  
Article 42 
Commission decision  
1. Within 12 days of receipt of the opinion of the Committee for Medicinal Products for 
Human Use , the Commission shall submit to the Standing Committee on Medicinal 
Products for Human Use  referred to in Article 214(1) a draft of the decision on the 
application, on the basis of the requirements set out in this Directive . 
In duly justified cases, the Commission may return the opinion to the Agency for 
further consideration.  
Where a draft decision envisages the granting of  a marketing authorisation, it shall 
include or make reference to the documents referred to in Article 41(5), second 
subparagraph.  
Where a draft decision differs from  the opinion of the Agency, the Commission shall 
provide  a detailed explanation of the reasons for the differences.  
The Commission shall send the draft decision to the competent authorities of  the 
Member States and the applicant or the marketing authorisation holder.  EN 79  EN 2. The Commission shall, by means of impleme nting acts, adopt a final decision  within 
12 days after obtaining the opinion of the Standing Committee on Medicinal 
Products for Human Use.  
Those implementing acts shall be adopted in accordance with the examination 
procedure referred to in Article 214(2)  and (3 ). 
3. Where a Member State raises important new questions of a scientific or technical 
nature that have not been addressed in the opinion delivered by the Agency, the 
Commission may refer the application back to the Agency for further consideration.  
In that case, the procedures set out in paragraphs 1 and 2 shall start again upon 
reception of the reply of the Agency.  
4. The decision referred to in paragraph 2 shall be addressed to all Member States and 
forwarded  for information to the applicant or th e marketing authorisation holder. The 
Member States concerned and the reference Member State shall adopt a decision to  
either grant or revoke the marketing authorisation, or vary its terms as necessary to 
comply with the decision referred to in paragraph 2  within 30 days following its 
notification. In the decision to grant,  suspend , revoke or vary the marketing 
authorisation, the Member States shall refer to the decision adopted pursuant to 
paragraph 2. They shall inform the Agency accordingly.  
5. Where the  scope of the procedure initiated under Article 95 includes medicinal 
products covered by centralised marketing authorisation  pursuant to Article 95(2), 
third subparagraph, the Commission shall, where necessary, adopt decisions to vary, 
suspend or revoke t he marketing authorisations or to refuse the renewal of the 
marketing authorisations concerned in accordance with this Article . 
SECTION  6  
RESULTS  OF EXAMINATION  OF A NATIONAL  MARKETING  AUTHORISATION  
APPLICATION  
Article 43   
Granting  of the national  marketing authorisation  
1. When a competent authority of the Member State grants a national  marketing 
authorisation, it shall inform  the applicant  of the marketing authorisation  of the 
summary of product characteristics , the package leaflet, the labelling as well as  any 
conditions established in accordance with Articles 44 and 45 together with any 
deadlines for the fulfilment of those conditions . 
2. The competent authorities of the Member State s shall take all necessary measures to 
ensure that the information given in the summary of product characteristics  is in 
conformity with that accepted when the national  marketing authorisation is granted  
or subsequently.  
3. The competent authorities of the M ember State s shall, without undue delay, make 
public ly available the national  marketing authorisation together with the summary of 
product characteristics , the package leaflet  as well as  any conditions established in 
accordance with Articles 44, 45 and any obligations imposed subsequently in 
accordance with Article  87, together with any deadlines for the fulfilment of those 
conditions and obligations  for each medicinal product that they have authorised.  EN 80  EN 4. The competent authority of the Member State may consider and decide upon 
additional evidence available, independently from the data submitted by the 
marketing authorisation holder. On that basis, the summary of product characteristics 
shall be updated if the additional evidence has an impact on the bene fit-risk balance 
of a medicinal product.  
5. The competent authorities of the Member States shall draw up an assessment report 
and make comments on the file as regards the results of the pharmaceutical and non-
clinical  tests, the clinical studies , the risk management system, the environmental 
risk assessment and the pharmacovigilance system of the medicinal product 
concerned.  
6. The competent authorities of the Member States shall make the assessment report 
public ly available without undue delay, together wi th the reasons for their opinion, 
after deletion of any information of a commercially confidential nature. The 
justification shall be provided separately for each therapeutic  indication applied for.  
7. The public assessment report referred to in paragraph 5 shall include a summary 
written in a manner that is understandable to the public . The summary shall contain, 
in particular, a section relating to the conditions of use of the medicinal product.  
Artic le 44   
National  marketing authorisation subject to conditions  
1. A marketing authorisation for a medicinal product  may be granted subject to one or 
more of the following conditions : 
(a) to take certain measures for ensuring the safe use of the medicinal product to 
be included in the risk management system;  
(b) to conduct post -authorisation safety studies;  
(c) to comply with obligations on the recording or reporting of suspected adverse 
reactions that are stricter than those referred to in Chapter IX; 
(d) any other conditions or restrictions with regard to the safe and effective use of 
the medicinal product;  
(e) the existence of an adequate pharmacovigilance system;  
(f) to conduct post -authorisation efficacy studies where concerns relating to some 
aspects of the efficacy of the medicinal product are identifi ed and can be 
resolved only after the medicinal product has been marketed ; 
(g) in case of medicinal products for which there is substantial uncertainty as to the 
surrogate endpoint relation to the expected health outcome, where appropriate 
and relevant for  the benefit -risk balance, a post -authorisation obligation to 
substantiate the clinical benefit;  
(h) to conduct post -authorisation environmental risk assessment studies, collection 
of monitoring data or information on use, where identified or potential 
concerns about risks to the environment or public health, including 
antimicrobial resistance need to be further investigated after the medicinal 
product has been marketed ; 
(i) to conduct post -authorisation studies to improve the safe and effective use of 
the medicinal product ; EN 81  EN (j) where appropriate, to carry out medicinal product -specific validation studies to 
replace animal -based control methods with non -animal -based  control methods.  
An obligation to conduct post authorisation efficacy studies referred to in the first 
subparagraph, point (f) , shall be based on the delegated acts adopted pursuant to 
Article 8 8. 
2. The marketing authorisation shall lay down deadlines for the fulfilment of the 
conditions referred to in paragraph 1 , first subparagraph , where neces sary.  
Article 45  
National m arketing authorisation under exceptional circumstances  
1. In exceptional circumstances where, in an application under Article 6 for a marketing 
authorisation of a medical product , or in an application under Article 92 for a new 
therapeutic indication of an existing  marketing authorisation, an applicant is unable 
to provide comprehensive data on the efficacy and safety of the medicinal product 
under normal conditions of use, the competent authorit y of the Member State may, 
by derogation to Article 6, grant an authorisation under Article 43, subject to specific 
conditions, where the following requirements are met:  
(a) the applicant has demonstrated, in the application file, that there are objective 
and verifiable reasons not to be able to submit comprehensive data on the 
efficacy and safety of the medicinal product under normal conditions of use 
based on one of the grounds set out in Annex II ;  
(b) except for the data referred to in point  (a), the application file is complete and 
satisfies all the requirements of this Directive;  
(c) specific conditions are included in the decision of the competent authorities of 
the Member States , in particular to ensure the safety of the medicinal product 
as well to ensure that the marketing a uthorisation holder notifies to the 
competent authorities of the Member States any incident relating to its use and 
takes appropriate action where necessary.  
2. The maintenance of the  authorised  new therapeutic indication and the validity  of the 
national  marketing authorisation  shall be linked to the reassessment of the conditions  
set out in paragraph 1  after two years from the date when the new therapeutic 
indication was authorised or the marketing authorisation  was granted , and thereafter 
at a risk -based  frequency  to be determined by the competent authorities of the 
Member State  and specified in the marketing authorisation . 
This reassessment shall be conducted on the basis of an application by the marketing 
authorisation holder to maintain the authorised new therapeutic indication or renew 
the marketing authorisation under exceptional circumstances.  
Article 46 
Validity  and renewal  of marketing  authorisation  
1. Without prejudice to paragraph 4, a marketing authorisation for a medicinal product 
shall be valid for an unlimited period.  
By way of derogation from the first subparagraph,  a national marketing authorisation 
granted in accordance with Article 45(1) shall be valid for five years and be subject 
to renewal in accordance with paragraph 2. EN 82  EN By way of derogation from the first subparagraph, a competent authority of the 
Member State may decide at the time of granting the national marketing 
authorisation, on objectively and duly justified ground s relating to safety of the 
medicinal product, to limit the validity of the national marketing authorisation to five 
years.  
2. The marketing authorisation holder may submit an  application  for a renewal of a 
national  marketing authorisation granted under paragraph 1, second or third 
subparagraph. Such application shall be submitted  at least nine months before the 
national  marketing authorisation ceases to be valid . 
3. Once the application for a renewal has been submitted within the time limit provided 
for in paragraph  2, the national marketing authorisation shall remain valid until the 
competent authority of the Member State adopts a decision.  
4. The competent authority of the Member State may renew the national marketing 
authorisatio n on the basis of a re -evaluation of the benefit -risk balance. Once 
renewed, the marketing authorisation shall be valid for an unlimited period.  
Article  47 
Refusal  of a national  marketing  authorisation  
1. The national  marketing authorisation shall be refused if, after verification of the 
particulars and documentations  referred to in  Article 6 and subject to the specific 
requirements laid down  in Articles 9 to 14, the view is taken that : 
(a) the benefit -risk balance is not considered to be favourable;  
(b) that the applicant has not properly or sufficiently demonstrated the quality, 
safety or efficacy of the medicinal product;  
(c) its qualitative and quantitative composition is not as declared ;  
(d) the environmental risk assessment is incomplete or insufficiently substantiated 
by the applicant or if the risks identified in the environmental risk assessment 
have not been sufficiently addressed by the applicant ; 
(e) the labelling and package leaflet proposed by the applicant are not in 
accordance with Chapter VI.  
2. The national m arketing a uthorisation shall also be refused if any particulars or 
documentations  submitted in support of the application do not comply with Article 6, 
paragraphs 1 to 6, and Articles  9 to 14. 
3. The applicant or the marketing authorisation holder shall be responsible for the 
accuracy of the particulars and  documen tation s submitted.  
SECTION  7 
SPECIFIC  REQUIREMENTS  FOR  PAEDIATRIC  MED ICINAL  PRODUCTS  
Article 48   
Compliance  with the paediatric  investigation  plan 
1. The competent authority of the Member State for which an application for marketing 
authorisation or variation of a marketing authorisation  is submitted under the  EN 83  EN provisions of this Chapter or of the Chap ter VIII, shall verify whether it complies 
with the requirements laid down in Article 6(5). 
2. Where the application is submitted in accordance with the procedure set out in this 
Chapter , Section s 3 and 4, the verification of compliance, including, as appropriate, 
requesting an opinion of the Agency in accordance with paragraph 3, point (b),  shall 
be conducted by the reference Member State.  
3. The Committee for Medicinal Products for Human  Use, as referred  to in Article 148 
of [revised Regulation (EC) No 726 /2004] may, in the following cases, be requested 
to give its opinion as to whether studies conducted by the applicant are in compliance 
with the agreed paediatric investigation plan as defined in Article  74 of [revised 
Regulation (EC)  No 726/2004] : 
(a) by the applicant, prior to submitting an application for a marketing 
authorisation or for a variation of a marketing authorisation;  
(b) by the competent authority of the Member State, when validating an 
application for a marketing authorisation or for a variation of a marketing 
authorisation  that does not already include such an opinion.  
4. In the case of a request in accordance with parag raph 3, point (a), the applicant shall 
not submit its application until the Committee for Medicinal Products for Human 
Use has provided its opinion, and a copy thereof shall be annexed to the application.  
5. Member States shall take due account of an opini on drawn up in accordance with 
paragraph 3.  
6. When the competent authority  of the Member State , during the scientific assessment 
of a valid application for a marketing authorisation or a variation of a marketing 
authorisation , concludes that the studies a re not in conformity with the agreed 
paediatric investigation plan, the medicinal product shall not be eligible for the 
rewards and incentives provided for in Article 86. 
Article 49   
Data deriving from a paediatric investigation plan  
1. Where a marketing authorisation or a variation of a marketing authorisation , is 
granted in accordance with the provisions under this Chapter  or of the provisions 
under Chapter VIII : 
(a) the results of all clinical studies, conducted in compliance with an a greed 
paediatric investigation plan as referred to in Article 6(5), point (a), shall be 
included in the summary of product characteristics and, if appropriate, in the 
package leaflet, or  
(b) any agreed waiver as referred to in Article 6(5), points (b) and (c), shall be 
recorded in the summary of product characteristics and, if appropriate, in the 
package leaflet of the medicinal product concerned . 
2. If the application complies with all the measures contained in the agreed completed 
paediatric investigation  plan and if the summary of product characteristics reflects 
the results of studies conducted in compliance with that agreed paediatric 
investigation plan, the competent authority of the Member State  shall include within 
the marketing authorisation a state ment indicating compliance of the application with 
the agreed completed paediatric investigation plan.  EN 84  EN 3. An application for new therapeutic indications, including paediatric indications, new 
pharmaceutical forms, new strengths and new routes of administration  of medicinal 
products authorised in accordance with the provisions under this Chapter or of the 
provisions under Chapter VIII  and which are protected either by a supplementary 
protection certificate under [Regulation (EC) No 469/2009  - OP pl ease replace 
reference by new instrument when adopted ], or by a patent which qualifies for the 
granting of the supplementary protection certificate, may be submitted under the 
procedure laid down in Articles 41 and 42. 
4. The procedure referred to in parag raph 3 shall be limited to the assessment of the 
specific section of the summary of product characteristics to be varied.  
Chapter IV 
Prescription status  
Article 50  
Prescription  status  of medicinal  products  
1. When a marketing authorisation is granted, the competent authorities shall , by 
applying the criteria laid down in Article 51, specify the prescription status of the 
medicinal product as: 
(a) a medicinal product subject to medical prescription ; or 
(b) a medicinal product not subject to medical prescript ion. 
2. The competent authorities may fix sub -categories for medicinal products that are 
subject to medical prescription . In that case, they shall specify  the following 
prescription status:  
(a) medicinal products subject to  medical prescription for renewab le or non -
renewable delivery;  
(b) medicinal products subject to special medical prescription;  
(c) medicinal products on ‘restricted’ medical prescription, reserved for use in 
certain specialised areas.  
Article 51  
Medicinal  products  subject  to medical  prescription  
1. A medicinal product shall be subject to medical prescription where it:  
(a) is likely to present a danger either directly or indirectly, even when used 
correctly, if used without medical supervision ; 
(b) is frequently and to a very wide exte nt used incorrectly, and as a result is likely 
to present a direct or indirect danger to human health ; 
(c) contains substances or preparations thereof, the activity or adverse reactions of 
which require further investigation ; 
(d) is normally prescribed by a doctor to be administered parenterally ; 
(e) is an antimicrobial; or  EN 85  EN (f) contains an active substance which are  persistent, bioaccumulative and toxic, 
or very persistent and very bioaccumulative, or persistent, mobile and toxic, or 
very persistent and ver y mobile for which  medical prescription is required as 
risk minimisation measure with regard to the environment, unless  the use of the 
medicinal product and the patient safety  require otherwise . 
2. Member States may set additional conditions  on the prescription of antimicrobials, 
restrict the validity of medical prescription and limit the quantities prescribed to the 
amount required for the treatment or therapy concerned  or submitting certain 
antimicrobial medicinal products to special medical prescr iption or restricted 
prescription.  
3. Where Member States provide for the sub -category of medicinal products subject to 
special medical prescription, they shall take account of the following factors:  
(a) the medicinal product contains, in a non -exempt quan tity, a substance 
classified as a narcotic or a psychotropic substance within the meaning of the 
international conventions ; 
(b) the medicinal product is likely, if incorrectly used, to present a substantial risk 
of medicinal abuse, to lead to addiction or be misused for illegal purposes ; or 
(c) the medicinal product contains a substance that, by reason of its novelty or 
properties, could be considered as belonging to the group set out  in point (a)  as 
a precautionary measure.  
4. Where Member States provide f or the sub -category of medicinal products subject to 
restricted prescription, they shall take account of the following factors:  
(a) the medicinal product, because  of its pharmaceutical characteristics or novelty 
or in the interests of public health, is res erved for treatments that can only be 
followed in a hospital environment;  
(b) the medicinal product is used in the treatment of conditions that must be 
diagnosed in a hospital environment or in institutions with adequate diagnostic 
facilities, although adm inistration and follow -up may be carried out elsewhere ; 
(c) the medicinal product is intended for outpatients but its use may produce very 
serious adverse reactions requiring a prescription drawn up as required by a 
specialist and special supervision throughout the treatment.  
5. A competent authority may waive application of the paragraphs 1, 3 and 4 having 
regard to:  
(a) the maximum single dose, the maximum daily dose, the strength, the 
pharmaceutical form, certain types of packaging; or  
(b) other cir cumstances of use that it has specified.  
6. If a competent authority does not designate medicinal products into sub -categories 
referred to in Article 50(2), it shall nevertheless take into account the criteria laid 
down  in paragraphs 3 and 4 in determining  whether any medicinal product shall be 
classified as a medicinal product  subject to medical prescription . 
Article 52  
Medicinal  products  not subject  to medical  prescription  EN 86  EN Medicinal products not subject to medical  prescription shall be those that do not meet the 
criteria laid down  in Article 51. 
Article 53  
List of medicinal  products  subject  to medical  prescription  
The competent authorities shall draw up a list of the medicinal products subject, on their 
territory, to medical prescription, specifying, if necessary, the category of prescription status. 
They shall update this list annually.  
Article 54  
Amendment  of prescription  status  
When new facts are brought to their attention, the competent authorities shall examine  and, as 
appropriate, amend the prescription status of a medicinal product by applying the criteria 
listed in Article 51. 
Article 55  
Data  protection  of evidence  for the change  of prescription  status  
Where a change  of prescription status of a medicinal product has been authorised on the basis 
of significant non-clinical  tests or clinical studies , the competent authority shall not refer to 
the results of those tests or studies  when examining an application by another  applicant for or 
marketing authorisation holder for a change of prescription status of the same substance for 
one year after the initial change was authorised.  
Chapter V  
Obligations and liability of the marketing authorisation holder  
Article 56  
General  obligations  
1. The marketing authorisation holder shall be responsible for the making available on 
the market of the medicinal product  covered by the marketing authorisation it has 
been granted . The designation of a marketing authorisation holder  represent ative  
shall not relieve the marketing authorisation holder of its legal responsibility.  
2. The marketing authorisation holder  of a medicinal product placed on the market in a 
Member State  shall notify the competent authority of the Member State concerned of 
the date of actual placing on the market of the medicinal product in that Member 
State, taking into account the various presentations authorised.  
3. The marketing authorisation holder of a medicinal product placed  on the market in a 
Member State shall, within the limits of its responsibility , ensure appropriate and 
continued supplies of th at medicinal product to wholesale distributo rs, pharmacies or 
persons authorised to supply medicinal products so that the needs of patients in the 
Member State in quest ion are covered.  
The arrangements for implementing the first subparagraph should, moreover, be 
justified on grounds of public health protection and be proportionate in relation to the EN 87  EN objective of such protection, in compliance with the Treaty rules, parti cularly those 
concerning the free movement of goods and competition.  
4. The marketing authorisation holder shall, at all stages of manufacturing and 
distribution ensure that the starting materials and ingredients of the medicinal 
products and the  medicinal  products themselves comply with the requirements of this 
Directive and, where relevant, the [revised Regulation (EC) No 726/2004] and other 
Union law  and shall verify that such requirements are met.  
5. For integral combination of a medicinal product with a medical device  and for 
combinations of a medicinal product  with a product  other than a medical device , the 
marketing authorisation holder shall be responsible for the whole product in terms of 
compliance of the medicinal product with the requirements of this Directive and the 
[revised Regulation  (EC) No 726/2004].  
6. The marketing authorisation holder shall be established in the Union.  
7. Where the marketing authorisation holder considers or has reason to believe that the 
medicinal product it has made ava ilable on the market is not in conformity with the 
marketing authorisation or this Directive  and the [revised Regulation (EC) No 
726/2004]  it shall immediately take the necessary corrective actions to bring that 
medicinal product into conformity, to withdr aw it or recall it, as appropriate. The 
marketing authorisation holder shall immediately inform the competent authorities 
and the distributors concerned  to that effect.  
8. Upon request, the marketing authorisation holder shall provide the competent 
authori ties with free samples in sufficient quantities to enable controls to be made on 
the medicinal products that it has placed on the market.  
9. Upon request the marketing authorisation holder shall provide the competent 
authority with all data relating to the  volume of sales of the medicinal product, and 
any data in its possession relating to the volume of prescriptions.  
Article  57 
Responsibilit y to report  on public  financial  support  
1. The marketing authorisation holder shall declare  to the public any direct  financial 
support received from any public authority or publicly funded body, in relation  to 
any activities for the research and development of the medicinal product covered by 
a national or a centralised marketing authorisation , irrespective of the legal entity that 
received that support . 
2. Within 30 days after the marketing authorisation is granted  the marketing 
authorisation holder shall:  
(a) draw  up an electronic report listing:  
(i) the amount of financial support received and the date thereof;  
(ii) the public authority or publicly funded body that provided the financial 
support referred to in point ( i); 
(iii) the legal entity that received the support referred to in point ( i). 
(b) ensure that the electronic report is accurate and that it has been aud ited by an 
independent external auditor;  
(c) make the electronic report accessible to the public via a dedicated webpage ; EN 88  EN (d) communicate  the electronic link to such webpage to the competent authority of 
the Member State or, where appropriate, to the Agenc y.  
3. For the medicinal products authorised under this Directive, the competent authority 
of the Member State shall communicate in a timely manner the electronic link to the 
Agency.  
4. The marketing authorisation holder shall keep the electronic link up to date and, as 
necessary, update the report annually.  
5. The Member States  shall take appropriate measures to ensure that paragraphs 1, 2 
and 4 are complied with by the marketing authorisation holder established in their 
country.  
6. The Commission  may adopt implementing act s to lay down the principles and format 
for the information to be reported pursuant to paragraph 2. Those implementing acts 
shall be adopted in accordance with the examination procedure referred to in  Article 
214(2). 
Artic le 58  
Traceability  of substances  used in the manufacture  of medicinal  products  
1. The m arketing authorisation holder shall , when necessary, ensure t he traceability of 
an active substance, starting material, excipient or any other substance intended or 
expected to be  present  in a medicinal product at all stages of manufacturing and 
distribution.  
2. The marketing authorisation holder shall be able to identify any natural or legal 
person from whom they have been supplied with an active substance, starting 
material,  excipient or any other substance intended or expected to be present in a 
medicinal product.  
3. The marketing authorisat ion holder  and its suppliers  of an active substance, starting 
material, excipient or any other substance used in the manufacturing of a medicinal 
product  shall have in place systems and procedures that allow for the information 
referred to in paragraph 2  to be made available , upon request,  to the competent 
authorities.  
4. The m arketing  authorisation hold er and its suppliers shall have in p lace systems and 
procedures to identify the other natural or legal persons  to whom  products referred  to 
in paragraph 2 have been supplied. This information shall , upon request,  be made 
available to the competent authorities.  
Article 59  
Placing on the market of products with paediatric indications  
Where medicinal products are authorised for a paediatric indication following completion of 
an agreed paediatric investigation plan and those medicinal products have already been 
marketed with other therapeuti c indications, the marketing authorisation holder shall, within 
two years of the date on which the paediatric indication is authorised, place the medicinal 
product on the market taking into account the paediatric indication in all Member States 
where the m edicinal product is already placed on the market.  
A register, coordinated by the Agency, and made publicly available, shall mention these 
deadlines.  EN 89  EN Article 60  
Discontinuation of the placing on the market of paediatric products  
If a medicinal product is au thorised for a paediatric indication and the marketing authorisation 
holder has benefited from rewards or incentives under Article 86 of this Directive  or Article 
93 of [revised Regulation (EC) No 726/2004] , and these periods of protection have expired, 
and if the marketing authorisation holder intends to discontinue placing the medicinal product 
on the market, the marketing authorisation holder shall transfer the marketing authorisation to 
a third party or allow a third party, which has declared its intent ion to continue to place the 
medicinal product in question on the market, to use the pharmaceutical, non-clinical  and 
clinical documentation contained in the file of the medicinal product on the basis of Article 
14. 
The marketing authorisation holder shall inform the competent authorities  of its intention to 
discontinue the placing on the market of the medicinal product no less than twelve  months 
before the discontinuation. The competent authorities  shall make this fa ct public ly available . 
Article  61 
Liability  of the marketing  authorisation  holder  
The m arketing a uthorisation shall not affect the civi l and criminal liability of the  marketing  
authorisation holder.  
Chapter V I 
Product information and labelling  
Article 62  
Summary  of product  characteristics  
1. The summary of product characteristics shall contain  the particulars listed in Annex 
V. 
2. For marketing  authorisations under  Article s 9 and 11 and subsequent variations  to 
such marketing authorisations , if one or more  of the  therapeutic indications, 
posologies, pharmaceutical forms, methods or routes of administration or any other 
way in which the medicinal product may be used are still covered by patent law or a 
supplementary protection certificate  for medicinal produ cts at the time when the 
generic or biosimilar  medicinal product  was marketed , the applicant for an 
authorisation for  a generic or biosimilar  medicinal product  may request  not to 
include this information  in their marketing author isation . 
3. For all medicinal products, a standard text shall be included in the summary of 
product characteristics  expressly asking healthcare professionals to report any 
suspected adverse reaction in accordance with the national reporting system referred 
to in Artic le 106 (1). Different ways of reporting, including electronic reporting, shall 
be available in compliance with Article 106 (1), second subparagraph . 
Article 63  
General principles on package leaflet  
1. A package leaflet shall be mandatory for medicinal products.  EN 90  EN 2. The package leaflet shall be written and designed in a clear and understandable  way, 
enabling users to act appropriately, when necessary with the help of healthcare 
professionals.  
3. Member States may decide that the package leaflet shall be made available in paper 
format or electronically, or both. In the absence of such specific rules in a Member 
State, a package leaflet in paper format shall be included in the packaging  of a 
medicin al product . If the package leaflet is only made available electronically, the 
patient’s right to a printed copy of the package leaflet should be guaranteed upon 
request and free of charge  and it should be ensured that the information in digital 
format is e asily accessible to all patients . 
4. By derogation from  paragraphs  1 and 2 , where  the information required under 
Articles 64 and 73 is directly conveyed on the outer packaging or on the immediate 
packaging, a package leaflet shall not be required.  
5. The C ommission is empowered  to adopt delegated acts in accordance with Article 
215 to amend paragraph 3 by making mandatory the electronic version of the 
package leaflet. That delegated act shall also establish  the patient’s right to a printed 
copy of the package leaflet upon request  and free of charge . The delegation of 
powers shall apply  as of [OP please insert the date = five years following 18 months 
after the date of entering into force of this Directive] . 
6. The Commission shall  adopt implementing acts in accordance with the examination 
procedure referred to in Article 214 (2) to establish common standards for the 
electronic version of the  package leaflet , the summary of  product characteristics  and 
the labelling , taking into account available technologies.  
7. Where  the package leaflet  is made available electronically, the individual right to 
privacy shall be ensured. Any technology giving access to the information shall not 
allow the identification or tracking of individuals, nor shall it be used for commercial 
purposes.  
Article 64  
Content of package leaflet  
1. The package leaflet shall be drawn up in accordance with the summary of product 
characteristics , referred to in Article 62(1) and shall include the particulars listed in  
Annex VI.  
2. For all medicinal products, a standardised text shall be included, expressly asking 
patients to communicate any suspected adverse reaction to their doctor, pharmacist, 
healthcare professional or directly to the national reporting system referred to in  
Article 106 (1), and specifying the different ways of reporting available (electronic 
reporting, postal address or others) in compliance with Article 106 (1), second 
subparagraph . 
3. The package leaflet shall reflect the results of consultatio ns with target patient groups 
to ensure that it is legible, clear and easy to use.  
Article 65  
Content of l abelling particulars  EN 91  EN 1. The outer packaging of medicinal products or, where there is no outer packaging, the 
immediate packaging , with the exception o f the pa ckaging referred to in Article 6 6, 
paragraphs  2 and 3 , shall include the labelling particulars listed in Annex IV . 
2. The Commission is empowered to adopt delegated acts in accordance with  Article 
215 to: 
(a) amend the list of labelling particulars set out in Annex IV in order to take 
account of scientific progress  or patient  needs ; 
(b) supplement Annex IV by setting out a reduced list of mandatory labelling 
particulars that shall appear on the outer packaging of multi -language 
packages.  
Article 66 
Labelling of blister packs or small immediate packaging  
1. The particulars laid down in Annex IV shall appear on immediate packagings other 
than those referred to in the paragraphs 2 and 3.  
2. The following particular s at least shall appear on immediate packagings that take the 
form of blister packs and are placed in an outer packaging that complies with the 
requirements laid down in  Articles 65 and 73. 
(a) the name of the medicinal product ; 
(b) the name of the marketing authorisation holder placing the product on the 
market ; 
(c) the expiry date ; 
(d) the batch number.  
3. The following particulars at least shall appear on small immediate packaging units on 
which the particulars laid down in Article s 65 and 73 cannot be displayed , shall 
include at least the following labelling particulars : 
(a) the name of the medicinal product and, if necessary, the route of 
administration ; 
(b) the method of administration ; 
(c) the expiry date ; 
(d) the batch number ; 
(e) the con tents by weight, by volume or by unit.  
Article 67  
Safety features  
1. Medicinal products subject to prescription shall bear the safety features referred to in 
Annex IV, unless they have been listed in accordance with the procedure referred  to 
in paragraph 2,  second subparagraph , point (b).  
Medicinal products not subject to prescription shall not bear the safety features 
referred to in Annex IV, unless, by way of exception, they have been listed in 
accordance with the procedure referred to in paragraph 2, second subparagraph , point 
(b).  EN 92  EN 2. The Commission shall adopt delegated acts in accordance with  Article 215  to 
supplement Annex IV by laying down detailed rules for the safety features . 
Those delegated acts shall set out:  
(a) the character istics and technical specifications of the unique identifier of the 
safety features referred to in Annex IV that enables the authenticity of 
medicinal products to be verified and individual packs to be identified ; 
(b) the lists containing the medicinal products or product categories that, in the 
case of medicinal products subject to prescription shall not bear the safety 
features, and in the case of medicinal products not subject to prescription shall 
bear the safety fe atures referred to in Annex IV ; 
(c) the procedures for the notification to the Commission provided for in 
paragraph  4 and a rapid system for evaluating and deciding on such notification 
for the purpose of applying point (b);  
(d) the modalities for the veri fication of the safety features referred to in Annex IV 
by the manufacturers, wholesal e distributor s, pharmacists and natural or legal  
persons authorised or entitled to supply medicinal products to the public and by 
the competent authorities ; 
(e) provision s on the establishment, management and accessibility of the 
repositories system in which information on the safety features, enabling the 
verification of the authenticity and identification of medicinal products, as 
provided for in Anne x IV, shall be conta ined.  
The lists referred to in the second subparagraph, point (b), shall be established 
considering the risk of falsification relating to the medicinal products or categories of 
medicinal products  concerned . To this end, at least the following criteria shall be 
applied:  
(a) the price and sales volume of the medicinal product;  
(b) the number and frequency of previous cases of falsified medicinal products 
being reported within the Union and in third countries and the evolution of the 
number and frequency o f such cases to date;  
(c) the specific characteristics of the medicinal products concerned;  
(d) the severity of the conditions intended to be treated;  
(e) other potent ial risks to public health.  
The modalities referred to in the second subparagraph, point (d), shall allow the 
verification of the authenticity of each supplied pack of the medicinal products 
bearing the safety features referred to in Annex IV and determine the extent of such 
verificatio n. When establishing those modalities, the particular characteristics of the 
supply chains in Member States, and the need to ensure that the impact of 
verification measures on particular actors in the supply chains is proportionate, shall 
be taken into acc ount. 
For the purposes of the second subparagraph, point (e), the costs of the repositories 
system shall be borne by the manufacturing authorisation holders of medicinal 
products bearing the safety features.  
3. When adopting delegated act s referred to in p aragraph  2, the Commission shall take 
due account of at least the following:  EN 93  EN (a) the protection of personal data as provided for in Union law;  
(b) the legitimate interests to protect information of a commercially confidential 
nature;  
(c) the ownership and confidentiality of the data generated by the use of the safety 
features; and  
(d) the cost -effectiveness of the measures.  
4. The competent authorities of the Member States shall notify the Commission of non -
prescription medicinal products that they judge to  be at risk of falsification and may 
inform the Commission of medicinal products that they deem not to be at risk of 
falsification in  accord ance with  the criteria set out in  paragraph 2,  second 
subparagraph, point (b) . 
5. Member States may, for the purpose s of reimbursement or pharmacovigilance, 
extend the scope of application of the unique identifier referred to in Annex IV to 
any medicinal product subject to prescription or subject to reimbursement.  
6. Member States may, for the purposes of reimbursement,  pharmacovigilance , 
pharmacoepidemiology or for data protection prolongation for market launch  use the 
information contained in the repositories system referred to paragraph 2, second 
subparagraph, point (e) . 
7. Member States may, for the purposes of patient safety, extend the scope of 
application of the anti -tampering device referred to in Annex IV to any medicinal 
product.  
Article 68  
Labelling  and instruction leaflet  of radionuclides and radiopharmaceuticals  
1. In addition to the rules laid down in this Chapter, t he outer carton and the container 
of medicinal products containing radionuclides shall be labelled in accordance with 
the regulations for the safe transport of radioactive materials laid down by the 
International Atomic Energy Agency. Moreover, the labelling shall comply with the 
provisions set out in paragraphs  2 and 3 . 
2. The label on the shielding shall include the particulars laid down  in Article 65 . In 
addition, the label on the shielding shall explain in full, the codings used on the vial 
and shall indicate, where necessary, for a given time and date, the amount of 
radioactivity per dose or per vial and the number of capsules, or, for liquids, the 
number of millilitres in the container.  
3. The v ial shall be labelled with the following information:  
(a) the name or code of the medicinal product, including the name or chemical 
symbol of the radionuclide ; 
(b) the batch identification and expiry date ; 
(c) the international symbol for radioactivity ; 
(d) the name and address of the manufacturer ; 
(e) the amount of radioactivity as specified in paragraph  2. 
4. The competent authority shall ensure that a detailed instruction leaflet is enclosed 
with the packaging of radiopharmaceuticals, radionuclide genera tors, radionuclide EN 94  EN kits or radionuclide precursors. The text of this leaflet shall be established in 
accordance with Article 64 (1). In addition, the leaflet shall include any precautions to 
be taken by the user and the patient during the preparation and ad ministration of the 
medicinal product and special precautions for the disposal of the packaging and its 
unused contents.  
Article 69  
Special information requirements for antimicrobials  
1. The marketing authorisation holder shall ensure availability of educational material  
to healthcare professionals, including through medical sales repr esentatives  as 
referred to  in Article 175 (1), point (c), regarding the appropriate use of diagnostic 
tools, testing or other diagnostic approaches related to antimicrobia l-resistant 
pathogens, that may inform on the use of the antimicrobial.  
2. The marketing authorisation holder shall include in the packaging of antimicrobials  a 
document that contains specific information about the medicinal product concerned 
and that is made available to the patient in addition to the product leaflet (“ awareness 
card”) with information on antimicrobial resistance and the appropriate use and 
disposal of antimicrobial s.  
Member States may decide that the awareness card shall be made availab le in paper 
format or electronically, or both. In the absence of such specific rules in a Member 
State, a n awareness card in paper format  shall be included in the packaging  of an 
antimicrobial . 
3. The text of the awareness card shall be aligned with Annex VI. 
Article 70  
Legibility  
The package leaflet and labelling particulars referred to in this Chapter shall be easily legible, 
clearly comprehensible and indelible.  
Article  71 
Accessibility  for persons with disabilities  
The name of the medicinal product  shall  also be expressed in Braille format on the packaging. 
The marketing authorisation holder shall ensure that the package leaflet referred to in Article 
63 is made available upon request from patients' organisations in formats appropriate for  
persons wi th disabilities, including  blind and partially -sighted  persons . 
Article 72  
Member States labelling requirements  
1. Notwithstanding Article 77 Member States may require the use of certain forms of 
labelling of the medicinal product making it possible to ascertain:  
(a) the price of the medicinal product ; 
(b) the reimbursement conditions of social security organisations ; 
(c) the legal status for s upply to the patient, in accordance with  Chapter IV; EN 95  EN (d) authenticity and identification in accordance with Article 67 (5). 
2. For medicinal products for which a centralised  marketing authorisation as referred to 
in Article 5 has been granted , Member States shall, when applying this Article, 
observe the detailed guidance referred to in Article 77. 
Article 73  
Symbols and pictogram  
The outer packaging and the package leaflet may include symbols or pictograms designed to 
clarify certain informatio n set out  in Article s 64(1) and 65 and other information compatible 
with the summary of product characteristics that is useful for the patient, to the exclusion of 
any element of a promotional nature.  
Article 74  
Requirements on l anguages  
1. The particulars for labelling listed in Articles 64 and 65, shall appear in an official 
language or official languages of the Member State where the medicinal product is 
placed on the market, as specified, for the purposes of this Directive, by that Member  
State.  
2. Paragraph 1 shall not prevent th ose particulars from being indicated in several 
languages, provided that the same particulars appear in all the languages used.  
3. The package leaflet must be clearly legible in an official language or official 
languages of the Member State where the medicinal product is placed on the market, 
as specified, for the purposes of this Directive, by that Member State.  
4. The competent authorities  of the Member State  may also grant a full or partial 
exemption to the obli gation that the labelling and the package leaflet must be in an 
official language or official languages of the Member State where the medicinal 
product is placed on the market, as specified, for the purposes of this Directive, by 
that Member State.  For the  purpose of multi -language packages, Member States may 
allow the use on the labelling and package leaflet of an official language of the 
Union that is commonly understood in the Member States where the multi -language 
package is marketed.  
 
Article 75  
Member States exemptions from requirements for labelling and package leaflet  
The competent authorities of the Member States may, subject to measures they consider 
necessary to safeguard public health, grant an exemption to the obligation that the particul ars 
required in Articles 64 and 65 should appear on the labelling and in the package leaflet in the 
following cases:  
(a) where the medicinal product is not intended to be delivered directly to the patient;  
(b) where there are problems in respect of the ava ilability of the medicinal product ; 
(c) where there are space constraints due to the size of the packaging or of the package 
leaflet or in case of multilingual packages or package leaflets;  EN 96  EN (d) in the context of a public health emergency ; 
(e) to facilitate  access to medicines in Member States.  
Article 76  
Approval of the labelling and package leaflet information  
1. One or more mock -ups of the outer packaging and the immediate packaging of a 
medicinal product, together with the package leaflet, shall be subm itted to the 
competent authorities for authorising marketing when the marketing authorisation is 
requested. The results of assessments carried out in cooperation with target patient 
groups shall also be provided to the competent authority.  
2. The competent  authority shall refuse the marketing authorisation if the labelling or 
the package leaflet do not comply with the provisions of this Chapter or if they are 
not in accordance with the particulars listed in the summary of product 
characteristics.  
3. All proposed changes to an aspect of the labelling or the package leaflet covered by 
this Chapter  and not connected with the summary of product characteristics shall be 
submitted to the competent authorities . If the competent authorities have not opposed 
a proposed change within 90 days following the introduction of the request, the 
applicant may put the change into effect.  
4. The fact that the competent authority do es not refuse a marketing authorisation 
pursuant to paragraph  2 or a change to the labelling  or the package leaflet pursuant to 
paragraph  3 does not alter the general legal liability of the manufacturer and the 
marketing authorisation holder.  
Article 77  
Guidance on labelling particulars  
In consultation with the Member States and the parties conce rned, the Commission shall draw 
up and publish detailed guidance concerning in particular:  
(a) the wording of certain special warnings for certain categories of medicinal products;  
(b) the particular information needs relating to non -prescription medicinal  products;  
(c) the legibility of particulars on the labelling and package leaflet;  
(d) the methods for the identification and authentication of medicinal products;  
(e) the list of excipients that must feature on the labelling of medicinal products and the 
way in which these excipients must be indicated;  
(f) harmonised provisions for the implementation of  Article 72.  
Article 78 
Placing on the market of labelled medicinal products  
Member States may not prohibit or impede the placing on the market of medicinal  products 
within their territory on grounds connected with labelling or the package leaflet where these 
comply with the requirements of this Chapter . EN 97  EN Article 79 
Non-compliance with the requirements for labelling and package leaflet  
Where the provisions of this Chapter are not complied with, and a notice served on the 
marketing authorisation holder concerned has remained without effect, the competent 
authorities of the Member States may suspend the marketing authorisation, until the labelling 
and the package leaflet of t he medicinal product in question have been made to comply with 
the requirements of this Chapter . 
Chapter VII 
Regulatory protection , unmet medical needs  and rewards for 
paediatric medicinal products  
Article 80  
Regulatory d ata and market protection  
1. The da ta referred to  in Annex I , originally  submitted with the view to obtaining  a 
marketing authorisation shall  not be referred to by another  applicant for a subsequent 
marketing authorisation  during the period determined in accordance with Article 81 
(‘regulatory data protection period’) . 
2. A medicinal product concerned by a subsequent marketing authorisation  referred to 
in paragraph 1 shall  not be placed on the market for a period of two years after the 
expiry of the relevant regulatory data protection period s referred to in Article 81. 
3. By way of derogation  from  paragraph  1, the marketing authorisation holder 
concerned may grant the marketing authorisation applicant for another marketing 
authorisation a letter of access to its data submitte d under Annex I , as referred to in 
Article 14. 
4. By way of derogation from the paragr aphs 1 and 2, when a compulsory licenc e has 
been granted by a relevant authority in the Union  to a party to address  a public health 
emergency, the data and market protection shall be suspended with regard to that 
party insofar as the compulsory licenc e requires , and during the duration period  of 
the compulsory licenc e.  
5. The data protection period set out to in paragraph 1 shall also apply in Member 
States where the medicinal product is not authorised or is no longer authorised.  
Article 81 
Regulatory d ata protection periods  
1. The regulatory data protection period shall b e six years from the date when the 
marketing authorisation for that medicinal product was granted in accordance with 
Article 6(2). For marketing authorisations that belong to the same global marketing 
authorisation the period of data protection shall start from the date when the initial 
marketing authorisation was granted in the Union.  
2. Subject to a scientific evaluation  by the relevant competent authority , the data 
protection period  referred to in paragraph  1 shall be prolonged  by: 
(a) 24 months , where the mar keting authorisation holder demonstrate s that the 
conditions referred to in Article 82 (1) are fulfilled within two years,  from the EN 98  EN date when the marketing authorisation was granted  or, within three  years from 
that date for any of the following  entities : 
(i) SMEs  within the meaning of Commission Recommendation 
2003/361/EC ; 
(ii) entities not engaged in an economic activity (‘not -for-profit entity’);  and 
(iii) undertakings that, by the time of granting  of a marketing authorisation, 
have received not more than five centralised marketing authorisations for 
the undertaking concerned or, in the case of an undertaking belonging to 
a group, for the group of which it is part, since the establishment of the 
undertaking or the group, whichever is earliest . 
(b) six months, where the marketing authorisation applicant demonstrates at the 
time of the initial marketing authorisation application that the medicinal 
product addresses an unmet medical need as referred to in Article 83;  
(c) six months, for medicinal  products containing a new active substance, where  
the clinical trials supporting  the initial marketing authorisation application use 
a relevant  and evidence -based  comparator in accordance with scientific advice 
provided by the Agency;  
(d) 12 months , where  the marketing authorisation holder obtains , during the data 
protection period,  an authorisation for  an additional  therapeutic indication for 
which the marketing authorisation holder has demonstrated , with supporting 
data,  a significant clinical benefit in  comparison with existing therapies.  
In the case of a conditional marketing authorisation granted in accordance with 
Article 19 of [revised Regulation (EC) No 726/2004] th e prolongation  referred to in 
the first subparagraph, point (b), shall only apply if , within four years of the granting 
of the conditional marketing authorisation , the medicinal product has been granted a 
marketing authorisation in accordance with  Article 19(7) of [revised Regulation (EC) 
No 726/2004 . 
The prolongation referred to in the f irst subparagraph, po int (d), may only be granted 
once.  
3. The Agency shall set the scientific guidelines referred to in paragraph 2, point ( c), on 
criteria for proposing a  comparator for a clinical trial, taking into account the results 
of the consultation of  the Commission and t he authorities or bodies  involved in the  
mechanism of consultation referred to  in Article 162 of [revised Regulation (EC) No 
726/2004 ]. 
Article 82 
Prolongation of the data protection  period  for medicinal products supplied in Member States   
1. The prolongation of the data protection period referred to  in Article  81(2), first 
subparagraph, point (a ), shall only be granted to medicinal products if they are 
released and continuously supplied into the supply chain in a sufficient quantity and 
in the presentations necessary to cover the needs of the patients in the Member States 
in which the marketing authorisation is valid.   
The prolongation referred to in the first subparagraph shall apply to medicinal 
products  that have been granted a centralised  marketing authorisation , as referred to EN 99  EN in Article 5  or that have been granted a national marketing authorisation through the 
decentr alised procedure, as referred to in Chapter III, Section 3.  
2. To receive a prolongation  referred to in Article  81(2), first subparagraph, point (a) , 
the marketing authorisation holder shall apply for a variation of the relevant 
marketing authorisation . 
The application for a variation shall be submitted  between 34 and 36 months  after the 
date when the initial marketing authorisation was granted , or for  entities referred to  
in Article 81( 2), first subparagraph, point (a),  between 46 and 48 months, after that 
date.  
The application  for a variation  shall contain documentation from the Member States 
in which the marketing authorisation is valid . Such documentation shall : 
(a) confirm that the conditions set out in  paragraph  1 have been satisfied in their 
territory; or  
(b) waive th e conditions set out in paragraph 1 in their territory for the purpose of 
the prolongation.  
Positive decisions adopted in accordance with Articles 2 and 6 of Council Directive 
89/105/EEC37 shall be con sidered equivalent to a confirmation referred  to in the third 
subparagraph, point (a).  
3. To receive the documentation referred to in paragraph 2, third subparagraph, the 
marketing authorisation holder shall make a request to the relevant Member State. 
Within 60 days from  the request of  the marketing authorisation holder , the Member 
State shall issue a confirmation of compliance  or, a reasoned statement of non -
compliance or alternatively provide a  statement of non -objection to prolong the 
period of regulatory data protection pursuant to this Article . 
4. In cases where a Member State ha s not repl ied to the application of the marketing 
authorisation holder  within the deadline referred to in paragraph  3, it shall be 
considered  that a statement of non -objection  has been provided.  
For medicinal products granted  a centralised  marketing authorisation the 
Commission  shall vary the marketing authorisation pursuant to Article 47 of [revised 
Regulation  (EC) No 726/2004 ] to prolong the data protecti on period . For medicinal 
products  granted a marketing authorisation in accordance with t he decentralised 
procedure , the competent authorities of the Member States shall vary  the marketing 
authorisation pursuan t to Article 92 to prolong the data protection period . 
5. Member States representatives  may request the Commission to discuss issues related 
to the practical application of  this Article  in the Committee established by Council 
Decision  75/320/EEC38 (‘Pharmaceutical Committee ’). The Commission may invite 
bodies responsible for health technology assessment as referred to in Regulation 
(EU) 2021/2282 or national bodies  responsible for pricing and reimbursement, as 
required , to participate in the delib erations of the Pharmaceutical Committee . 
                                                 
37 Council Directive 89/105/EEC of 21 December 1988 relating to the transparen cy of measures 
regulating the  prices of medicinal products for human use and their inclusion in the scope of national 
health insurance systems  (OJ L 40, 11.2.1989, p. 8 ). 
38 Council Decision of 20 May 1975 setting up a pharmaceutical committee (OJ L 147, 9. 6.1975, p. 23 ). EN 100  EN 6. The Commission, based on the experience of Member States  and relevant 
stakeholders , may adopt implementing measures relating to the procedural aspects 
outlined in this Article and regarding the conditions mentioned in paragraph 1 . Those 
implementing acts shall be adopted in accordance with the procedure  referred to in  
Article 214(2) . 
Article 83  
Medicinal products addressing an unmet medical need  
1. A medicinal product shall be considered as addressing an unmet medica l need if at 
least one of its therapeutic indications relates to a life threatening or severely 
debilitating disease  and the following conditions are met:  
(a) there is  no medicinal product  authorised in the Union  for such  disease , or, 
where despite medicinal products being authorised for such disease  in the 
Union , the disease is associated with a remaining high morbidity or mortality;   
(b) the use of the medicinal product  results in  a meaningful reduction in disease 
morbidity or mortality for the relevant patient population . 
2. Designated  orphan medicinal products referred to in Article 67 of [revised 
Regulation (EC) No 726/2 004] shall be considered as addressing an unmet medical 
need. 
3. Where the  Agency adopts scientific guidelines for the application of  this Article it 
shall consult the Commission and the authorities or bodies  referred to in Article 162 
of [revised Regulation (EC) No 726/2004 ]. 
Article 84 
Data protection for repurposed medicinal products  
1. A regulatory data protection period of four years shall be granted for a medicinal 
product with respect to a new  therapeutic indication  not previously authorised in the 
Union , provided that : 
(a) adequate non -clinical or clinical studies were carried out in relation to the 
therapeutic indication demonstrating that it is of significant clinical benefit , and  
(b) the medicinal product  is authorised  in accordance with Articles 9 to 12  and has 
not previously benefitted from dat a protection , or 25 years have passed since 
the granting of the initial marketing authorisation  of the medicinal product 
concerned.   
2. The data protection period referred to in paragraph 1 may  only be granted once for 
any given medicinal product.  
3. During the data protection period referred to in paragraph 1 , the marketing 
authorisation shall indicate that the medicinal product is an existing medicinal 
product authorised in the Union  that has been authorised with a n additional 
therapeutic indication . 
Article 85 
Exemption  to the protection of intellectual property rights  EN 101  EN Patent rights , or supplementary protection certificates under  the [Regulation  (EC) No 
469/2009  - OP please replace reference by new instrument when adopted ] shall not be 
regarded as infringed when a reference medicinal product is used for the purposes of : 
(a) studies, trials and other activities conducted to generate data for an application , for: 
(i) a marketing authori sation of generic, biosimilar, hybrid or bio -hybrid  
medicinal product s and for subsequent variations ; 
(ii) health technology assessment  as defined in Regulation (EU) 2021/2282 ; 
(iii) pricing and reimbursement.  
(b) the activit ies conducted exclusively  for the purposes set out in  point  (a), may cover  
the submission of the application for a marketing authorisation and the offer, 
manufacture, sale, supply,  storage, import, use and purchase of patented medicinal 
products or processes, including by third party suppliers and service providers.   
This exception shall not cover the placing on the market of the medicinal products 
resulting from such activities . 
Article 86  
Rewards for paediatric medicinal  products  
1. Where an application for marketing authorisation, includes the results of all studies 
conducted in compliance with an agreed paediatric investigation plan, the holder of 
the patent or supplementary protection certificate shall be entitled to a six -month 
extension of the period referred to in Article 13 , paragraphs 1 and 2 of [Regulation 
(EC) No 469/2009  - OP please replace reference by new instrument when adopted ]. 
The first subparagraph shall also apply where completion of the agreed paediatric 
investigation plan fails to lead to the authorisation of a paediatric indication, but the 
results o f the studies conducted are reflected in the summary of product 
characteristics and, if appropriate, in the package leaflet of the medicinal product 
concerned.  
2. The inclusion in a marketing authorisation of the statement referred to in Article 
49(2) of this Directive or in Article 90(2) of [revised Regulation (EC) No 726/2004] 
shall be used for the purposes of applying paragraph 1.  
3. Where the procedures laid down in Chapter III , Sections 3 and 4 , have been used, the 
six-month extension of the period ref erred to in paragraph 1 shall be granted only if 
the product is authorised in all Member States.  
4. In the case of an application for new therapeutic indications, including paediatric 
indications, new pharmaceutical forms, new strengths and new routes of 
administration  of authorised medicinal products which are protected either by a 
supplementary protection certificate under [Regulation (EC) No 469/2009  - OP 
please replace reference by new instrument when adopted ], or by a patent which 
qualifies for the granting of the supplementary protection certificate which leads to 
the authorisation of a new paediatric indication, paragraphs 1, 2 and 3 shall not apply 
if the applicant applies for, and obtains, a one -year exten sion of the period of 
marketing protection for the medicinal product concerned, on the grounds that this 
new paediatric indication brings a significant clinical benefit in comparison with 
existing therapies, in accordance with Article 81 (2), first subparag raph, point (d) . EN 102  EN Chapter VIII  
Post-marketing authorisation measures  
Article 87 
Imposed post -authorisation studies  
1. After the granting of a marketing authorisation, the competent authority of the 
Member State may impose an obligation on the marketing authorisation holder:  
(a) to conduct a post -authorisation safety study if there are concerns about the risks 
of an authorised medicinal product. If the same concerns apply to more than 
one medicinal product, the competent authority of the Member State shall, 
following consultation with the Pharmacovigilance Risk Assessment 
Committee, encourage the marketing authorisation holders concerned to 
conduct a joint post -authorisation safety study;  
(b) to conduct a post -authorisation efficacy study when the understa nding of the 
disease or the clinical methodology indicate that previous efficacy evaluations 
might have to be revised significantly. The obligation to conduct the post -
authorisation efficacy study shall be based on the delegated acts adopted 
pursuant to Article 88  while taking into account the scientific guidance referred 
to in Article 123 . 
(c) to conduct a post -authorisation environmental risk assessment study, collection 
of monitoring data or information on use, if there are concerns about the risks 
to th e environment or public health, including antimicrobial resistance, due to 
an authorised medicinal product, or related active substance.  
If the same concerns apply to more than one medicinal product , the competent 
authority of Member State shall, following  consultation with the Agency, 
encourage the marketing authorisation holders concerned to conduct a joint 
post-authorisation environmental risk assessment study.  
The imposition of such an obligation shall be duly justified, notified in writing, and 
shall include the objectives and timeframe for submission and conduct of the study.  
2. The competent authority of the Member State shall provide the marketing 
authorisation holder with an opportunity to present written observations in response 
to the imposition of the obligation within a time limit which it shall specify, if the 
marketing authorisation holder so requests within 30 days of receipt of the written 
notification of the obligation.  
3. On the basis of the written observations submitted by the marketing authorisation 
holder, the competent authority of the Member State shall withdraw or confirm the 
obligation. Where the competent authority of the Member State confirms the 
obligation, the marketing authorisation shall be varied to include the obligation as a 
condition of the marketing authorisation and, where appropriate, the risk 
management system shall be updated accordingly.  
Article 88 
Delegated acts on p ost-authorisation efficacy studies  EN 103  EN 1. In order to determine the situations in which post -authorisation  efficacy studies may 
be required under Articles 44 and 87, the Commission may adopt, by means of 
delegated acts in accordance with Article 215 , measures supplementing the 
provisions in Articles 44  and 87. 
2. When adopting such delegated acts, the Commission shall act in accordance with the 
provisions of this Directive.  
Article 89 
Recording of conditions related to marketing authorisations  
1. The marketing authorisation holder shall incorporate any safety or efficacy  conditions 
referred to in Articl es 44 , 45 and 87 in the risk management system.  
2. The Member States shall inform the Agency of the marketing authorisations that they 
have granted subject to conditions pursuant to Articles 44 , 45 and of any obligations 
imposed in accordance with  Article  87. 
Article 90 
Update of  marketing authorisation related to scientific and technological progress  
1. After a marketing authorisation has been granted  in accordance with Chapter III , the 
marketing authorisation holder shall, in respect of the methods of manufacture and 
control stated in the application for that marketing authorisation, take account of 
scientific and technical progress and introduce any changes that may be required to 
enable the medicinal product to be manufactured and controlled 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 without undue delay provide the competent 
authority of the Member  State with any new information that might entail the 
amendment of the particulars or document ations  referred to in Article s 6, 9 to 13, 62, 
41(5), Annex I  or Annex II . 
In particular, the marketing authorisation holder shall without undue delay inform the 
competent authority of the Member State of any prohibition or restriction imposed on 
the marketing authorisation holder or any entity in contractual relationship with the 
marketing authorisation holder by the competent authorities of any country  in which 
the medicinal product is marketed and of any other new information that might 
influence the evaluation of the benefits and risks of the medicinal product concerned. 
The information shall include both positive and negative results of clinical tria ls or 
other studies in all therapeutic 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 outside the terms of the marketing authorisation.  
3. The marke ting authorisation holder shall ensure that the terms of the marketing 
authorisation including the summary of product characteristics, the labelling and 
package leaflet  are kept up to date with current scientific knowledge, including the 
conclusions of the assessment and recommendations made public ly available  by 
means of the European medicines web -portal  set up  in accordance with Article 10 4 
of [revised Regulation (EC) No 726/20 04]. EN 104  EN 4. The competent authority of the Member State may at any time request  the marketing 
authorisation holder to submit  data demonstrating that the benefit -risk balance 
remains favourable. The marketing authorisation holder shall answer fully and within 
the time limit set, any such request. The marketing authorisation holder shall also 
respond fully and within the time limit set to any request of a competent authority 
regarding the implementation of any measures previously imposed, including risk 
minimisat ion measures.  
5. The competent authority of the Member State may at any time ask the marketing 
authorisation holder to submit a copy of the pharmacovigilance system master file. 
The marketing authorisation holder shall submit that copy at the latest seven  days 
after receipt of the request.  
6. The marketing authorisation holder shall also respond fully and within the time limit 
set to any request of a competent authority regarding the implementation of any 
measures previously imposed with regard to risks to  the environment or public 
health, including antimicrobial resistance.   
Article 91 
Update of risk management plans  
1. The marketing authorisation holder of a medicinal product referred to in Article s 9 
and 11  shall submit to the competent authorities of the Member States concerned a 
risk management plan and a summary thereof, where the marketing authorisation for 
the reference medicinal product is withdrawn but the marketing authorisation for the 
medicinal prod uct referred to in Article s 9 and 11  is maintained.  
The risk management plan and the summary thereof shall be submitted to the 
competent authorities of the Member States concerned within 60 days of the 
withdrawal of the marketing authorisation for the refe rence medicinal product  by 
means of a variation . 
2. The competent authority of the Member State may impose an obligation on a 
marketing authorisation holder for a medicinal product referred to Articles 9 and 11  
to submit a risk management plan and summary thereof where:  
(a) additional risk minimisation measures have been imposed concerning the 
reference medicinal product; or  
(b) it is justified on pharmacovigilance grounds.  
3. In the case referred to in paragraph 2 , point (a), the risk management plan shall  be 
aligned with the risk management plan for the reference medicinal product.  
4. The imposition of the obligation referred to in paragraph 3 shall be duly justified in 
writing, notified to the marketing authorisation holder and shall include the deadline 
for submission of the risk management plan and the summary  by means of a 
variation . 
Article 92 
Variation of marketing authorisation  
1. An application for variation of a marketing authorisation by the marketing 
authorisation holder shall be made electronically in the formats made available by EN 105  EN the Agency, unless the variation is an update by the marketing authorisation holder 
of their information held in a database.  
2. Variations shall be classified in different categories depending on the level of  risk to 
public health and the potential impact on the quality, safety and efficacy of the 
medicinal product concerned. Those categories shall range from changes to terms of 
the marketing authorisation that have the highest potential impact on the quality,  
safety or efficacy of the medicinal product, to changes that have no or minimal 
impact thereon and to administrative changes.  
3. The procedures for examination of applications for variations shall be proportionate 
to the risk and impact involved. Those pr ocedures shall range from procedures that 
allow implementation only after approval based on a complete scientific assessment 
to procedures that allow immediate implementation and subsequent notification by 
the marketing authorisation holder to the competen t authority. Such procedures may 
also include updates by the marketing authorisation holder of their information held 
in a database.  
4. The Commission is empowered to adopt delegated acts in accordance with Article 
215 to supplement this Directive by estab lishing the following : 
(a) the categories referred to in paragraph 2  in which variations shall be classified;  
(b) rules  for the examination of applications for variations to the terms of 
marketing authorisations , including procedures for updates through a database ; 
(c) the conditions for submission of a single application for more than one change 
to the terms of the same marketing authorisation and for the same change to the 
terms of several marketing authorisations;  
(d) specifying exemptions to the variati on procedures where the update of 
information in the marketing authorisation referred to in Annex I may be 
directly implemented ; 
(e) the conditions and procedures for cooperation with competent authorities of 
third countries or international organisations  on examination of applications for 
variations to the terms of marketing authorisation.  
Article 93  
Variation of marketing authorisation under the decentralised or mutual recognition 
procedure  
1. Any application by the marketing authorisation holder to vary a marketing 
authorisation that has been granted in accordance with the provisions of Chapter III, 
Sections 3 and 4,  shall be submitted to all the Member States that have previously 
authorised th e medicinal product concerned. The same shall apply where the initial 
marketing authorisations were granted through separate procedures.  
2. In case of arbitration submitted to the Commission, the procedure laid down in 
Articles 41 and 42 shall apply by ana logy to variations made to marketing 
authorisations.  
Article 94 
Variation of marketing authorisations on the basis of paediatric studies  EN 106  EN 1. On the basis of relevant paediatric clinical studies received in accordance with 
Article 4 5(1) of Regulation (EC) No 1901/2006 of the European Parliament and of 
the Council39, the competent authorit ies of  the Member States may vary the 
marketing authorisation of the medicinal product concerned accordingly and update 
the summary of product characteristics and package le aflet of the medicinal product 
concerned. The c ompetent authorities shall exchange information regarding the 
studies submitted and, as appropriate, their implications for any marketing 
authorisations concerned.  
2. The activities pursuant to paragraph 1 shall be concluded within five years from [OP 
please insert the date =  18 months after the date of entering into force of this 
Directive ]. 
3. When a medicinal product has been authorised under the provisions of Chapter III, 
on the basis of the information received in accordance with Article 91 of [revised 
Regulation (EC) No 726/2004], the competent authorities of the Member States may 
vary the marketing authorisation of the medicinal product concerned accordingly and 
update th e summary of product characteristics and package leaflet.  
4. The Member States shall exchange information regarding the studies submitted and, 
as appropriate, their implications for any marketing authorisations concerned.  
5. The Agency shall coordinate the  exchange of information.  
Article 95 
Union interest referral procedure  
1. The Member States or the Commission  shall, in specific cases where the interests of 
the Union are involved, refer the matter to the Committee  for Medicinal Products for 
Human Use  for the application of the procedure laid down in  Articles 41 and 42 
before any decision is reached on an application for a marketing authorisation or on 
the suspension or revocation of a marketing authorisation, or on any other variation 
of the marketing authorisation that appears necessary. The Member States and the 
Comm ission shall take due account of any requests by the applicant or the marketing 
authorisation holder.  
Where the referral results from the evaluation of data relating to pharmacovigilance 
of an authorised medicinal product, the matter shall be referred to t he 
Pharmacovigilance Risk Assessment Committee and Article 115 (2) may be applied. 
The Pharmacovigilance Risk Assessment Committee shall issue a recommendation 
according to the procedure laid down in Article 41. The final recommendation shall 
be forwarded t o the Committee for Medicinal Products for Human Use  or to the 
coordination group, as appropriate, and the procedure laid down in Article 11 5 shall 
apply.  
However, where one of the criteria listed in Article 114 (1) is met, the procedure laid 
down in Articl es 114 , 115 and 116 shall apply.  
                                                 
39 Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 
2001/20/EC, Directive 2001/83/EC and Regulation (E C) No 726/2004 (OJ L 378, 27.12.2006, p. 1).  EN 107  EN The Member State concerned or the Commission shall clearly identify the question 
that is referred to the Committee for consideration and shall inform the applicant or 
the marketing authorisation holder.  
The Member States an d the applicant or the marketing authorisation holder shall 
supply the Committee with all available information relating to the matter in 
question.  
2. Where the referral to the Committee concerns a range of medicinal products or a 
therapeutic class, the Agency may limit the procedure to certain specific parts of the 
authorisation.  
In that event,  Article 93 shall apply to those medicinal products only if they were 
covered by the authoris ation procedures referred to in  Chapter I II, Sections 3 and 4 . 
Where t he scope of the procedure initiated under this Article concerns a range of 
medicinal products or a therapeutic class, medicinal products covered by a 
centralised marketing authorisation that belong to that range or class shall also be 
included in the proce dure.  
3. Without prejudice to paragraph  1, a Member State may, where urgent action is 
necessary to protect public health at any stage of the procedure, suspend the 
marketing authorisation and prohibit the use of the medicinal product concerned on 
its terri tory until a definitive decision is adopted. It shall inform the Commission, the 
Agency and the other Member States, no later than the following working day, of the 
reasons for its action.  
4. Where the scope of the procedure initiated under  this Article, a s determined in 
accordance with paragraph  2, includes medicinal products covered by a centralised 
marketing authorisation , the Commission may, where urgent action is necessary to 
protect public health, at any stage of the procedure suspend the marketing 
authorisations and prohibit the use of the medicinal products concerned until a 
definitive decision is adopted. The Commission shall inform the Agency and the 
Member States no later than the following working day of the reasons for its action.  
Chapter  IX 
Pharmacovigilance  
SECTION  1 
GENERAL  PROVISIONS  
Article  96 
Member State pharmacovigilance system  
1. Member States shall operate a pharmacovigilance system for the fulfilment of their 
pharmacovigilance tasks and their participation in the Union pharmacovigilance 
activities.  
The pharmacovigilance system shall be used to collect information on the risks of 
medicinal products as regards health of the patients or the public . That information 
shall in particular refer to adverse reactions in human beings, arising from use of the 
medicinal product within the terms of the marketing authorisation as well as from use EN 108  EN outside the terms of the marketing authorisation, and to adverse reactions associated 
with 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 concerning the marketing 
authorisation as necessary. They shall p erform a regular audit of their 
pharmacovigilance system and take corrective actions if necessary.  
3. Each Member State shall designate a competent authority for the performance of 
pharmacovigilance tasks.  
4. The Commission may request the Member States to  participate, under the 
coordination of the Agency, in international harmonisation and standardisation of 
technical measures in relation to pharmacovigilance.  
Article  97 
Member State responsibilities for pharmacovigilance activities  
1. The Member States sh all: 
(a) take all appropriate measures to encourage patients, doctors, pharmacists and 
other healthcare professionals to report suspected adverse reactions to the 
competent authority  of the Member State  and may involve  organisations 
representing consumers, patients and healthcare professionals for those tasks  
where  appropriate;  
(b) facilitate patient reporting through the provision of alternative reporting 
formats in addition to web -based formats;  
(c) take all appropria te measures to obtain accurate and verifiable data for the 
scientific evaluation of suspected adverse reaction reports;  
(d) ensure  that the public is given important information on pharmacovigilance 
concerns relating to the use of a medicinal product in a timely manner through 
public ation on the web -portal and through other means of public ly available 
information as necessary;  
(e) ensure, through the methods for collecting information and where necessary 
through the follow -up of suspected adverse reaction r eports, that all appropriate 
measures are taken to identify clearly any biological medicinal product 
prescribed, dispensed, or sold in their territory that is the subject of a suspected 
adverse reaction report, with due regard to the name of the medicinal product, 
and the batch number . 
2. For the purposes of paragraph 1, point s (a) and (e) , the Member States may impose 
specific obligations on doctors, pharmacists and other healthcare professionals.  
Article  98 
Member State delegation of pharmacovigilance tasks  
1. A Member State may delegate any of the tasks entrusted to it under this Chapter to 
another Member State subject to a written agreement of the latter. Each Member 
State may represent no more than one other Member State.  EN 109  EN 2. 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 ly available . 
Article  99 
Marketing authorisation holder pharmacovigilance s ystem  
1. Marketing authorisation holder s shall operate a pharmacovigilance system for the 
fulfilment of their pharmacovigilance tasks equivalent to the relevant Member 
State’s pharmacovigilance system referred to in  Article 9 6(1). 
2. Marketing authorisation holder s shall by means of the pharmacovigilance system 
referred to in Article 9 6(1) evaluate all information scientifically, consider options 
for risk minimisation and prevention and take appropriate measures as necessary.  
3. Marketing author isation holder s shall perform a regular audit of their 
pharmacovigilance system. They 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 corr ective action plan is prepared and 
implemented. Once the corrective actions have been fully implemented, the note may 
be removed.  
4. As part of the pharmacovigilance system, marketing authorisation holder s shall:  
(a) have permanently and continuously at th eir disposal an appropriately qualified 
person responsible for pharmacovigilance;  
(b) maintain and make available on request by a competent authority a 
pharmacovigilance system master file;  
(c) operate  a risk management system for each medicinal product;  
(d) monitor the outcome of risk minimisation measures that are contained in the 
risk management plan pursuant to Article 21  or that are laid down as conditions 
of the marketing authorisation pursuant to Articles 44, 45 and any obligations 
imposed in accord ance with Article 87; 
(e) update the risk management system and monitor pharmacovigilance data to 
determine whether there are new risks or whether risks have changed or 
whether there are changes to the benefit -risk balance of medicinal products.  
5. The qualified person referred to  in paragraph 4,  point (a), shall reside and operate in 
the Union and shall be responsible for the establishment and maintenance of the 
pharmacovigilance system. The marketing authorisation holder shall submit the 
name and conta ct details of the qualified person to the competent authority of the 
Member State  and the Agency.  
6. The marketing authorisation holder shall, on request from  the competent authorit y of 
a Member State , nominat e a contact person for pharmacovigilance issues  in that 
Member State  who shall report to the qualified person referred to in paragraph 4, 
point (a) . 
Article  100 
Risk management system  EN 110  EN 1. Holders of marketing authorisations granted before 21 July 2012 shall, by way of 
derogation from Article 99(4), point (c), not be required to operate a risk 
management system for each medicinal product.  
2. The competent authority of a Member State may impose an obligation on a 
marketing authorisation holder of a national marketing authorisation to operate a risk 
management system, as referred to in Article 9 9(4), point (c), if there are concerns 
about the risks affecting the benefit -risk balance of an authorised medicinal product. 
In that context, the competent authority of a Member State shall also oblige the 
marketing authorisation holder to submit a risk management plan for the risk  
management system that  they intend to introduce for the medicinal product 
concerned.  
3. The obligation referred to in paragraph 2  shall be duly justified, no tified in writing , 
and shall include the timeframe for submission of the risk management plan.  
4. The competent authority of a Member State shall provide the marketing authorisation 
holder with an opportunity to submit  written observations in response to t he 
imposition of the obligation within a time limit which it shall specify, if the 
marketing authorisation holder so requests within 30 days of receipt of the written 
notification of the obligation.  
5. On the basis of the written observations submitted by the marketing authorisation 
holder, the competent authority of a Member State shall withdraw or confirm the 
obligation. Where the competent authority of a Member State confirms the 
obligation, the marketing authorisation shall be varied accordingly to include the 
measures to be taken as part of the risk management system as conditions of the 
marketing authorisation referred to in Article 44, point (a) . 
Article 101  
Funds for pharmacovigilance activities  
1. 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 competent authorities of the M ember States in order to 
guarantee their independence in the performance of those pharmacovigilance 
activities.  
2. Paragraph  1 shall not preclude the competent authorities of the Member States from 
charging fees to marketing authorisation holders for performing pharmacovigilance  
activities on the condition that the independence in the performance of those 
pharmacovigilance activities is strictly guaranteed.  
SECTION  2 
TRANSPARENCY  AND  COMMUNICATI ONS 
Article  102 
National web -portal  
1. Each Member State shall set up and maintain a national medicines web -portal which 
shall be linked to the European medicines web -portal established in accordance with 
Article 104 of [revised Regulation (EC) No 726/2004]. By means of the national EN 111  EN medicines web -portals, the Member States shall make public ly available at least the 
following:  
(a) public assessment reports, together with a summary thereof;  
(b) summaries  of product characteristics and package leaflets;  
(c) summaries  of risk management plans for medicinal products covered  by a 
national marketing authorisation  in accordance with Chapter III ; 
(d) information on the different ways of reporting suspected adverse reactions to 
medicinal products to competent authorities of the Member States by 
healthcare professionals and patients, including the web -based structured forms 
referred to in Article 102 of [revised Regulation (EC) No 726/2004].  
2. The summaries referred to in paragraph 2, point (c) , shall  include , where relevant,  a 
description of additional risk minimisation measures.  
Article 103 
Public ation of assessment  
The Agency shall make public ly available  the final assessment conclusions, 
recommendations, opinions and decisions referred to in Articles 10 7 to 11 6, by means of the 
European medicines web -portal.  
Article  104 
Public announcements  
1. As soon as the marketing authorisation holder intends to make a public 
announcement relating to information on pharmacovigilance concerns in relation to 
the use of a medicinal product, and in any event at the same time or before the public 
announcement is made, they shall be required to inform the competent authorities  of 
the Member States , the Agency and the Commission.  
2. The marketing authorisation holder shall ensure that information to the public is 
presented objectively and is not misleading.  
3. Unles s 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 24 hours prior to a public announcement relating to information on 
pharmacovigilance conc erns.  
4. For active substances contained in medicinal products authorised in more than one 
Member State, the Agency shall be responsible for the coordination between 
competent authorities of the Member States of safety announcements and shall 
provide timet ables for the information being made public ly available . 
5. Under the coordination of the Agency, the Member States shall make all reasonable 
efforts to agree on a common message in relation to the safety of the medicinal 
product concerned and the timetabl es for their distribution. The Pharmacovigilance 
Risk Assessment Committee shall, at the request of the Agency, provide advice on 
those safety announcements.  
6. When the Agency or competent authorities of the Member States make public ly 
available  informati on referred to in paragraph s 2 and 3 , any personal data or data of a  EN 112  EN commercially confidential nature shall be deleted unless its public disclosure is 
necessary for the protection of public health.  
SECTION  3 
RECORDING  AND  REPORTING  OF SUSPECTED  ADVERSE  REACTIONS  
Article  105 
Recording and reporting  of suspected adverse reactions  by the marketing authorisation 
holder  
1. Marketing authorisation holders shall record all suspected adverse reactions in the 
Union or in third countries that are brought to their attention, whether reported 
spontaneously by patients or healthcare professionals, or occurring in the context of a 
post-authorisation study  including data relating to off -label use of the product . 
Marketing authorisation holders shal l ensure that those reports are accessible at a 
single point within the Union.  
By way of derogation from the first subparagraph, suspected adverse reactions 
occurring in the context of a clinical trial shall be recorded and reported in 
accordance with  Regu lation (EU) No 536/2014.  
2. Marketing authorisation holders shall not refuse to consider reports of suspected 
adverse reactions received electronically or by any other appropriate means from 
patients or healthcare professionals.  
3. Marketing authorisation holders shall submit electronically to the database and data -
processing network referred to in Article 101 of [revised Regulation (EC) No 
726/2004] (‘Eudravigilance database’) information on all serious suspected adverse 
reactions that occur in the Union and in third countries within 15 days following the 
day on which the marketing authorisation holder concerned gained knowledge of the 
event.  
Marketing authorisation holders shall submit electronically to the Eudravigilance 
database information on all non-serious suspected adverse reactions that occur in the 
Union, within 90 days following the day on which the marketing authorisation holder 
concerned gained knowledge of the event.  
For medicinal products containing active substances referred to in the li st of 
public ations monitored by the Agency pursuant to Article 105 of [revised 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 list ed 
publications , but they shall monitor all other medical literature and report any 
suspected adverse reactions  recorded therein . 
4. Marketing authorisation holders shall establish procedures in order to obtain accurate 
and verifiable data for the scientif ic evaluation of suspected adverse reaction reports. 
They shall also collect follow -up information on th ose reports and submit the updates 
to the Eudravigilance database.  
5. Marketing authorisation holders shall collaborate with the Agency and the competen t 
authorities of the  Member States in the detection of duplicates of suspected adverse 
reaction reports.  EN 113  EN 6. This Article  shall apply mutatis mutandis  to undertakings  supplying medicinal 
products used in accordance with Article 3, paragraphs 1 or 2. 
Article  106 
Recording and reporting  of suspected adverse reactions  by Member States  
1. Each Member State shall record all suspected adverse reactions that occur in its 
territory and that are brought to its attention from healthcare professionals and 
patients. This shall include all authorised medicinal products and  medicinal products 
used in accordance with Article 3, paragraphs  1 or 2. Member States shall involve 
patients and healthcare professionals, as appropriate, in the follow -up of any reports 
they receive in order to comply with Article 9 7(1), points (c) and (e) . 
Member States shall ensure that reports of such reactions may be submitted by means 
of the national medicines web -portals  or by other means.  
2. For reports submitted by a marketing authorisation holder, Member States on whose 
territory the suspected adverse reaction occurred may involve the marketing 
authorisation holder in the follow -up of the reports.  
3. Member States shal l collaborate with the Agency and the marketing authorisation 
holders in the detection of duplicates of suspected adverse reaction reports.  
4. Member States shall, within 15 days following the receipt of the reports of serious 
suspected adverse reactions r eferred to in paragraph  1, submit the reports 
electronically to the Eudravigilance database.  
Member States  shall, within 90 days from the receipt of the reports referred to in 
paragraph  1, submit reports of non -serious suspected adverse reactions electroni cally 
to the Eudravigilance database.  
Marketing authorisation holders shall have  access to the  reports referred to in this 
paragraph  through the Eudravigilance database.  
5. Member States shall ensure that reports of suspected adverse reactions arising from 
an error associated with the use of a medicinal product that are brought to their 
attention are made available to the Eudravigilance database and to any authorities, 
bodies , organisations or institutions, responsible for patient safety within that 
Member State  concerned . They shall also ensure that the authorities responsible for 
medicinal products within that Member State are informed of any suspected adverse 
reactions brou ght to the attention of any other authority within that Member State. 
These reports shall be appropriately identified in the forms referred to in Article 102 
of [revised Regulation (EC) No 726/2004].  
6. Unless there are justifiable grounds resulting from p harmacovigilance activities, 
Member States shall not impose any additional obligations on marketing 
authorisation holders for the reporting of suspected adverse reactions.  
SECTION  4 
PERIODIC  SAFETY  UPDATE  REPORTS  
Article  107 
Periodic safety update reports  EN 114  EN 1. Marketing authorisation holders shall submit to the Agency periodic safety update 
reports containing:  
(a) summaries of data relevant to the benefit -risk balance  of the medicinal product, 
including results of all studies with a consideration of their pot ential impact on 
the marketing authorisation;  
(b) a scientific evaluation of the benefit -risk 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, including an estimate of the population exposed to the medicinal 
product.  
The data provided in accordance with the first subparagraph , point (c) , shall 
differentiate between sales and volumes generated with in the Union and those 
generated outside the Union . 
2. The evaluation referred to in paragraph 1,  first subparagraph,  point (b) , shall be 
based on all available data, including data from clinical trials in unauthorised 
therapeutic indications and populations.  
The periodic safety update reports shall be submitted electronically.  
3. The Agency shall make available the reports referred to in paragraph  1 to the 
competent authorities  of the Member States , the members of the Pharmacovigilance 
Risk Assess ment Committee, the Committee for Medicinal Products for Human Use 
and the coordination group by means of the repository referred to in Article 103 of 
[revised Regulation (EC) No 726/2004].  
4. By way of derogation from paragraph 1, the marketing authorisation  holders  for 
medicinal products referred to in  Article s 9, or 13, and the registration holders  for 
medicinal products referred to in Articles 126 or 134(1), shall only be required to  
submit periodic safety update reports for such medicinal products to the competent 
authority  in the following cases:  
(a) where such obligation has been laid down as a condition in the marketing 
authorisation in accordance with Article s 44 or 45; or 
(b) when requested by a competent authority on the basis of concerns relating to 
pharmacovigilance data or due to the lack of periodic safety update reports 
relating to an active substance after the marketing authorisation has been 
granted.  
The assessment report s of the periodic safety update reports referred to in the first 
subparagraph  shall be communicated by the competent authority  to the 
Pharmacovigilance Risk Assessment Committee, which shall consider whether there 
is a need for a single assessment report f or all marketing authorisations for medicinal 
products containing the same active substance and which shall  inform the 
coordination group or the Committee for Medicinal Products for Human Use 
accordingly, in order to apply the procedures laid down in Article s 108(4) and 110. 
Article  108 
Frequency of periodic safety update reports  
1. The frequency with which the periodic safety update reports are to be submitted shall 
be specified in the marketing authorisation.  EN 115  EN The dates of submission according to the specified frequency shall be calculated 
from the date when then marketing  authorisation  was granted . 
2. Holder s of marketing authorisations which have been  granted before 21 July 2012, 
and for which the frequency an d 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 until 
another frequency or other dates o f submission of the reports are laid down in the 
marketing authorisation or determined in accordance with the paragraph s 4, 5 and 6 . 
Periodic safety update reports shall be submitted to the competent authorities 
immediately upon request:  
(a) where a medici nal product has not yet been placed on the market, at least every 
six months following the marketing  authorisation and until the placing on the 
market;  
(b) where a medicinal 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. Paragraph 2 shall also apply to medicinal products that are authorised only in one 
Member State and for which paragraph  4 does not apply.  
4. Where medicinal products that are subject to different marketing authorisations 
contain the same active substance or the same combination of active substances, the 
freque ncy and dates of submission of the periodic safety update reports resulting 
from the application of the paragraph s 1 and 2 may be amended and harmonised to 
enable a single assessment to be made in the context of a periodic safety update 
report work -sharing  procedure and to set a Union reference date from which the 
submission dates to be  calculated.  
The harmonised frequency for the submission of the reports and the Union reference 
date may be determined, after consultation of the Pharmacovigilance Risk 
Asses sment 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 th e centralised 
procedure provided for in Article 3 of [revised Regulation (EC) No 726/2004];  
(b) the coordination group, in other cases than those referred to in point (a).  
The harmonised frequency for the submission of the reports determined pursuant to 
the first and second subparagraphs shall be made public ly available  by the Agency. 
Marketing authorisation holders shall submit an application for a variation of the 
marketing authorisation accordingly.  
5. For the purposes of paragraph  4, the Union reference  date for medicinal products 
containing the same active substance or the same combination of active substances 
shall be one of the following:  
(a) the date when  the first marketing authorisation was granted  in the Union for a 
medicinal product containing th at active substance or that combination of 
active substances;  EN 116  EN (b) if the date referred to in point (a) cannot be ascertained, the earliest of the 
known dates of the marketing authorisations for a medicinal product containing 
that active substance or that c ombination of active substances.  
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 determine Union reference dates or to change the frequency of 
submission of periodic saf ety update reports on one of the following grounds:  
(a) for reasons relating to public health;  
(b) in order to avoid a duplication of the assessment;  
(c) in order to achieve international harmonisation.  
Such requests shall be submitted in writing and shall  be duly justified. The 
Committee for Medicinal Products for Human Use or the coordination group shall, 
following the consultation with the Pharmacovigilance Risk Assessment Committee, 
either approve or deny such requests. Any change in the dates or the fr equency of 
submission of periodic safety update reports shall be made public ly available  by the 
Agency. The marketing authorisation holders shall submit an application for a 
variation of the marketing authorisation  accordingly . 
7. The Agency shall make public a list of Union reference dates and frequency of 
submission of periodic safety update reports by means of the European medicines 
web-portal.  
Any change to the dates of submission and frequency of periodic safety update 
reports specified in the marke ting authorisation as a result of the application of the 
paragraph s 4, 5 and 6  shall take effect four months after the date of the public ation  
referred to in the first subparagraph . 
Article  109 
Assessment of periodic safety update reports  
The competent aut horities of the Member State shall assess periodic safety update reports to 
determine whether there are new risks or whether risks have changed or whether there are 
changes to the benefit -risk balance of medicinal products.  
Article  110 
Single assessment of  periodic safety update reports  
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 
referred to in  Article 10 8, paragraphs 4, 5 and 6, for all medicinal products 
containing the same active substance or the same combination of active substances 
and for which a Union reference date and a frequency of periodic safety update 
reports has been established.  
The single assessment shall be condu cted by either of the following:  
(a) a Member State appointed by the coordination group where none of the 
marketing authorisations concerned has been granted in accordance with the 
centralised procedure provided for in Article 3  of [revised Regulation (EC)  No 
726/2004];  EN 117  EN (b) a rapporteur appointed by the Pharmacovigilance Risk Assessment Committee, 
where at least one of the marketing authorisations concerned has been granted 
in accordance with the centralised procedure provided for in Article 3 of 
[revised Regulation (EC) No 726/2004].  
When selecting the Member State in accordance with the second  subparagraph , point 
(a), the coordination group shall take into account whether any Member State is 
acting as a reference Member State, in accordance with Chapter I II, Sections 3 and 4 . 
2. The Member State or rapporteur, as appropriate, shall prepare an assessment report 
within 60 days of receipt of the periodic safety update report and send it to the 
Agency and to the Member States concerned. The Agency shall send t he report to the 
marketing authorisation holder.  
Within 30 days of receipt of the assessment report, the Member States and the 
marketing authorisation holder may submit comments to the Agency and to the 
rapporteur or Member State.  
3. Following the receipt of the comments referred to in paragraph  2, the rapporteur or 
Member State shall within 15 days update the assessment report taking into account 
any comments submitted, and forward it to the Pharmacovigilance Risk Assessment 
Committee. The Pharmacovigilanc e Risk Assessment Committee shall adopt the 
assessment report with or without further changes at its next meeting and issue a 
recommendation. The recommendation shall mention any divergent positions with 
the grounds on which they are based. The Agency shal l include the adopted 
assessment report and the recommendation in the repository set up under Article 103 
of [revised Regulation (EC) No 726/2004] and forward them  to the marketing 
authorisation holder.  
Article  111 
Regulatory action on periodic safety update reports  
Following the assessment of periodic safety update reports  referred to in Article 107 , the 
competent authorities of the Member States shall consider whether any action concerning the 
marketing authorisation for the medicinal product concerned is necessary  and shall maintain, 
vary, suspend or revoke the marketing authorisation as appropriate.  
Article  112 
Procedure for regulatory action on periodic safety update reports  
1. In the case of a single assessment of periodic safety update reports in accordance 
with Article 1 10(1) which  recommends action concerning more than one marketing 
authorisation that does not include any centralised marketing authorisation, the 
coordination group shall, within 30 days of receipt of the assessment  report of the 
Pharmacovigilance Risk Assessment Committee, consider the assessment  report and 
reach a position on the maintenance, variation, suspension or revocation of the 
marketing authorisations concerned, including a timetable for the implementation of 
the agreed position.  
2. If, within the coordination group, the Member States represented reach an agreement 
on the action to be taken by consensus, the chairperson shall record the agreement 
and se nd it to the marketing authorisation holder and the Member States. The 
Member States shall adopt necessary measures to maintain, vary, suspend or revoke EN 118  EN the marketing authorisations concerned in accordance with the timetable for 
implementation determined i n the agreement.  
In the event of a variation, the marketing authorisation holder shall submit to the 
competent authorities of the Member States an appropriate application for a 
modification, including an updated summary of product characteristics and an 
updated  package leaflet within the determined timetable for implementation.  
If an agreement by consensus cannot be reached, the position of the majority of the 
Member States represented within the coordination group shall be forwarded to the 
Commission which  shall apply the procedure laid down in Article 42. 
Where the agreement reached by the Member States represented within the 
coordination group or the position of the majority of Member States differs from the 
recommendation of the Pharmacovigilance Risk Assessment Committee, the 
coordination group shall attach to the agreement or the majority position a detailed 
explanation of the scientific grounds for the differences together with the 
recommendation.  
3. In the case of a single assessment of periodic saf ety update reports in accordance 
with Article 1 10(1) that recommends action concerning more than one marketing 
authorisation that includes at least one centralised marketing authorisation, the 
Committee for Medicinal Products for Human Use shall, within 30  days of receipt of 
the report of the Pharmacovigilance Risk Assessment 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 imp lementation of 
the opinion.  
4. Where the opinion of the Committee for Medicinal Products for Human Use referred 
to in paragraph 3 differs from the recommendation of the Pharmacovigilance Risk 
Assessment Committee, the Committee for Medicinal Products for H uman Use shall 
attach to its opinion a detailed explanation of the scientific grounds for the 
differences together with the recommendation.  
5. On the basis of the opinion of the Committee for Medicinal Products for Human Use 
referred to in paragraph  3, the Commission shall , by means of implementing acts : 
(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 provided for in thi s section; and  
(b) where the opinion states that regulatory action concerning the marketing 
authorisation is necessary, adopt a decision to vary, suspend or revoke the 
centralised marketing authorisations  and concerned by the procedure provided 
for in this  section.  
6. Article 42 shall apply to the adoption of the decision referred to in paragraph 5, point 
(a), and to its implementation by the Member States.  
7. Article 1 3 of [revised Regulation (EC) No 726/2004] shall apply to the decision 
referred to in par agraph  5, point (b) . Where the Commission adopts such decision, it 
may also adopt a decision addressed to the Member States pursuant to Article 55 of 
[revised Regulation (EC) No 726/2004] . EN 119  EN SECTION  5 
SIGNAL  DETECTION  
Article  113 
Signal monitoring and detection  
1. Regarding medicinal products  authorised in accordance with Chapter III , competent 
authorities of the Member States shall  in collaboration with the Agency, take the 
following measures:  
(a) monitor the outcome of risk minimisation measures contained in risk 
management plans and of the conditions referred to in Articles 44, 45 and any 
obligations imposed in accordance with Article  87; 
(b) assess updates to the risk management system;  
(c) monit or the data in the Eudravigilance database to determine whether there are 
new risks or whether risks have changed and whether those risks impact on the 
benefit -risk balance.  
2. The Pharmacovigilance Risk Assessment Committee shall perform the initial 
analy sis and prioritisation of signals of new risks or risks that have changed or 
changes to the benefit -risk balance. Where it considers that follow -up action may be 
necessary, the assessment of those signals and agreement on any subsequent action 
concerning t he marketing authorisation shall be conducted in a timescale 
commensurate with the extent and seriousness of the issue.  
3. The Agency and competent authorities of the Member States and the marketing 
authorisation holder shall inform each other in the event  of new risks or risks that 
have changed or changes to the benefit -risk balance being detected.  
4. Member States shall ensure that marketing authorisation holders inform the Agency 
and competent authorities of the Member State in the event of new risks or risks that 
have changed or when changes to the benefit -risk balance have been detected.  
SECTION  6 
URGENT  UNION  PROCEDURE  
Article  114 
Initiation of an urgent Union procedure  
1. A Member State or the Commission, as appropriate, shall, on the basis of concerns 
resulting from the evaluation of data from pharmacovigilance activities, initiate the 
procedure provided for in this Section (the ‘urgent Union procedure’)  by informing 
the o ther Member States, the Agency and the Commission where:  
(a) it considers suspending or revoking a marketing authorisation;  
(b) it considers prohibiting the supply of a medicinal product;  
(c) it considers refusing the renewal of a marketing authorisation; or EN 120  EN (d) it is informed by the marketing authorisation holder that, on the basis of safety 
concerns, the marketing authorisation holder has interrupted the placing on the 
market of a medicinal product or has taken action to have a marketing 
authorisation wit hdrawn, or intends to take such action or has not applied for 
the renewal of a marketing authorisation.  
2. A Member State or the Commission, as appropriate, shall, on the basis of concerns 
resulting from the evaluation of data from pharmacovigilance activi ties, inform the 
other Member States, the Agency and the Commission where it considers that a new 
contraindication, a reduction in the recommended dose or a restriction to the 
therapeutic indications of a medicinal product is necessary. The information sha ll 
outline the action considered and the reasons therefor e. 
Any Member State or the Commission, as appropriate, shall, when urgent action is 
considered necessary in any of the cases referred to in th e first subparagraph, initiate 
the urgent Union procedure . 
Where the urgent Union  procedure is not initiated, for medicinal products authorised 
in accordance with Chapter III, Sections 3 and 4, the case shall be brought to the 
attention of the coordination group.  
Article 9 5 shall apply  where the interests of the  Union are involved.  
3. Where the urgent Union  procedure is initiated, the Agency shall verify whether the 
safety concern relates to medicinal products other than the one covered by the 
information, or whether the safety concern  is common to all medicinal  products 
belonging to the same range or therapeutic class.  
Where the medicinal product involved is authorised in more than one Member State, 
the Agency shall without undue delay inform the initiator of the urgent Union  
procedure of the outcome of the verif ication, and the procedures laid down in 
Articles 115 and 11 6 shall apply. Otherwise, the safety concern shall be addressed by 
the Member State concerned. The Agency or the Member State, as applicable, shall 
make the information that the urgent Union  procedure has been initiated available to 
marketing authorisation holders.  
4. Without prejudice to paragraph s 1 and 2, and Articles 11 5 and 116, a Member State 
may, where urgent action is necessary to protect public health, suspend the marketing 
authorisat ion and prohibit the use of the medicinal product concerned on its territory 
until a definitive decision is adopted  in the urgent Union procedure . It shall inform 
the Commission, the Agency and the other Member States no later than the following 
working da y of the reasons for its action.  
5. At any stage of the procedure laid down in Articles 115 and 116, the Commission 
may request a Member State in which the medicinal product is authorised to take 
temporary measures immediately.  
Where the scope of the procedure, as determined in accordance with paragraph s 1 
and 2, includes medicinal products covered by centralised marketing authorisation s, 
the Commission may, at any stage of the urgent Union procedure, take temporary 
measures imme diately in relation to those marketing authorisations.  
6. The information referred to in this Article may relate to individual medicinal 
products or to a range of medicinal products or a therapeutic class.  
If the Agency identifies that the safety concern r elates to more medicinal products 
than those that are covered by the information or that the safety concern  is common EN 121  EN to all medicinal products belonging to the same range or therapeutic class, it shall 
extend the scope of the procedure accordingly.  
Where the scope of the urgent Union  procedure concerns a range of medicinal 
products or therapeutic class, medicinal products covered by the centralised 
marketing authorisation,  that belong to that range or class shall also be included in 
the procedure.  
7. At th e time the information referred to in paragraph s 1 and 2  is provided , the 
Member State shall make available to the Agency all relevant scientific information 
that it has at its disposal and any assessment by the Member State.  
Article  115 
Urgent Union procedure scientific assessment  
1. Following receipt of the information referred to in  Article 11 4, paragraphs 1 and 2, 
the Agency shall public ly announce the initiation of the urgent Union  procedure by 
means of the European medicines web -portal. In parallel, Member States may 
public ly announce the initiation of the procedure  on their national medicines web -
portals.  
The announcement shall specify the matter submitted to the Agency in accordan ce 
with Article 11 4, and the medicinal products and, where applicable, the active 
substances concerned. It shall contain information on the right of the marketing 
authorisation holders, healthcare professionals and the public to submit to the 
Agency inform ation relevant to the procedure and it shall state how such information 
may be submitted.  
2. The Pharmacovigilance Risk Assessment Committee shall assess the matter that has 
been submitted to the Agency in accordance with Article 11 4. The rapporteur, as 
referred to in Article 1 52 of [revised Regulation (EC) No 726/2004], shall closely 
collaborate with the rapporteur appointed by the Committee for Medicinal Products 
for Human Use and with the reference Member State for the medicinal products 
concerned.  
For the purposes of the assessment  referred to in the first subparagraph , the 
marketing authorisation holder may submit comments in writing.  
Where the urgency of the matter permits, the Pharmacovigilance Risk Assessment 
Committee may hold public hearings, where it considers that this is appropriate on 
justified grounds particularly with regard to the extent and seriousness of the safety 
concern. The hearings shall be held in accordance with the modalities specified by 
the Agency and shall be announced by me ans of the European medicines web -portal. 
The announcement shall specify the modalities of participation.  
The Agency shall, in consultation with the parties concerned, draw up Rules of 
Procedure on the organisation and conduct of public hearings, in accord ance with 
Article 163 of [revised Regulation (EC) No 726/2004].  
Where a marketing authorisation holder or another person intending to submit 
information , has confidential data relevant to the subject matter of the procedure, 
they may request permission to present that data to the Pharmacovigilance Risk 
Assessment Committee in a non -public hearing.  EN 122  EN 3. Within 60 days of the submission of the information, the Pharmacovigilance Risk 
Assessment Committee shall make a recommendation, stating the reasons on which 
it is based, having due regard to the therapeutic effect of the medicinal product. The 
recommendation shall mention any divergent positions and the grounds on which 
they are based. In the case of urgency, and on the basis of a proposal by its 
chairperson, the Pharmacovigilance Risk Assessment Committee may agree to a 
shorter deadline. The recommendation shall include any or a combination of the 
following conclusions:  
(a) no further evaluation or action is required at Union level;  
(b) the marketing authorisa tion holder should conduct further evaluation of data 
and carry out a  follow -up of the results of that evaluation;  
(c) the marketing authorisation holder should sponsor a post -authorisation safety 
study and carry out a  follow up evaluation of the results o f that study;  
(d) the Member States or marketing authorisation holder should implement risk 
minimisation measures;  
(e) the marketing authorisation should be suspended, revoked or not renewed;  
(f) the marketing authorisation should be varied.  
4. For the purposes of paragraph  3, point (d) , the recommendation shall specify the risk 
minimisation measures recommended and any conditions or restrictions to which the 
marketing authorisation should be made subject , including the timeline for 
implementatio n. 
5. For the purposes of  paragraph  3, point (f), where  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 shall indicate  where in the summary of product characteristics, the 
labelling or package leaflet such wording should be placed.  
Article  116 
Follow -up of recommendation made in the framework  of the urgent Union procedure  
1. Where the scope of the urgent Union  procedure, as determined in accordance with  
Article 11 4(6), does not include any centralised marketing authorisation, the 
coordination group shall, within 30 days of receipt of the recommendation of the 
Pharmacovigilance  Risk Assessment Committee, consider the recommendation and 
reach a position on the maintenance, variation, suspension, revocation or refusal of 
the renewal of the marketing authorisation concerned, including a timetable for the 
implementation of the agree d position. Where an urgent adoption of the position is 
necessary, the coordination group may , on the basis of a proposal by its chairperson, 
agree to a shorter deadline.  
2. If, within the coordination group, the Member States represented reach an agreement 
on the action to be taken by consensus, the chairperson shall record the agreement 
and send it to the marketing authorisation holder and the Member States. The 
Member States shall adopt necessary measures to maintain, vary, suspend, revoke or 
refuse renewal of the marketing authorisation concerned in accordance with the 
implementation timetable determined in the agreement.  EN 123  EN In the event that a variation is agreed upon, the marketing authorisation holder shall 
submit to the competent authorities of the Member States an appropriate application 
for a variation, including an updated summary of product characteristics and  an 
updated  package leaflet within the determined timetable for implementation.  
If an agreement by consensus cannot be reached, the pos ition of the majority of the 
Member States represented within the coordination group shall be forwarded to the 
Commission which shall apply the procedure laid down in Article 42. 
Where the agreement reached by the Member States represented within the 
coord ination group or the position of the majority of the Member States represented 
within the coordination group differs from the recommendation of the 
Pharmacovigilance Risk Assessment Committee, the coordination group shall attach 
to the agreement or majorit y position a detailed explanation of the scientific grounds 
for the differences together with the recommendation.  
3. Where the scope of the procedure, as determined in accordance with Article 11 4(6), 
includes at least one central ised marketing authorisation, the Committee for 
Medicinal Products for Human Use shall, within 30 days of receipt of the 
recommendation of the Pharmacovigilance Risk Assessment Committee, consider 
the recommendation and adopt an opinion on the maintenance, vari ation, suspension, 
revocation or refusal of the renewal of the marketing authorisations concerned. 
Where an urgent adoption of the opinion is necessary, the Committee for Medicinal 
Products for Human Use may , on the basis of a proposal by its chairperson, agree to 
a shorter deadline.  
Where the opinion of the Committee for Medicinal Products for Human Use differs 
from the recommendation of the Pharmacovigilance Risk Assessment Committee, 
the Committee for Medicinal Products for Human Use shall attach to its opinion a 
detailed explanation of the scientific grounds for the differences together with the 
recommendation.  
4. On the basis of the opinion of the Committee for Medicinal Products for Human Use 
referred to in paragraph  3, the Commission shall , by means o f implementing acts : 
(a) adopt a decision addressed to the Member States concerning the measures to be 
taken in respect of marketing authorisations that are granted by the Member 
States and that are subject to the  urgent Union  procedure;  
(b) where the opin ion states that regulatory action concerning the marketing 
authorisation is necessary, adopt a decision to vary, suspend , revoke  or refuse 
the renewal of  the centralised m arketing authorisations and concerned by the  
procedure provided for in this section.  
5. Article 42 shall apply to the adoption of the decision referred to in paragraph  4, point 
(a), and to its implementation by the Member States.  
6. Article 13  of [revised Regulation (EC) No 726/2004] shall apply to the decision 
referred to in paragraph  4, point (b). Where the Commission adopts such decision, it 
may also adopt a decision addressed to the Member States pursuant to  Article 55 of 
[revised Regulation (EC) No 726/2004].  EN 124  EN SECTION  7 
SUPERVISION  OF POST -AUTHORISATION  SAFETY  STUDIES  
Article  117 
Non-interventional post -authorisation safety studies  
1. This Section applies to non -interventional post -authorisation safety studies that are 
initiated, managed or financed by the marketing authorisation holder voluntarily or 
pursuant to obligations impose d in accordance with Articles 44 or 87, and that 
involve the collection of safety data from patients or healthcare professionals.  
2. This Section is without prejudice to Member States  and Union requirements for 
ensuring the well -being and rights of participants in non -interventional post -
authorisation safety studies.  
3. The studies shall not be performed where the act of conducting the study promotes 
the use of a medicinal product.  
4. Payments to healthcare professionals for participating in non -interventional post -
authorisation safety studies shall be restricted to the compensation for time and 
expenses incurred.  
5. The competent authority of the Member State may require the marketing 
authorisation holder to submit the protocol and the progress reports to the competent 
authorities of the Member States in which the study is conducted.  
6. The marketing authorisation holder shall send the final report  of the study  to the 
competent authorit ies of the Member States in which the study was conducted within 
12 months of the end of data collection.  
7. While a study is being conducted, the marketing authorisation holder shall monitor 
the data generated and consider its implications for the benefit -risk balance of the 
medicinal product concerned.  
Any new information that might influence the evaluation of the benefit -risk balance 
of the medicinal product shall be communicated to the competent authorities of the 
Member State in which the medicinal pro duct has been authorised in accordance 
with Article 90. 
The obligation laid down in the second subparagraph is without prejudice to the 
information on the results of studies that the marketing authorisation holder shall 
make available by means of the perio dic safety update reports as laid down in Article 
107. 
8. Articles 11 8 to 121 shall apply exclusively to studies referred to in paragraph 1 that 
are conducted pursuant to an obligation imposed in accordance with Articles 44 or 
87. 
Article  118 
Agreement of a protocol for a non -interventional post -authorisation safety study  
1. Before a study is conducted, the marketing authorisation holder shall submit a draft 
protocol to the Pharmacovigilance Risk Assessment Committee, except for studies to 
be conducted in o nly one Member State that requests the study in accordance with  EN 125  EN Article 87. For such studies, the marketing authorisation holder shall submit a draft 
protocol to the competent authority of the Member State in which the study is 
conducted.  
2. Within 60 days  of the submission of the draft protocol referred to in paragraph 1  the 
competent authority of the Member State or the Pharmacovigilance Risk Assessment 
Committee, as appropriate, shall issue:  
(a) a letter endorsing the draft protocol;  
(b) a letter of objection, which shall set out in detail the grounds for the objection, 
where : 
(i) it considers that the conduct of the study pro motes the use of a medicinal 
product;  
(ii) it considers that the design of the study does not fulfil the study 
objectives; or  
(c) a letter notifying the marketing authorisation holder that the study is a clinical 
trial falling under the scope of Regulation (EU)  No 536/2014 . 
3. The study may commence only when the written endorsement from the competent 
authority of the Member State or the Pharmacovigilance Risk Assessment 
Committee, as appropriate, has been issued.  
Where a letter of endorsement of the draft protocol  as referred to in paragraph 2, 
point (a) , has been issued, the marketing authorisation holder shall  forward the 
protocol to the competent authorities of the Member States in which the study is to 
be conducted and may thereafter commence the study according to the endorsed 
protocol.  
Article  119 
Update of a protocol for a non -interventional post-authorisation  safety stud y 
After a study has been commenced, any substantial amendments to the protocol shall be 
submitted, before their implementation, to the competent authority of the Member State or to 
the Pharmacovigilance Risk Assessment Committ ee, as appropriate. The competent authority 
of the Member State or the Pharmacovigilance Risk Assessment Committee, as appropriate, 
shall assess the amendments and inform the marketing authorisation holder of its endorsement 
or objection. Where applicable,  the marketing authorisation holder shall inform the Member 
States in which the study is conducted.  
Article  120 
Final study report on a non-interventional post -authorisation safety stud y 
1. Upon completion of the study, a final study report shall be submit ted to the 
competent authority of the Member State or the Pharmacovigilance Risk Assessment 
Committee within 12 months of the end of data collection unless a written waiver has 
been granted by the competent authority of the Member State or the 
Pharmacovigilance Risk Assessment Committee, as appropriate.  
2. The marketing authorisation holder shall evaluate whether the results of the study 
have an impact on the marketing authorisation and shall, if necessary, submit to the EN 126  EN competent authorities of the Member States an application to vary the marketing 
authorisation.  
3. Together with the final study report, the marketing authorisation holder shall 
electronically submit an abstract of the study results to the competent authority of the 
Member State or the Pharmacovigilance Risk Assessment Committee.  
Article  121 
Recommendations following the submission of a final study report on non -interventional post -
authorisation safety studies  
1. Based on the results of the study and after consultation of the marke ting authorisation 
holder, the Pharmacovigilance Risk Assessment Committee may make 
recommendations concerning the marketing authorisation, stating the reasons on 
which they are based. The recommendations shall mention any divergent positions 
and the groun ds on which they are based.  
2. When recommendations for the variation, suspension or revocation of a national 
marketing authorisation are made, the Member States represented within the 
coordination group shall agree on a position on the matter taking into account the 
recommendation referred to in paragraph 1 and shall includ e a timetable for the 
implementation of the agreed position.  
If, within the coordination group, the Member States represented reach an agreement 
on the action to be taken by consensus, the chairperson shall record the agreement 
and send it to the marketing authorisation holder and the Member States. The 
Member States shall adopt necessary measures to vary, suspend or revoke the 
marketing authorisation concerned in accordance with the imp lementation timetable 
determined in the agreement.  
In the event that a variation is agreed upon, the marketing authorisation holder shall 
submit to the competent authorities of the Member State an appropriate application 
for a variation, including an updat ed summary of product characteristics and an 
updated  package leaflet within the determined timetable for implementation.  
The agreement shall be made public ly available  on the European medicines web -
portal established in accordance with Article 104 of [revised Regulation (EC) No 
726/2004].  
3. If an agreement by consensus cannot be reached, the position of the majority of the 
Member States represented within the coordination group shall be forwarded to the 
Commission, which shall apply the procedure laid  down in Article 42. 
4. Where the agreement reached by the Member States represented within the 
coordination group or the position of the majority of Member States differs from the 
recommendation of the Pharmacovigilance Risk Assessment Committee, the 
coordination group shall attach to the agreement or majority position a detailed 
explanation of the scientific grounds for the differences together with the 
recommendation.  EN 127  EN SECTION  8 
IMPLEMENTATION , GUIDANCE  AND  REPORTING  
Article  122 
Implementing measures related to pharmacovigilance activities  
1. In order to harmonise the performance of the pharmacovigilance activities provided 
for in this Directive, the Commission shall adopt implementing measures in the 
following areas for which pharmacovigilance activit ies are provided for in Annex I , 
Articles 9 6, 99, 100, 105 to 107, 113, 118 and 1 20 by setting out : 
(a) the content and the rules on the maintenance of the pharmacovigilance system 
master file kept by the marketing authorisation holder;  
(b) minimum requirements for the quality system for the performance of 
pharmacovigilance activities by the competent authorities of the Member 
States and the marketing authorisation holder;  
(c) rules on  the use of internationally agreed terminology, formats an d standards 
for the performance of pharmacovigilance activities;  
(d) minimum requirements for the monitoring of data in the Eudravigilance 
database to determine whether there are new risks or whether risks have 
changed;  
(e) the format and content of the el ectronic transmission of suspected adverse 
reactions by Member States and the marketing authorisation holder;  
(f) the format and content of electronic periodic safety update reports and risk 
management plans;  
(g) the format of protocols, abstracts and fina l study reports for the post -
authorisation safety studies.  
2. Those measures shall take account of the work on international harmonisation carried 
out in the area of pharmacovigilance. Those measures shall be adopted in accordance 
with the regulatory proce dure referred to in  Article 214(2) . 
Article  123 
Guidance to facilitate the performance of pharmacovigilance activities  
The Agency shall, in cooperation with competent authorities  of the Member States  and other 
interested parties, draw up:  
(a) guidance on good pharmacovigilance practices for both competent authorities and 
marketing authorisation holders;  
(b) scientific guidance on post -authorisation efficacy studies.  
Article  124 
Reporting on pharmacovigilance tasks  EN 128  EN The Agency shall make public a report on t he performance of pharmacovigilance tasks by the 
Member States and the Agency every three  years . The first report shall be  made public by 
[three years after application date of [revised Regulation (EC) No 726/2004 ]. 
Chapter  X 
Homeopathic medicinal products  and traditional herbal medicinal 
products  
SECTION  1 
SPECIFIC  PROVISIONS  APPLICABLE  TO HOMEOPATHIC  MEDICINAL  PRODUCTS  
Article  125 
Registration or authorisation of homeopathic medicinal products  
1. Member States shall ensure that homeopathic medicinal products manufactured and 
placed on the market in the Union are registered in accordance with Articles 126 and 
127 or authorised in accordance with Article  133(1), except where such homeopathic 
medicina l products are covered by a registration or authorisation granted in 
accordance with national legislation on or before 31 December 1993. In case of 
registrations, Chapter III, Sections 3 and 4 , and A rticle  38, paragraphs 1, 2 and  3 
shall apply.  
2. Member States shall establish a simplified registration procedure referred to in 
Article 126  for the homeopathic medicinal products.  
Article  126 
Simplified registration procedure for homeopathic medicinal products  
1. Homeopathic medicinal products that satisfy all of the following conditions may be 
subject to a simplified registration procedure:  
(a) they are administered orally or externally ; 
(b) no specific therapeutic indication appears on the labelling of the medicinal 
product or in any information r elating thereto ; 
(c) there is a sufficient degree of dilution to guarantee the safety of the medicinal 
product . 
For the purposes of point (c), the medicinal product may not contain either more than 
one part per 10000 of the mother tincture or more than 1/1 00th of the smallest dose 
used in allopathy with regard to active substances whose presence in an allopathic 
medicinal product results in the obligation to submit a doctor’s prescription.  
The Commission is empowered to adopt delegated acts in accordance with Article 
215 to amend the first subparagph , point (c) , in order to take account of scientific 
progress . 
At the time of registration, Member States shall determine the prescription  status  for 
the dispensing of the homeopathic  medicinal product.  EN 129  EN 2. The criteria and rules of procedure provided for in Article 1(10), point (c) , Article 30, 
Chapter III, Section 6 , Articles 191, 195 and 204 shall apply by analogy to the 
simplified registration procedure for homeopathic medicinal products, with the 
exception of the proof of therapeutic efficacy.  
Article  127 
Application requirements for simplified registration  
An application a simplified registration may cover a series of homeopathic  medicinal products 
derived from the same homeopathic stock or stocks . The following shall be included with the 
application in order to demonstrate, in particular, the pharmaceutical quality and the batch -to-
batch homogeneity of the homeopathic medicinal  products concerned:  
(a) the scientific name or other name given in a pharmacopoeia of the homeopathic stock 
or stocks, together with a statement of the various routes of administration, 
pharmaceutical forms and degree of dilution to be registered ; 
(b) a dossier describing how the homeopathic stock or stocks are obtained and  
controlled, and justifying their homeopathic use, on the basis of an adequate 
bibliography ; 
(c) the manufacturing and control file for each pharmaceutical form and a description of 
the method of dilution and potentisation ; 
(d) the manufacturing authorisat ion for the homeopathic  medicinal product concerned ; 
(e) the copies of any registrations or authorisations  obtained for the same homeopathic  
medicinal product in other Member States ; 
(f) one or more mock -ups of the outer packaging and the immediate packaging of the 
homeopathic  medicinal products to be registered ; 
(g) the data concerning the stability of the homeopathic  medicinal product.  
Article  128 
Application of decentralised and mutual recognition procedures to homeopathic medicinal 
products  
1. Article 38, paragraphs 4 and 6, Articles 3 9 to 42 and  95 shall not apply to the 
homeopathic medicinal products referred to in Article 12 6. 
2. Chapter III, Sections 3 to 5, shall not apply to the homeopathic medicinal products 
referred to in Article 133 (2). 
Article  129 
Labelling of homeopathic medicinal products  
Homeopathic medicinal products , with the exception those referred to in Article 12 6(1), shall 
be labelled in accordance with the provisions of Chapter  VI and shall be identified by a 
reference on their labels, in clear and legible form, to their homeopathic nature.  
Article  130 
Specific requirements for labelling of certain homeopathic medicinal products  EN 130  EN 1. The labelling and, where appropriate, the package insert for  homeopathic  medicinal 
products referred to in Article 126(1) in addition to the clear mention of the words 
‘homeopathic medicinal product’, shall bear the following, and no other, 
information:  
(a) the scientific name of the stock or stocks followed by the degree of dilution, 
making use of the symbols of the pharmacopoeia used in accordance with 
Article 4(62); 
(b) name and address of the registration holder and, where appropri ate, of the 
manufacturer;  
(c) method of administration and, if necessary, route  of administration ; 
(d) pharmaceutical form;  
(e) expiry date, in clear terms (month, year);  
(f) contents of the sales presentation;  
(g) special storage precautions, if any;  
(h) a special warning if necessary for the medicinal product;  
(i) manufacturer's batch number;  
(j) registration number;  
(k) ‘homeopathic medicinal product without approved therapeutic indications’;  
(l) a warning advising the user to consult a doctor if the symptoms persist.  
As regards the first subparagraph, point (a), if the homeopathic medicinal product is 
composed of two or more stocks, the scientific names of the stocks on the labelling 
may be supplemented by an invented name.  
2. Notwithstanding paragraph  1, Member States may require the use of certain types of 
labelling in order to show:  
(a) the price of the homeopathic  medicinal product ; 
(b) the conditions for refunds by social security bodies.  
Article  131 
Advertising of homeopathic medicinal pr oducts  
1. Chapter XIII shall apply to homeopathic medicinal products .  
2. By derogation from paragraph  1, Article 176 (1) shall not apply to medicinal products 
referred to in Article 126 (1). 
However, only the information specified in Article 130(1) may be used in the 
advertising of such homeopathic  medicinal products.  
Article  132 
Exchange of information on homeopathic medicinal products  
Member States shall communicate to each other all the information necessary to guarantee the 
quality and safety of homeopathic medicinal products manufactured and marketed within the 
Union , and in particular the information referred to in  Articles 20 2 and 203. EN 131  EN Article  133 
Other requirements for homeopathic medicinal products  
1. Homeopathic medicinal products other than  those referred to in  Article 126(1) shall 
be granted a marketing  authori sation  in accordance with Article s 6 and 9 to 14  and 
labelled in accordance with  Chapter VI.  
2. A Member State may introduce or retain in its territory specific rules for the non-
clinical  tests and clinical studies  of homeopathic medicinal products other than those 
referred to in Article 126 (1), in accordance with the principles and characteristics of 
homeopathy as practised in that Member State.  
In this case, the Member State concerned shall notify the Commission of the specific 
rules in force . 
3. Chapter IX shall apply to homeopathic medicinal products , with the exception  of 
those referred to in Article 12 6(1). Chapter X I, Chapter XII, Section 1,  and Chapter 
XIV shall apply to  homeopathic medicinal products . 
SECTION  2 
SPECIFIC  PROVISIONS  APPLICABLE  TO TRADITIONAL  HERBAL  MEDICINAL  
PRODUCTS  
Article  134 
Simplified registration procedure for traditional herbal medicinal products  
1. Herbal medicinal products that satisfy all of the following conditions may be subject 
to a simplified registration procedure (‘traditional -use registration’):  
(a) they have therapeutic indications exclusively appropriate to traditional herbal 
medicinal pro ducts that, by virtue of their composition and purpose, are 
intended and designed for use without the supervision of a medical practitioner 
for diagnostic purposes or for prescription or monitoring of treatment;  
(b) they are exclusively for administration in accordance with a specified strength 
and posology;  
(c) they are an oral, external or inhalation preparation;  
(d) the period of traditional use as laid down in  Article 136 (1), point (c), has 
elapsed;  
(e) the data on the traditional use of the herbal  medicinal product referred to in  
Article 136 (1), point (c) , are sufficient . 
The data on the use of a medicinal product referred to in  the first subparagraph, point 
(e), shall be considered sufficient where  the herbal medicinal  product proves not to 
be harmful in the specified conditions of use and the pharmacological effects or 
efficacy of the herbal  medicinal product are plausible on the basis of long -standing 
use and experience.  
2. Notwithstanding Article 4(1), point (6 4), the presence in the herbal medicinal 
product of vitamins or minerals for the safety of which there is well -documented 
evidence shall not prevent the herbal medicinal  product from being eligible for 
registration in accordance with paragraph  1, provided that t he action of the vitamins EN 132  EN or minerals is ancillary to that of the herbal active substances regarding the specified 
claimed therapeutic indication(s).  
3. However, in cases where the competent authorities  judge that a herbal medicinal 
product that fulfils the conditions laid down in paragraph 1 (‘traditional herbal 
medic inal product’)  fulfils the criteria for a national marketing  authorisation in 
accordance with Article 5 or for a simplified  registration in accordance with Article 
126, the prov isions of this Section  shall not apply.  
Article  135 
Submission of dossier for traditional herbal medicinal product  
1. The applicant and the traditional -use registration holder shall be established in the 
Union . 
2. In order to obtain  a traditional -use registration, the applicant shall submit an 
application to the competent authority of the Member State concerned.  
Article  136 
Application requirements  for traditional -use registration  
1. An application for traditional -use registration  shall be accompanied by: 
(a) the particulars and documentation : 
(i) referred to in points (1), (2), (3),  (5) to ( 9), (16) and (17) of Annex I ; 
(ii) the results of the pharmaceutical tests referred to in Annex I ; 
(iii) the summary of product characteristics, without the clinical particulars  as 
specified in Annex V ; 
(iv) in case of combinations, as referred to in Article 4(1), point (64), or in 
Article 134 (2), the information referred to in Article 134 (1), first 
subparagraph, point (e), relating to the combination as such; if the 
individual active substances are not sufficiently known, the data shall 
also relate to the individual active substances ; 
(b) any national marketing  authorisation or registration obtained by the applicant 
in anoth er Member State, or in a third country, to place the  herbal  medicinal 
product on the market, and details of any decision to refuse to grant a  national 
marketing  authorisation or registration, whether in the Union  or a third country, 
and the reasons for any  such decision;  
(c) bibliographical or expert evidence to the effect that the herbal  medicinal 
product in question, or a corresponding medicinal product has been in 
medicinal use throughout a period of at least 30 years preceding the date of the 
application, including at least 15 years within the Union ; 
(d) a bibliographic review of safety data together with an expert report, and where 
required by the competent authority  of the Member State , upon additional 
request, data necessary for assessing the safety of the herbal  medicinal product.   
For the purposes of the first subparagraph, point (c),  at the request of the Member 
State where the application for traditional -use registration has been submitted, the 
herbal  medicinal  product s working group  shall draw up an opinion on the adequacy EN 133  EN of the evidence of the long -standing use referred to in  the first subparagraph,  point 
(c), of the herbal  medicinal  product, or of the corresponding herbal medicinal  
product . The Member State shall submit relevant documentation supporting the 
referral.  
For the purposes of the first subparagraph, point (d), if the individual active 
substances are not sufficiently known, the data referred to in the first subparagraph, 
point (a)(iv) , shall also relate to the individual active substances . 
Annex II  shall apply by analogy to the particulars and document ation s specified in 
the first subparagraph, point (a).  
2. The requirement to show medicinal use throughout the period of at least  30 years, set 
out in paragraph  1, first subparagraph, point (c) , is satisfied even where the 
marketing of the herbal  medicinal  product has not been based on a specific marketing  
authorisation. It is likewise satisfied where  the number or quantity of ingredients of 
the herbal  medicinal product has been reduced during that period.  
3. Where the herbal  medicinal  product has been used  in the Union  for less than 15 years 
but is otherwise eligible for a traditional -use registration  in accordance with 
paragraph 1 , the competent authority of  the Member State where the application for 
traditional -use registration has been submitted shall refer the application for the 
traditional  herbal  medicinal  product to the herbal medicinal products  working group  
and submit relev ant documentation supporting this  referral . 
The herbal medicinal products  working group  shall consider whether the criteria 
other  than the period of transitional use  for a traditional -use registration as referred to 
in Article 134  are complied with. If the herbal medicinal products  working group 
considers it possible, it shall establish a Union  herbal monograph as referred to in 
Article 141 (3) which shall be taken into account by the competent authority of 
Member State when taking its final decision  on the application  for the traditi onal use 
registration . 
Article  137 
Application of  mutual recognition to traditional herbal medicinal products  
1. Chapter III, Sections 3  to 5, shall apply by analogy to traditional -use registrations 
granted in accordance with Article 13 4, provided that:  
(a) a Union  herbal monograph has been established in accordance with  Article 
141(3); or 
(b) the traditional  herbal medicinal product consists of herbal substances,  herbal  
preparations or combinations thereof contained in the list referred to in Article 
139. 
2. For traditional  herbal medicinal products not covered by paragraph 1 , the competent 
authority of  each Member State shall, when evaluating an application for traditional -
use registration, take due account of registrations granted by the competent autho rity 
of another Member State in accordance with this Section.  
Article  138 
Refusal of registration of traditional herbal medicinal products  EN 134  EN 1. Traditional -use registration shall be refused if the application does not comply with  
Articles 134 , 135 or 136 or if at least one of the following conditions is fulfilled:  
(a) the qualitative or quantitative composition is not as declared;  
(b) the therapeutic indications do not comply with the cond itions laid down in  
Article 134 ; 
(c) the traditional herbal medicinal  product could be harmful under normal 
conditions of use;  
(d) the data on traditional use are insufficient, especially if pharmacological effects 
or efficacy are not plausible on the basis of long -standing use and experience;  
(e) the pharmaceutical quality is not satisfactorily demonstrated.  
2. The competent authorities of the Member States shall notify the applicant, the 
Commission and any competent authority  of the Member State  that requests it, of 
any decision they take to refuse traditional -use registrat ion and the reasons for the 
refusal.  
Article  139 
List of herbal substances , herbal  preparations  and combinations thereof   
1. The Commission shall adopt implementing act s to establish  a list of herbal 
substances, preparations and combinations thereof for use in traditional herbal 
medicinal products , taking into account the draft list prepared by the herbal 
medicinal products working group . Those implementing acts shall be adopted  in 
accordance with the examination  procedure referred to in Article 214(2) . The list 
shall contain, with regard to each herbal substance, the therapeutic indication, the 
specified strength and the posology, the route of administration and any other 
information necessary for the safe use of the herbal substance as a traditional herbal  
medicinal product.   
2. If an application for traditional -use registration relates to a herbal substance, 
preparation or a combination thereof contained in the list referred to in paragraph  1, 
the data specified in Article 136 (1), point s (b), (c) and (d), shall not be required  and 
Article 138 (1), point s (c) and (d) , shall not apply.  
3. If a herbal substance, preparation or a combination is no longer included  in the list 
referred to in paragraph  1, registrations pursuant to paragraph  2 for herbal medicinal 
products containing this substance shall be revoked unless the particulars and 
documentations  referred to in Article 13 6(1) are submitted within three months.  
Article  140 
Other requirements for traditional herbal medicinal products  
1. Article 1(5), point s (a) and  (b) and Article 1(10) , point ( c), Article s 6 to 8, 29, 30, 44, 
46, 90, 155, Article  188, paragraphs  1 and 11, Article s 191, 195, 196, 198, 199(2), 
202, 203 and 204 and Chapters IX and XI of this Directive as well as Commission  EN 135  EN Directive 2003/94/EC40 shall apply, mutadis mutandis , to traditional -use registration s 
granted under this Section . 
2. In addition to the requirements set out in  Articles 63 to 66, 70 to 79 and Annex IV, 
any labelling and package leaflet of a traditional herbal medicinal product  shall 
contain a statement to the effect that:  
(a) the product is a traditional herbal medicinal product for use in specified 
therapeutic indication(s) exclusively based upon long -standing use; and  
(b) the user should consult a doctor or a qualified healthcare practitioner if the 
symptoms persist during the use of the traditional herbal  medicinal product or 
if adverse effects not mentioned in the package leaflet occur.  
A Member State may require that the  labelling and the package leaflet shall also state 
the nature of the tradition in question.  
3. In addition to the requirements set out in  Chapter XIII, any advertisement for a 
traditional herbal  medicinal product registered under this Section  shall contai n the 
following statement: Traditional herbal medicinal product for use in specified 
therapeutic indication(s) exclusively based upon long -standing use.  
Article  141 
Herbal medicinal products  working group   
1. A herbal medicinal products  working group  is established  as referred to in Article 
142 of [revised Regulation (EC) No 726/2004] . That working group  shall be part of 
the Agency and shall have the following competence:  
(a) as regards traditional -use registrations, to:  
(i) perform the tasks arising from Article 136 , paragraphs 1 and 3 ; 
(ii) perform the tasks arising from  Article 137 ; 
(iii) prepare a draft list of herbal substances, preparations and combinations 
thereof, as referred to in Article 139 (1); 
(iv) establish Union  monographs for traditional herbal medicinal products, as 
referred to in paragraph 3; 
(b) as regards  marketing  authorisations of herbal medicinal products, to establish 
Union  herbal monographs for herbal medicinal products, as referred to in 
paragraph 3; 
(c) as regards referrals to the Agency under Chapter III, Section 5, or Article 95 , in 
relation to traditional  herbal medicinal products as referred to in Article 134 , to 
perform the tasks set out in Article 4 1; 
(d) where a matter concerning  medicinal prod ucts, other than the traditional -use 
medicinal products , other medicinal products containing herbal substances  is 
referred to the Agency under Chapter  III, Section 5 , or Article 95 , to give an 
opinion on the herbal substance , where appropriate.  
                                                 
40 Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of 
good manufacturing practice in respect of medicinal products for human use and investigational 
medicinal products for human use (OJ L 262, 14.10.2003, p. 22).  EN 136  EN Appropriate coordination with the Committee for Human Medicinal Products for 
Human Use  shall be ensured by a procedure to be determined by the Executive 
Director of the Agency in accordance with Article 1 45(10) of [revised Regulation 
(EC) No 726/2004 ]. 
2. Each Member State shall appoint, for a three -year term which may be renewed, one 
member and one alternate to the herbal medicinal working group.  
The alternates shall represent and vote for the members in their absence. Members 
and alternates shall be chosen for their role and experience in the evaluation of herbal 
medicinal products and shall represent the competent authorities  of the Member 
States . 
The members of the herbal medicinal products  working group  may be accompanied 
by experts in specific sci entific or technical fields.  
3. The herbal medicinal products  working group  shall establish Union  herbal 
monographs for herbal medicinal products with regard to the application submitted in 
accordance with  of Article 13 as well as traditional herbal medicinal products.  
Where the Union  herbal monographs have been established, they shall be taken into 
account by the competent authorities of  Member States when examining an 
application . Where no such Union  herbal monograph h as yet been established, other 
appropriate monographs, public ations or data may be referred to.  
When new Union  herbal monographs are established, the traditional -use registration 
holder shall consider whether it is necessary to modify the registration doss ier 
accordingly. The traditional -use registration holder shall notify any such 
modification to the competent authority of the Member State concerned.  
The herbal monographs shall be published.  
4. Provisions of A rticle 146, paragraphs  3 to 5 of the [revised Regulation (EC) No 
726/2004] applying to the working party shall apply by analogy to herbal medicinal 
products working group.  
5. The h erbal medicinal products working group shall draft its rules of procedure.  
Chapter  XI 
Manufacturing  and import  
SECTION  1 
MANUFACTURING  AND  IMPORT  OF MEDICINAL  PRODUCTS  
Article  142 
Manufacturing authorisation  
1. Member States shall take all appropriate measures to ensure that the manufacture of 
the medicinal products within their territory is subject to authorisation  (the 
“manufacturing authorisation”) . The manufacturing authorisation  shall be required 
also if the medicinal products manufactured are intended for export.  EN 137  EN 2. The manufacturing  authorisation referred to in paragraph  1 shall be required for both 
total and partial manufacture, and for the various processes of dividing up, packaging 
or presentation.  
3. By derogation from paragraph 2,  the manufacturing  authorisation shall not be 
required for the following:   
(a) preparation , dividing up, changes in packaging or presentation where these 
processes are carried out, solely for retail supply, by pharmacists in dispensing 
pharmacies or by persons legally authorised  in the Member States to carry out 
such processes; or 
(b) decentral ised sites carrying out manufacturing or testing steps under the 
respons ibility of the qualified person  of a central site referred to in Article 
151(3).  
4. A manufacturing authorisation shall also be required for imports of medicinal 
products  coming from third countries into a Member State . 
This Chapter and Article s 195(5) and 198 shall apply to imports of medicinal 
products from third countries . 
5. Member States shall enter the information relating to the manufacturing authorisation 
referred to in paragraph 1 in the Union database referred to in Article 1 88(15). 
Article  143 
Requirements for a manufacturing authorisation  
1. In order to obtain the manufacturing  authorisation , the applicant shall submit an 
application by electronic means to the competent authority of the Member State 
concerned.  
That application shall include the following particulars:  
(a) the medicinal products, the pharmaceutical forms and the manufacturing 
operations that  are to be manufactured, imported or carried out  and the place 
where the activity will take place;   
(b) proof that the applicants  have at their disposal, for the manufacture or import of 
the above, suitable and sufficient premises, technical equipment and control 
facilities complying with the legal requirements that the Member State 
concerned lays down as regards both manufacture and control and the storage 
of medicinal products, in accordance with Article 8 ; 
(c) proof that the applicants  have at their disposal the services of at least one 
qualified person within the meaning of Article 151 ; 
(d) explanation on whether  the site is the central site responsible for the oversight 
of decentralised sites . 
2. The applicant shall provide, by electronic means, particulars in support of the above 
in their application.  
Article  144 
Granting  of a manufacturing authorisation  EN 138  EN 1. The official representatives of the  competent authority of the Member State 
concerned shall  carry out an inspection to ensure the accuracy of the particulars 
included in the application submitted in accordance with Article 143 . 
Where the accuracy of the particulars is confirmed in accordance with the first 
subparagraph  and no later than 90 days after the receipt of the application submitted 
in accordance with Article 143 , the competent authority of the Member State shall 
grant or refuse a manufacturing authorisation.  
2. To ensure that the particulars referred to in Article 143 are duly submitted, the 
competent authority of the Member State may grant a manufacturing authorisation 
subject to conditions.  
For central sites, a manufacturing authorisation shall include for each decentralised 
site a  written confirmation that th e manufacturer of the medicinal product has 
verified compliance of the decentralised site with principles of good manufacturing 
practice referred to in Article 160  by conducting regular audits in accordance with 
Article 147(1), first subparagraph, point (f ). 
3. The manufacturing  authoris ation  shall apply only to the medicinal products, 
pharmaceutical forms, the manufacturing operations and the  premises specified in the 
application and to the premises of the corresponding central site where  decentralised 
manufacturing or testing activities ar e carried out  in decentrali sed sites , which are 
registered in accordance with Article 148. 
Article  145 
Changes in a manufacturing authorisation  
If the manufacturing  authorisation  holder  requests a change in any of the particulars referred 
to in Article 143 (1), second subparagraph , the competent authority of the  Member State shall 
amend the manufacturing authorisation no later than 30 days from such request . In 
exceptional cases this perio d of time may be extended to 90 days.  
Article  146 
Request for additional information  
The competent authority of the  Member State may request  the applicant to submit  additional 
information on the particulars supplied pursuant to  Article 143 (1) and on the qualified person 
referred to in Article 151 ; where the  competent authority of the  Member State make s such 
request,  the time  limits referred to in Articles 144(1), second subparagraph,  and 145 shall be 
suspended until the additional information  has been supplied.  
Article  147 
Obligations of the m anufacturing authorisation holder  
1. Member States shall ensure that manufacturing authorisation holders shall:  
(a) have at their disposal the services of staff who comply with the legal 
requirements existing in the Member State both as regards manufacture and 
controls;  
(b) dispose of the medicinal products that have been granted a marketing 
authorisation only in accordance with the  legislation of the Member States;  EN 139  EN (c) give prior notice to the competent authority of the Member State  of any 
changes they may wish to make to any of the particulars provided in 
accordance to Article 143; 
(d) allow the official representatives  of the comp etent authority of the Member 
State access to their premises and, where sites carry out manufacturing or 
testing activities in connection with a central site in the decentralised site , to 
the premises of the central or the decentralised sites  at any time;  
(e) enable the qualified person s referred to in Article 151  to carry out their duties, 
where appropriate also in decentralised sites, for example by placing at their 
disposal all the necessary resources;  
(f) comply, in any relevant site and at all times with the principles of good 
manufacturing practice for medicinal products ; 
(g) use only active substances that have been manufactured in accordance with 
good manufacturing practice for active substances and distributed in 
accordance with good distribution practices for active substances;  
(h) inform the competent authority of the Member State and the marketing 
authorisation holder immediately if they obtain information that medicinal 
products that come under the scope of their manufacturing authorisation are , or 
are suspected of being, falsified irrespective of the way the medicinal products 
were distributed;  
(i) verify that the manufacturers, importers or distributors from whom they obtain 
active substances are registered with the competent authority of the Member 
State in which they are established;  and 
(j) verify the authenticity and quality of the active substances and the excipients.  
As regards  the first subparagraph,  point (c), the competent authority of the Member 
State shall, in any event, be immediate ly informed if the qualified person referred to 
in Articles 143(1), point (c), and 151 is replaced unexpectedly.  
For the purposes of points (f) and (g), manufacturing authorisation holders shall 
verify compliance, respectively, by the manufacturer or distributors of active 
substances with good manufacturing practice and good distribution practices by 
conducting audits at the manufacturing and distribution sites of the manufacturer and 
distributors of active substances. Manufacturing authorisation holde rs shall verify 
such compliance either by themselves or through an entity acting on their behalf 
under a contract.  
2. The manufacturing authorisation holder  shall ensure that the excipients are suitable 
for use in medicinal products by ascertaining the app ropriate good manufacturing 
practice on the basis of a formalised risk assessment .  
3. The manufacturing authorisation holder  shall ensure that the appropriate good 
manufacturing practice ascertained in accordance with paragraph 2,  is applied. The 
manufact uring authorisation holder  shall document the measures taken in accordance 
with paragraph s 1 and  2. 
Article  148 
Registration  and listing  process of decentralised sites  EN 140  EN 1. The manufacturing authorisation holder of the central site shall register all of its 
decentralised sites in accordance with the provisions of this Article.  
2. The manufacturing authorisation holder of the central site shall request the competent 
authority of the Member State in which the decentralised site is established, to 
register the d ecentralised site.  
3. The marketing authorisation holder may commence the activity in the decentralised 
site in connection with the central site only when the decentralised site is registered 
in the Union database  referred to in Article 18 8(15) and the li nk is made in the 
database with the authorisation of the corresponding central site by the competent 
authority of the Member state where the decentralised site is located.  
4. The competent authority of the Member State in which the decentralised site is 
established, is responsible, in accordance with  Article 188, for the supervision of the 
manufacturing and testing activities carried out in the decentralised site.  
5. For the purpose of paragraph 2 the manufacturing authorisation holder of the central 
site shall submit a registration form that shall include, at least, the following 
information:  
(a) name or corporate name and permanent address of the decentralised site and a 
proof of establishment in the Union;  
(b) the medicinal product s that are subject to manufacturing or testing steps in the 
decentralised site, including the manufacturing or testing activities  to be 
performed for those medicinal products;  
(c) particulars regarding the premises of the decentralised site and the technic al 
equipment to carry out the relevant activities;  
(d) the reference to the manufacturing authorisation of the central site;  
(e) the written confirmation  referred to in Article  144(2), second subparagraph , 
that the manufacturer of the medicinal product has  verified compliance of the 
decentralised site with principles of good manufacturing practice referred to in 
Article  160 by conducting audits . 
6. The competent authority of the Member State supervising the decentralised site 
pursuant to paragraph 4 may decide to carry out an inspection as referred to in   
Article 188 (1), first subparagraph, point (a). In such cases, that competent authority 
shall cooperate with the competent authority of the Member State responsible for the 
supervision of the central site . 
7. Following  the registration of the decentralised site pursuant to paragraph 2, the 
manufacturing authorisation holder of the central site shall list the registered 
decentralised site in the manufacturing authorisation of the central site.  
8. The compe tent authority of the Member State supervising the decentralised site 
pursuant to paragraph 4 shall cooperate with the relevant authorities responsible for 
the supervision of the manufacturing or testing activities under other Union acts as 
regards the fol lowing:  
(a) the medicinal products that were manufactured in a decentralised site, the 
testing or manufacturing of which involves using raw material, medicinal 
products regulated under other relevant Union law, or medicinal products that 
are intended to b e combined with medical devices;  EN 141  EN (b) where specific manufacturing or testing activities are applied to the medicinal 
products containing, consisting or derived from SoHO for which specific 
manufacturing or testing activities are applied within a decentralised site that is 
also authorised under [SoHO Regulation].  
9. Where  relevant, competent authorities of the Member State supervising the central 
and decentralised sites may liaise with the competent authority of the Member State 
responsible for the  supervision of the marketing authorisation . 
Article 14 9 
Conditions related to the safety feature  
1. The safety features referred to in Annex IV shall not be removed or covered, either 
fully or partially, unless the following conditions are fulfilled:  
(a) the manufacturing authorisation holder verifies, prior to partly or fully 
removing or covering those safety features, that the medicinal product 
concerned is authentic and that it has not been tampered with;  
(b) the manufacturing authorisation holder compl ies with Annex IV by replacing 
those safety features with safety features that are equivalent as regards the 
possibility to verify the authenticity, identification and to provide evidence of 
tampering of the medicinal product. Such replacement shall be con ducted 
without opening the immediate packaging.  
Safety features shall be considered equivalent if they:  
(i) comply with the requirements set out in the delegated acts adopted 
pursuant to Article 67 (2); and  
(ii) are equally effective in enabling the verific ation of authenticity and 
identification of medicinal products and in providing evidence of 
tampering with medicinal products;  
(c) the replacement of the safety features is conducted in accordance with 
applicable good manufacturing practice for medicinal p roducts; and  
(d) the replacement of the safety features is subject to supervision by the 
competent authority  of the Member State . 
2. Manufacturing authorisation holders, including those performing the activities 
referred to in paragraph  1, shall be regarde d as producers and therefore held liable for 
damages in the cases and under the conditions set forth in Directive 85/374/EEC.  
Article 150 
Potential ly falsified medicinal products  
1. By derogation from  Article 1(2 ), and without prejudice to  Chapter XII, Section 1 , 
Member States shall take the necessary measures in order to prevent medicinal 
products that are introduced into the Union, but are not intended to be placed on the 
market in the Union, from entering into circulation if there are sufficient groun ds to 
suspect that those products are falsified.  
2. Member States shall organise meetings involving patients ’ and consumers’ 
organisations and, as necessary, Member States’ enforcement officers, in order to EN 142  EN communicate public information about the actions undertaken in the area of 
prevention and enforcement to combat the falsification of medicinal products.  
3. In order to establish what the necessary measures referred to in paragraph 1 are the 
Commission is empowered to  adopt delegated acts in accordance wi th Article 215 , to 
supplement paragraph 1 by specifying  the criteria to be considered and the 
verifications to be made when assessing the potential falsified character of medicinal 
products introduced into the Union but not intended to be placed on the mar ket. 
Article 151 
Availability of qualified person  
1. Member  States shall take all appropriate measures to ensure that the manufacturing 
authorisation  holder  has permanently and continuously at their disposal the services 
of at least one qualified person residing and operating in the Union , in accordance 
with the conditions laid down in Article 152, responsible in particular for carrying 
out the duties specified in Article 153 . 
2. A manufacturing  authorisation  holder  who is a natural person and  personally fulfils 
the conditions laid down in  Annex III may assume the responsibility referred to in 
paragraph  1. 
3. Where the manufacturing authorisation is granted to a central site specified  in the 
application pursuant to Article 144(3), the qualified person referred to in paragraph  1 
shall also be responsible for carrying out the duties specified in Article 153(4) 
regarding the decentralised site s. 
Article 152 
Qualification of qualified person  
1. Member States shall ensure that the qualified person referred to in Article 151 fulfils 
the conditions of qualification set out in Annex III.  
2. The manufacturing authorisation holder and the qualified person shall ensure that the 
practical experience acq uired is appropriate to the types of products to be certified . 
3. The competent authority of the Member State may lay down appropriate 
administrative procedures to verify that a qualified person referred to in the 
paragraph 1 fulfils the conditions set out  in Annex III.  
Article 153 
Responsibilities of the qualified person  
1. Member States shall take all appropriate measures to ensure that the qualified person 
referred to in Article 151, without prejudice to their relationship with the 
manufacturing authorisation  holder , are responsible, subject to  the procedures 
referred to in Article 154, for securing:  
(a) in the case of medicinal products manufactured within the Member States 
concerned, that each production  batch  of medicinal products has been 
manufactured and checked in compliance with the laws in force in that 
Member State and in accordance with the requirements of the marketing 
authorisation ; EN 143  EN (b) in the case of medicinal products imported  from third countries, i rrespective of 
whether they have  been manufactured in the Union that each production batch 
has undergone in a Member State a full qualitative analysis, a quantitative 
analysis of at least all the active substances and all the other tests or checks 
necessar y to ensure the quality of the medicinal products in accordance with 
the requirements of the marketing authorisation.  
The qualified person referred to in Article 151  shall in the case of medicinal products 
intended to be placed on the  Union  market, ensure that the safety features referred to 
in Annex IV have been affixed on the packaging.  
The batches of medicinal products that have undergone the controls referred to in the 
first subparagraph , point (b) , in a Member State shall be exempt from those  controls 
if they are marketed in another Member State, accompanied by the control reports 
signed by the qualified person.  
2. In the case of medicinal products imported from a third country, where appropriate 
arrangements have been made by the Union  with t he exporting country to ensure that 
the manufacturer applies standards of good manufacturing practice at least equivalent 
to those laid down by the Union , and to ensure that the controls referred to in 
paragraph 1, first subparagraph , point (b ), have  been carried out in the exporting 
country, the qualified person may be relieved of responsibility for carrying out those 
controls.  
3. In all cases and particularly where the medicinal products are released for sale, the 
qualified person shall  certify in a regis ter or equivalent format  provided for that 
purpose, that each production batch satisfies the provisions of this Article; that 
register or equivalent format  shall  be kept up to date during the time when  operations 
are carried out and shall  remain at the dis posal of the official representatives  of the 
competent authority of the Member State  for the period specified in the provisions of 
the Member State concerned and in any event for at least five years.  
4. For the purposes of Article 151(3), the qualified person shall, in addition :  
(a) supervise that the  manufacturing or testing activities carried out at the 
decentralised sites comply with principles of relevant good manufacturing 
practices  referred to in Article 160  and conform to the mark eting authorisation;  
(b) provide a written confirmation   as referred to in Article 144(2), second 
subparagraph ; 
(c) notify to the competent authority of the Member State where the decentralised 
site is established, an inventory of the changes that have taken place as regards 
the information provided in the registration form  submitted pursuant to Article 
148(5). 
Any changes that may have an impact on the quality or safety of the medicinal 
products that are manufactured or tested at the decentralised site must be 
notified immediately.  
The Commission is empowered to adopt a delegated act in accordance with Article 
215 to supplement the first subparagraph, point (c) , specifying  the notification made 
by the qualified person.  EN 144  EN Article 15 4 
Professional code of c onduct  
1. Member  States shall ensure that the duties of qualified persons referred to in Article 
151 are fulfilled, either by means of appropriate administrative measures or by 
making such persons subject to a professional code of conduct.  
2. Member States may provide for the temporary suspension of a qualified  person 
referred to in Article 151 upon the commencement of administrative or disciplinary 
procedures against that qualified person  for failure to fulfil its duties set out in 
Article 153 . 
Article 155  
Certificate for export of a medicinal product  
1. At the request of the manufacturer, the exporter or the competent  authorities of an 
importing third country, Member States shall certify that a manufacturer of medicinal 
products is in possessi on of a manufacturing authoris ation . When issuing such 
certificates Member States shall:  
(a) comply with  the prevailing administrative arrangements of the World Health 
Organization;  
(b) for medicinal products intended for export that are already authorised  in their 
territory, supply the summary of product characteristics as approved  by them  in 
accordance with Article 43 . 
2. When the manufacturer is not in posses sion of a marketing authoris ation  it shall 
provide the competent authorities responsible for issuing  the certificate referred to in 
paragraph  1, with a declaration expl aining why a marketing authoris ation  is not 
available.  
SECTION  2 
MANUFACTURING , IMPORT  AND  DISTRIBUTION  OF ACTIVE  SUBSTANCE S 
Article  156 
Manufacture of active substances  
For the purposes of this Directive, manufacture of active substances used in the 
manufacturing process of a medicinal product  shall include both total and partial manufacture 
or import of an active substance and the various processes of dividing up, packag ing or 
presentation prior to its incorporation into a medicinal product, including repackaging or re -
labelling, such as are carried out by a distributor of active substances . 
Article 157  
Registration of importers, manufacturers and distributors of active s ubstances  
1. Importers, manufacturers and distributors of active substances who are established in 
the Union shall register their activity with the competent authority of the Member 
State in which they are established.  EN 145  EN 2. The registration form, to be submitted by electronic means , shall include, at least, the 
following information:  
(a) name or corporate name and permanent address;  
(b) the active substances that are to be imported, manufactured or distributed;  
(c) particulars regarding the premises and the technical equipment for their 
activity.  
3. The persons referred to in paragraph 1 shall submit, by electronic means,  the 
registration form to the competent authority of the Member State  at least 60 days 
prior to t he intended commencement of their activity.  
4. The competent authority of the Member State  may, based on a risk assessment, 
decide to carry out an inspection. If the competent authority of the Member State  
notifies the applicant within 60 days of the recei pt of the registration form that an 
inspection will be carried out, the activity shall not begin before the competent 
authority of the Member State  has notified the applicant that they may commence the 
activity. If within 60 days of the receipt of the regi stration form the competent 
authority of the Member State  has not notified the applicant that an inspection will be 
carried out, the applicant may commence the activity.  
5. Annually, t he persons referred to in paragraph 1 shall communicate, by electronic 
means,  to the competent authority of the Member State an inventory of the changes 
that have taken place as regards the information provided in the registration form. 
Any changes that may have an impact on the quality or safety of the active 
substances that are manufactured, imported or distributed must be notified 
immediately.  
6. The comptetent authority of the Member State shall enter the information provided in 
accordance with paragraph 2 in the Union database referred to in Article 188 (15). 
Article  158 
Conditions for importing active substances  
1. Member States shall take appropriate measures to ensure that the manufacture, 
import and distribution on their territory of active substances, including active 
substances that are intended for export, comply wi th the principles of  good 
manufacturing practice and good distribution practices for active substances  
specified in the delegated acts adopted in accordance with  Article 160 . 
2. Active substances shall only be imported if the following conditions are fulfi lled: 
(a) the active substances have been manufactured in accordance with the principles 
of good manufacturing practice s at least equivalent to those laid down by the 
Union pursuant to  Article 160; and  
(b) the active substances are accompanied by a written confirmation issued by the  
competent authority of the exporting third country stating that : 
(i) the principles  of good manufacturing practice s applicable to the 
manufacturing site manufacturing the exported active substance are at 
least equivalent to those  laid down by the Union pursuant  Article 160;  
(ii) the manufacturing site concerned is subject to regular, strict and  
transparent controls and to the effective enforcement of good EN 146  EN manufacturing practice, including repeated and unannounced inspections, 
so as to ensure a protection of public health at least equivalent to that in 
the Union; and  
(iii) in the event of findings relating to non -compliance, information on such  
findings is supplied by the exporting third country to the Union without 
undue  delay.  
3. The conditions  set out in paragraph 2,  point (b) , shall not apply if the exporting 
country is included in the list referred to in  Article 159(2). 
4. The conditions  set out in paragraph 2,  point (b) , may be waived by any competent 
authority of a Member State for a period not exceeding the validity of the certificate 
of good manufacturing practice  issued in accordance with Article 188(13) where a 
site manufacturing an active substance for export has been inspected by the 
competent authority of  a Member State and was found to comply with the principles 
of good manufacturing practice laid down pursuant to Article 160. 
Article 159 
Active substances imported from third countries  
1. At the request of a third country, the Commission shall assess whether that country’s 
regulatory framework applicable to active substances exported to the Union and the 
respective control and enforcement activities ensure a level of protection of public 
health equivalent to that of the Union.  
The assessment shall take the form of a review of relevant documentation submitted 
by electronic means  and, unless arrangements as referred to in  Article 153 (2) are in 
place that cover this area of activity, that assessment shall include an on -site review 
of the third country’s regulatory system and, if necessary, an observed inspection of 
one or more of the third country’s manufacturing sites for active substances.  
2. Based on the assessment referred to in paragraph 1,  the Commission may adopt 
implementin g acts to include the third country in a list and to  apply the requirements 
set out in the second subparagraph . Those implementing acts shall be adopted in 
accordance with the examination  procedure referred to in Article 214(2) . 
When assessing the third country pursuant to paragraph 1, the Commission shall take 
account of  the following : 
(a) the country’s rules for good manufacturing practice;  
(b) the regularity of inspections to verify compliance with good manufacturing 
practice;  
(c) the effectiveness of enforcement of good manufacturing practice;  
(d) the regularity and rapidity of information provided by the third country relating 
to non -compliant manufacturers of active substances.  
3. The Commission shall verify regularly whether the conditions laid down  in 
paragraph 1 are fulfilled. The first verification shall take place no later than 3 years 
after the  third  country has been included in the list referred to in paragraph  2. 
4. The Commission shall perform the assessment referred to in pargarph 1  and 
verification referred to in paragraph  3 in cooperation with the Agency and the 
competent authorities of the Member States.  EN 147  EN SECTION  3 
PRINCIPLES OF GOOD MA NUFACTURING AND GOOD  DISTRIBUTION PRACTI CES 
Article 160 
Rules applicable to medicinal products and  active substances  
The Commission may adopt implementing ac ts in accordance with Article 21 4(2) to 
supplement this Directive by specifying:  
(a) the principles of good manufacturing and good distribution practices for medicinal 
products complemented , where relevant , by specific measures applicable notably to 
pharmaceutical forms, medicinal  products or manufacturing activities in line with 
good manufacturing principles;  
(b) the principles of good manufacturing and good distribution practices for active  
substances.  
Where relevant, these principles shall be specified in coherence with any principles of good 
practices established under any other Union legal framework.  
Article 161 
Rules applicable to excipients  
The Commission is empowered to adopt delegate d acts in accordance with Article 21 5 to 
supplement this Directive on the formalised risk assessment for ascertaining the appropriate 
good manufacturing practice for excipients referred to in Article 147(2). Such risk assessment 
shall take into account req uirements under other appropriate quality systems as well as the 
source and intended use of the excipients and previous instances of quality defects.  
Chapter  XII 
Wholesale distribution and sale at a distance  
SECTION  1 
WHOLESALE  DISTRIBUTION  AND  BROKERING  OF MEDICINAL  PRODUCTS  
Article  162 
Wholesale d istribution of medicinal products  
1. Without prejudice to Article 5 , Member States shall take all appropriate action to 
ensure that only medicinal products in respect of which a marketing authorisation  has 
been granted in accordance with Union  law are distributed on their territory.  
2. In the case of wholesale distribution  including  storage, medicinal products shall be 
covered by either  a centralised marketing authorisation or by a national marketing 
authorisation . 
3. Distributor s who intend to  import  a medicinal product from another Member State 
shall notify the marketing authorisation holder and the competent authority of the EN 148  EN Member State to which the medicinal product is to be imported of their intention to 
import that medicinal  product.  
4. In the case of medicinal products covered by  a national marketing authorisation , the 
notification referred  to in paragraph 3  to the competent authority of the Member 
State  shall be without prejudice to additi onal procedures provided for in the 
legislation of that Member State and to fees payable to the competent authority of the 
Member State  for examining the notification.  
5. In the case of medicinal products covered by  a centralised marketing authorisation , 
the distributor shall submit the same  notification referred to in paragraph 3 to the 
Agency  which will be in charge  of checking that the conditions laid down in Union 
law on medicinal products and in the marketing authorisations are observed.  For this 
check, a fee shall be payable to the Agency . 
Article  163 
Authorisation for w holesale distribution of medicinal products  
1. The competent authority of the  Member  State  concerned  shall take all appropriate 
measures to ensure that the wholesale distribution of medicinal products is subject to 
an authorisation  to engage in activity as a wholesaler in medicinal products  
(“wholesale distribution authorisation”). The wholesale distribut ion authorisation 
shall indicate  the premises , the medicinal products and the wholesale distribution 
operations  for which it is valid.  
2. Where persons authorised  or entitled to supply medicinal products to the public may 
also, under national law, engage in wholesale business, such persons shall be subject 
to the authorisation  provided for in paragraph  1. 
3. A m anufacturing authorisation  required under Article 142 shall include an 
authorisation  to distribute by wholesal e the medicinal products that it  cover s. A 
wholesale distribution authorisation  shall not give dispensation from the obligation 
set out in Article  142 to hold a manufacturing authorisation  and to comply with the 
conditions set out in that respect, even whe re the manufacturing or import business is 
secondary.  
4. The competent authority of the  Member State concerned  shall enter the information 
relating to the wholesale distribution  authorisations in the Union database referred to 
in Article 188 (15). 
5. The competent authority of the Member State that granted the wholesale distribution 
authorisation for premises located in its territory shall ensure that controls  of the 
persons authorised to engage in activity as a wholesaler in medicinal products, and 
inspec tions of their premises, are carried out at an appropriate frequency.  
The competent authority of  the Member State that granted the wholesale distribution  
authorisation  shall suspend or revoke it if the conditions for granting it set out in 
Article 162  cease to be met . In such event the Member State  shall without undue 
delay inform the other Member States and the Commission thereof.  
6. Where  a competent authority of a  Member State consider s that the conditions for 
granting a wholesale distribution  author isation set out in Article 162 are not met with 
respect to a wholesale distribution  authorisation  granted by the competent authority 
of another Member State, it shall without undue delay  inform the Commission and 
the competent authority of the  other Member State thereof.  The competent authority EN 149  EN of the  other Member State  shall take the measures it considers necessary and shall 
inform the Commission and the competent authority of the  first Member State of 
those measures  and the reasons for them . 
Article 164 
Requirements for  a wholesale distribution authorisation  
1. In order to obtain a wholesale  distribution authorisation, applicants shall submit an 
application by electronic means to the competent authority of the Member State 
concerned.  
2. The application referred to in paragraph 1 shall include the following particulars:  
(a) a confirmation and proof that the applicants have at  their disposal suitable and 
adequate premises, installations and equipment, to ensure proper conservation 
and distr ibution of the medicinal products;  
(b) a confirmation and proof that the applicants have at their disposal  appropriately 
trained  staff, and in particular, a qualified person designated as responsible, 
meeting the conditions provided for by the legislation of the Member State 
concerned;  
(c) an undertaking to fulfil the obligations incumbent on them under the terms of 
Article 166 . 
Article 165 
Granting of  a wholesa le distribution authorisation  
1. The official representatives of the competent authority of the Member State 
concerned shall carry out an inspection to confirm the accuracy of the particulars  
provided in accordance with  Article 164.  
Where  the accuracy of the particulars is confirmed in ac cordance with the first 
subparagraph  and no later than 90 days after the receipt of the application submitted 
in accordance with Article 164, the competent authority of the Member State shall 
grant or refuse a wholesale distribution authorisation.  
2. The co mpetent authority of the Member State concerned may require the applicant to 
supply, by electronic means, all necessary information concerning the particulars for 
granting the wholesale distribution authorisation. In such case, the period laid down 
in paragraph 1 shall be suspended until the requisite additional information is 
supplied.  
3. The competent authority of the Member State may grant a wholesale distribution 
authorisation subject to conditions.  
4. The wholesale distribution  authorisation shall apply only to the  premises specified in 
the authorisation.  
Article 166 
Obligations of the wholesale distribution authorisation holder  
1. Member States shall ensure that  wholesale distribution authorisation holders shall:  EN 150  EN (a) have at their disposal the services of staff who comply with the legal 
requirements existing in the Member State as regards wholesale distribution;  
(b) allow the official representatives of the competent authority of the Member 
State access to their premises , installations and equip ment referred to in  Article 
164(2), point (a) , at all times ; 
(c) obtain , including by financial transactions,  their supplies of medicinal products 
only from persons who are themselves in possession of a wholesale  distribution 
authorisation  in the Union or a manufacturing  authorisation  referred to  in 
Article 163(3); 
(d) supply , including by financial transaction,  medicinal products only to persons 
who are themselves wholesale  distribution authorisation holders  or who are 
authorised  or entitled to supply medicinal products to the public ; 
(e) verify that the medicinal products received are not falsified by checking the 
safety features on the outer packaging, in accordance with the requirements 
laid down in the delegated acts adopted p ursuant to  Article 67 (2), second 
subparagraph ; 
(f) have an emergency plan that ensures effective implementation of any recall 
from the market ordered by the competent authorities or carried out in 
cooperation with the manufacturer or marketing authorisatio n holder for the 
medicinal product concerned;   
(g) keep records giving, for any medicinal products received, dispatched or 
brokered, at least the following information:  
(i) the date of receipt, dispatch or brokering of the medicinal product,  
(ii) the name of the medicinal product,  
(iii) the quantity of the medicinal product received, supplied or brokered,  
(iv) the name and address of the supplier of the medicinal product or the 
consignee, as appropriate,  
(v) the batch number of the medicinal products, at le ast for medicinal 
products bearing the safety features referred to in Article 67 ; 
(h) keep the records referred to in point  (g) available to the competent authorities  
of the Member States , for inspection purposes, for a period of five years;  
(i) comply with the principles of good distribution practices  for medicinal 
products laid down in  Article 160; 
(j) maintain a quality system setting out responsibilities, processes and risk 
management measures in relation to their activities;  
(k) immediately i nform the competent authority  of the Member State  and, where 
applicable, the marketing authorisation holder, of medicinal products they 
receive or are offered that they identify as falsified or suspect to be falsified;  
(l) continuously guarantee the appropriate and continued supply of an adequate 
range of medicinal products to meet the requirements of a specific 
geographical area, and deliver the supplies requested over the whole of the area 
in question, within a reasonable timeframe, which shall be d efined in the 
national legislation;  EN 151  EN (m) cooperate with marketing authori sation holders and competent authorities of 
the Member States on the security of supply.  
2. Where the medicinal product is obtained from  another wholesale distributor, the 
wholesale di stribution authorisation holders obtaining the product shall verify 
compliance with the principles of good distribution practices by the supplying 
wholesale distributor. This includes verifying whether the supplying wholesale 
distributor holds a wholesale distribution authorisation, or a manufacturing 
authorisation referred to in Article 163(3). 
3. Where the medicinal product is obtained from a manufacturer or importer, wholesale 
distribution authorisation holders shall verify that the manufacturer or importer holds 
a manufacturing authorisation.  
4. Where the medicinal product is obtained through brokering of medicinal products, 
wholesale distribution authorisation holders shall verify that the person brokering the 
medicinal product fulfils the requirem ents set out in Article 171 . 
Article 167 
Obligation of s upply of medicinal products  
1. With regard to the supply of medicinal products to pharmacists and persons 
authorised or entitled to supply medicinal products to the public , Member States shall 
not imp ose upon the wholesale  distribution authorisation holder  that has been granted 
by another Member State any obligation, in particular public service obligations, 
more stringent than those they impose on persons whom they have themselves 
authorised to engage  in equivalent activities.  
2. The wholesale distributors of a medicinal prod uct placed on the market in a Member 
State shall, within the limits of their responsibilities, ensure appropriate and 
continued supplies of that medicinal product to pharmacies and  persons authorised to 
supply medicinal products so that the needs of patients in the Member State in 
question are covered . 
3. The arrangements for implementing this Article should, moreover, be justified on 
grounds of public health protection and be propo rtionate in relation to the objective 
of such protection, in compliance with the Treaty rules, particularly those concerning 
the free movement of goods and competition.  
Article 168 
Documentation accompanying supplied medicinal products  
1. For all supplies of medicinal products to a person authorised  or entitled to supply 
medicinal products to the public in the Member State concerned, the authorised  
wholesaler must enclose a document that makes it possible to ascertain the 
following : 
(a) the da te of the supply ; 
(b) the name and pharmaceutical form of the medicinal product ; 
(c) the quantity of the medicinal product  supplied ; 
(d) the name and address of the supplier of the medicinal product  and consign ee; EN 152  EN (e) the batch number of the medicinal prod ucts at least for products bearing the 
safety features referred to in Article  67. 
2. Member States shall take all appropriate measures to ensure that persons authorised  
or entitled to supply medicinal products to the public are able to provide information 
that makes it possible to trace the distribution path of every medicinal product.  
Article 169 
National requirements on wholesale distribution  
The provisions of this Chapter  shall not prevent the application of more stringent 
requirements laid down by Member States in respect of the wholesale distribution of:  
(a) narcotic or psychotropic substances ; 
(b) medicinal products derived from blood ; 
(c) immunological medicinal products ; and  
(d) radiopharmaceuticals.  
Article 170 
Wholesale distribution to third countries  
In the case of wholesale distribution of medicinal products to third countries, Article s 162 and 
166(1), point (c) , shall not apply.  
Where wholesale distributors supply medicinal products to persons in third countries, they 
shall ensure that such supplies are only made to persons who are authorised or entitled to 
receive medicinal products for wholesale distribution or supply to the public in accordance 
with the applicable legal and administrative provisions of the third country concerned.  
Article 168 shall apply to the supply of medicinal products to persons in third countries 
authorised or entitled to supply medicinal products to the public . 
Article 171 
Brokering medicinal products  
1. Persons brokering medicinal products shall ensure that the brokered medicinal 
products are covered by a valid  marketing authorisation . 
Persons brokering medicinal products shall have a permanent address and contact 
details in the Union, so as to ensure accurate identification, location, communication 
and supervision of their activities by competent authorities  of the Member States . 
The requirements set out in Article 166 (1), points (e) to (j) , shall apply  mutatis 
mutandis  to the brokering of medicinal products.  
2. Persons may only broker medicinal products if they are registered with the 
competent authority of the Member State where they have  their permanent address 
referred to in paragraph  1, second subpa ragraph . Those persons shall submit, by 
electronic means,  at least, their name, corporate name and permanent address to the 
competent authority  in order to register. They shall notify, by electronic means,  the 
competent authority of the Member State  of any changes thereof without delay.  EN 153  EN The competent authority of the Member State  shall enter the information referred to 
in the first subparagraph in a register that shall be public ly available . 
3. The principles  referred to in  Article 160 shall include specific provisions for 
brokering.  
4. Inspections referred to in Article  188 shall be carried out under the responsibility of 
the Member State where the person brokering medicinal products is registered.  
If a person brokering medicinal products does not comply with the requirements set 
out in this Article, the competent authority of the Member State  may decide to 
remove that person from the register referred to in paragraph  2. In such event,  the 
competent authority of the Member State  shall notify that person thereof.  
SECTION  2 
SALE  AT A DISTANCE  TO THE  PUBLIC  
Article 172 
General requirements for sale at distance  
1. Without prejudice to national legislation prohibiting the offer for sale at a distance of 
prescription medicinal products to the public by means of information society 
services, Member States shall ensure that medicinal products are offered for sale at a 
distance to the public by means of services as defined in Directive (EU) 2015/1535  
of the European Parliament and of the Council41 laying down a procedure for the 
provision of information in the field of technical regulations and of rules on 
Information Soci ety services under the following conditions:  
(a) the natural or legal person offering the medicinal products is authorised or 
entitled to supply medicinal products to the public , also at a distance, in 
accordance with national legislation of the Member State in which that person 
is established;  
(b) the person referred to in point (a) has notified the Member State in which that 
person is established of at least the following information:  
(i) name or corporate name and permanent address of the place of act ivity 
from where those medicinal products are supplied;  
(ii) the starting date of the activity of offering medicinal products for sale at a 
distance to the public by means of information society services;  
(iii) the address of the website used for that purp ose and all relevant 
information necessary to identify that website;  
(iv) if applicable, the prescription status  in accordance with Chapter IV of the 
medicinal products offered for sale at a distance to the public by means 
of information society services.  
Where appropriate, that information shall be updated;  
                                                 
41 Directive (EU) 2015/1535 of the European Parliament and of the Council of 9 September 2015 laying 
down a procedure for the provision of information in the field of technical regulations and of rules on 
Informa tion Society services (OJ L 241, 17.9.2015, p. 1).  EN 154  EN (c) the medicinal products comply with the national legislation of the Member 
State of destination in accordance with Article 5 (1); 
(d) without prejudice to the information requirements set out in Direc tive 
2000/31/EC of the European Parliament and of the Council42, the website 
offering the medicinal products contains at least:  
(i) the contact details of the competent authority of the Member State  or the 
authority notified pursuant to point (b);  
(ii) a hyperlink to the website referred to in  Article 174 of the  Member State 
of establishment ; 
(iii) the common logo referred to in Article 173  clearly displayed on every 
page of the website that relates to the offer for sale at a distance to the 
public of medicinal products. The common logo shall contain a hyperlink 
to the entry of the person in the list referred to in Article 174(1) , point 
(c). 
2. Member States may impose conditions, justified on grounds of public health 
protection, for the retail supply on  their territory of medicinal products for sale at a 
distance to the public by means of information society services.  
3. Without prejudice to Directive 2000/31/EC and the requirements set out in this 
Section , Member States shall take the necessary measures to ensure that other 
persons than those referred to in paragraph  1 that offer medicinal products for sale at 
a distance to the public by means of information society services and that operate on 
their territory are subject to effective, proportion ate and dissuasive penalties.  
Article 17 3 
Requirements for common logo  
1. A common logo shall be established that is recognisable throughout the Union, while 
enabling the identification of the Member State where the person offering medicinal 
products for s ale at a distance to the public is established. That logo shall be clearly 
displayed on websites offering medicinal products for sale at a distance to the public 
in accordance with Article 172(1), point (d) . 
2. In order to harmonise the functioning of the common logo, the Commission shall 
adopt implementing acts regarding:  
(a) the technical, electronic and cryptographic requirements for verification of the 
authenticity of the common logo;  
(b) the design of the common logo.  
Those implementing acts shall, where necessary, be amended to take account of 
technical and scientific progress. Those implementing acts shall be adopted in 
accordance with the procedure referred to in Article 214(2) . 
                                                 
42 Directive 2000/31/EC of the European Parliament and of the Council of 8 June 2000 on certain legal 
aspects of information society services, in particular electronic commerce, in the Internal Market 
(Directive on electronic commerce (OJ L 178, 17.7.2000, p. 1).  EN 155  EN Article  174 
Information about the supp ly at distance to the public  
1. Each Member State shall set up a website providing at least the following:  
(a) information on the national legislation applicable to the offering of medicinal 
products for sale at a distance to the public by means of information society 
services, including information on the fact that there may be differences 
between Member States regarding classification of medicinal products and the 
conditions for their supply;  
(b) information on the purpose of the common logo;  
(c) the list of persons offering the medicinal products for sale at a distance to the 
public by means of information society services in accordance with Article 172 
as well as their website addresses;  
(d) background information on the risks related to medicinal  products supplied 
illegally to the public by means of information society services.  
This website shall contain a hyperlink to the website referred to in paragraph  2. 
2. The Agency shall set up a website providing the information referred to in paragraph 
1, first subparagraph, points (b) and (d), information on the Union law applicable to 
falsified medicinal products as well as hyperlinks to the websites of the Member 
States  referred to in paragraph  1. The Agency’s website shall explicitly mention that 
the Member States’ websites contain information on persons authorised or entitled to 
supply medicinal products by sales  at a distance  in the Member State concerned.  
3. The Commission shall, in cooperation  with the competent  authorities, conduct or 
promote information campaigns aimed at the general public on the dangers of 
falsified medicinal products. Those campaigns shall raise consumer awareness of the 
risks related to medicinal products supplied illegal ly by sales  at a distance  as well as  
of the functioning of the common logo  and the  websites referred to in paragraphs 1 
and 2 . 
Chapter XIII 
Advertising  
Article  175 
Definition of advertising of medicinal products  
1. For the purposes of this Chapter , ‘advertising of medicinal products’ shall include 
any form of door -to-door information, canvassing activity or inducement designed to 
promote the prescription, supply, sale or consumption of medicinal products . 
It shall include in particular:  
(a) the advertising of medicinal products to the general public ; 
(b) advertising of medicinal products to persons qualified to prescribe , administer  
or supply them ; 
(c) visits by medical sales representatives to persons qualified to prescribe 
medicinal products ; 
(d) the supply of samples  of medicinal products ; EN 156  EN (e) the provision of inducements to prescribe or supply medicinal products by the 
gift, offer or promise of any benefit or bonus, whether in money or in kind, 
except when their intrinsic value is minimal ; 
(f) sponsorship of promotional meetings attended by persons qualified to prescribe 
or supply medicinal products ; 
(g) sponsorship of scientific congresses attended by persons qualified to prescribe 
or supply medicinal products and in particular payment of their travelling and 
accommodation expenses in connection therewith ; 
(h) advertising related to medicinal products, that does not refer to specific 
medicinal product s. 
2. The following are not covered by this Chapter : 
(a) the labelling and package leaflets, which are subject to the provisions of 
Chapter VI; 
(b) correspondence , possibly accompanied by material of a non -promotional 
nature, needed to answer a specific question about a particular medicinal 
product ; 
(c) factual , informative announcements and reference material relating, for 
example, to pack changes, adverse -reaction warnings as part of general drug 
precautions, trade catalogues and price lists, provided they include no product 
claims ; 
(d) information  relating to human health or diseases, provided that there is no 
reference, even indirect, to medicinal products.  
Article 1 76 
General provisions on advertising of medicinal products  
1. Member States shall prohibit any advertising of a medicinal product in respect of 
which a  marketing authorisation has not been granted.  
2. All parts of the advertising of a medicinal product must comply with the particulars 
listed in the summary of product characteristics.  
3. The advertising of a medicinal product:  
(a) shall encourage the rational use of the medicinal product, by presenting it 
objectively and without exaggerating its properties ; 
(b) shall be accurate, verifiable and  not be misleading.  
4. Any form of advertising that aims to highlight negatively another medicinal product 
shall be prohibited. Advertising  that suggest s that a medicinal product is safer or 
more effective than  another medicinal product shall also be prohibited , unless 
demonstra ted and supported by the summary of product characteristics . 
Article 177  
Restrictions on advertising of medicinal products  
1. Member States shall prohibit the advertising to the general public of medicinal 
products that: EN 157  EN (a) are available on medical prescription only, in accordance with  Chapter  IV; 
(b) contain substances classified  as psychotropic or narcotic within the meaning of  
international conventions . 
2. Medicinal products may be advertised to the general public where, by virtue of their 
composition and purpose, they are intended and designed for use without the 
intervention of a medical practitioner for diagnostic purposes or for the prescription 
or monitoring of treatment, with the advice of the pharmacist, if necess ary. 
3. Member States shall be entitled to ban, on their territory, advertising to the general 
public of medicinal products the cost of which may be reimbursed.  
4. The prohibition contained in paragraph 1 shall not apply to vaccination campaigns 
carried ou t by the industry and approved by the competent authorities of the Member 
States.  
5. The prohibition referred to in paragraph 1 shall apply without prejudice to Article 21 
of Directive 2010/13/EU . 
6. Member States shall prohibit the direct distribution of medicinal products to the 
public by the industry for promotional purposes.  
Article 178 
Advertising to the general public  
1. Without prejudice to Article 177 , all advertising to the general public of a medicinal 
product shall:  
(a) be set out in such a way that it is clear that the message is an advertisement and 
that the product is clearly identified as a medicinal product;  
(b) include the following minimum information:  
(i) the name of the medicinal product, as well as the common name if the 
medicinal produ ct contains only one active substance ; 
(ii) the information necessary for correct use of the medicinal product ; 
(iii) an express, legible invitation to read carefully the instructions on the 
package leaflet or on the outer packaging, as the case may be.  
2. Member States may decide that the advertising of a medicinal product to the general 
public may, notwithstanding paragraph  1, include only the name of the medicinal 
product or its active substance , or the trademark if it is intended solely as a reminder . 
Article 179 
Restrictions  on advertising to the general public  
1. The advertising of a medicinal product to the general public  shall not contain any 
material that: 
(a) gives the impression that a medical consultation or surgical operation is 
unnecessary, in  particular by offering a diagnosis or by suggesting treatment by 
mail;  EN 158  EN (b) suggests that th e effects of taking the medicin al product  are guaranteed, are 
unaccompanied by adverse reactions or are better than, or equivalent to, those 
of another treatment or  medicinal product;  
(c) suggests that the health of the subject can be enhanced by taking the medicin al 
product ; 
(d) suggests that the health of the subject could be affected by not taking the 
medici nal product ; 
(e) is directed exclusively or principally a t children;  
(f) refers to a recommendation by scientists, healthcare  professionals or persons 
who are neither of the foregoing but who, because of their celebrity, could 
encourage the consumption of medicinal products;  
(g) suggests that the medicinal produ ct is a food, cosmetic or other consumer 
product;  
(h) suggests that the safety or efficacy of the medicinal product is due to the fact 
that it is natural;  
(i) could, by a description or detailed representation of a case history, lead to 
erroneous self -diagnosis;  
(j) refers, in improper, alarming or misleading terms, to claims of recovery;  
(k) uses, in improper, alarming or misleading terms, pictorial representations of 
changes in the human body caused by disease or injury, or of the action of a 
medicinal product on the human body or parts thereof.  
2. The prohibition  set out in the paragraph  1, point (d),  shall not apply to the 
vaccination campaigns referred to in Article 177 (4). 
Article  180 
Advertising to persons qualified to prescribe , administer  or supply medicinal product s 
1. Any advertising of a medicinal product to persons qualified to prescribe , administer  
or supply such products shall include:  
(a) essential information compatible with the summary of product characteristics;  
(b) the supply prescription status  of the medicinal product.  
Member States may also require such advertising to include the selling price or 
indicative price of the various presentations and the conditions for reimbursement by 
social security bodies.  
2. Member States ma y decide that the advertising of a medicinal product to persons 
qualified to prescribe , administer  or supply such products may, notwithstanding 
paragraph  1, include only the name of the medicinal product, or its international non -
proprietary name, where this exists, or the trademark, if it is intended solely as a 
reminder.  
Article  181 
Supporting documentation  for advertising  to persons qualified to prescribe , administer  or 
supply medicinal product s EN 159  EN 1. Any documentation relating to a medicinal product that is transmitted as part of the 
promotion of that medicinal  product to persons qualified to prescribe , administer  or 
supply it shall include, as a minimum, the particulars listed in Article 180(1) and 
shall state the date on which it was drawn up or last re vised.  
2. All the information contained in the documentation referred to in paragraph 1 shall 
be accurate, up -to-date, verifiable and sufficiently complete to enable the recipient to 
form their own opinion of the therapeutic value of the medicinal product concerned.  
3. Quotations as well as tables and other illustrative matter taken from medical journals 
or other scientific works for use in the documentation referred to in paragraph 1 shall 
be faithfully reproduced and the precise sources indicated.  
Article  182 
Obligations related to medical sales representatives  
1. Medical sales representatives shall be given adequate training by the undertaking  that 
employs them and shall have sufficient scientific knowledge to be able to provide 
information that is precise and as complete as possible about the medicinal products 
that they promote.  The information provided by medical sales representatives shall 
be in accordance with Article 176.  
2. During each visit, medical sales representatives shall give the pe rsons visited, or 
have available for them, summaries of the product characteristics of each medicinal 
product they present together, if the legislation of the Member State so permits, with 
details of the price and conditions for reimbursement referred to i n Article 180 (1), 
second subparagraph . 
3. Medical sales representatives shall transmit to the scientific service referred to in 
Article 187 (1) any information about the use of the medicinal products they 
advertise, with particular reference to any adverse reactions reported to them by the 
persons they visit.  
Article 183 
Promotion of medicinal products  
1. Where medicinal products are being promoted to persons qualified to prescribe or 
supply them, no gifts, pecuniary advantages or benefits in kind may be sup plied, 
offered or promised to such persons unless they are inexpensive and relevant to the 
practice of medicine or pharmacy.  
2. Hospitality at sales promotion events shall always be strictly limited to their main 
purpose and must not be extended to persons  other than persons qualified to 
prescribe or supply medicinal products . 
3. Persons qualified to prescribe or supply medicinal products shall not solicit or accept 
any inducement prohibited under paragraph 1 or contrary to paragraph  2. 
4. Existing measures  or trade practices in Member States relating to prices, margins and 
discounts shall not be affected by the rules set out in  paragraph s 1, 2 and 3 . 
Article 1 84 
Hospitality at scientific events  EN 160  EN The provisions of Article 183(1) shall not prevent hospitality being offered, directly or 
indirectly, at events for purely professional and scientific purposes . Such hospitality shall 
always be strictly limited to the main scientific objective of the event . It must not be extended 
to persons other than persons qualifi ed to prescribe or supply medicinal products . 
Article  185 
Provision of samples of medicinal products  
1. Free samples of medicinal products  shall be provided on an exceptional basis only to 
persons qualified to prescribe them and on the following conditions:  
(a) the number of samples for each medicinal product each year on prescription 
shall be  limited;  
(b) any supply of samples shall be in r esponse to a written request, signed and 
dated, from the persons qualified to prescribe or supply  medicinal products ; 
(c) the persons qualified to supply  samples shall maintain an adequate system of 
control and accountability;  
(d) each sample shall be no l arger than the smallest presentation on the market;  
(e) each sample shall be marked ‘free medical sample — not for sale’ or shall 
show some other wording having the same meaning;  
(f) each sample shall be accompanied by a copy of the summary of product 
characteristics;  
(g) no samples of medicinal products containing substances classified as  
psychotropic or narcotic within the meaning of international conventions may 
be supplied.  
2. On an exceptional basis,  free samples of medicinal products not s ubject to medical 
prescription may also be provided to persons qualified to supply them , subject to the 
conditions of paragraph  1. 
3. Member States may also place further restrictions on the distribution of samples of 
certain medicinal products.  
Article  186 
Implementation of advertising provisions by the Member States  
1. Member States shall ensure that there are adequate and effective methods to monitor 
the advertising of medicinal products. Such methods, which may be based on a 
system of prior vetting, shall in any event include legal provisions under which 
persons or organisations  regarded under national law as having a legitimate interest 
in prohibiting any advertisement inconsistent with this Chapter , may take legal action 
against such advertisement, or bring such advertisement before the competent 
authority of the Memb er State  either to decide on complaints or to initiate 
appropriate legal proceedings.  
2. Under the legal provisions referred to in paragraph  1, Member States shall confer 
upon the courts or competent  authorities of the Member States  powers enabling 
them, i n cases where they deem such measures to be necessary, taking into account 
all the interests involved, and in particular the public interest:  EN 161  EN (a) to order the cessation of, or to institute appropriate legal proceedings for an 
order for the cessation of, mi sleading advertising ; or 
(b) if misleading advertising has not yet been published but public ation is 
imminent, to order  the prohibition of, or to institute appropriate legal 
proceedings for an order for the prohibition of, such public ation . 
Member States shall confer upon the courts or competent authorities of the Member 
States the powers referred to in the first subparagraph, points (a) and (b),  even 
without proof of actual loss or damage or of intention or negligence on the part of the 
advertiser.   
3. Member States shall make provision for the measures referred to in paragraph 2 to be 
taken under an accelerated procedure, either with interim effect or with definitive 
effect.  
It shall be for each Member State to decide which of the two options set out in t he 
first subparagraph to select.  
4. Member States may confer upon the courts or competent  authorities of the Member 
States  powers enabling them, with a view to eliminating the continuing effects of 
misleading advertising the cessation of which has been ord ered by a final decision:  
(a) to require public ation of that decision in full or in part and in such form as they 
deem adequate ; 
(b) to require in addition the public ation of a corrective statement.  
5. The p aragraph s 1 to 4 shall not exclude the voluntary control of advertising of 
medicinal products by self -regulatory bodies and recourse to such bodies, if 
proceedings before such bodies are possible in addition to the judicial or 
administrative proceedings referred to in paragraph  1. 
Article 187 
Implementat ion of advertising provisions by the marketing authorisation holder  
1. The marketing authorisation holder s shall establish, within their undertaking or not -
for-profit entities,  a scientific service in charge of information about the medicinal 
products  that they place  on the market.  
2. The marketing authorisation holder shall:  
(a) keep available for, or communicate to, the competent  authorities of the 
Member States  or bodies responsible for monitoring advertising of medicinal 
products, a sample of all advert isements emanating from its undertaking or not -
for-profit entities  together with a statement indicating the persons to whom it is 
addressed, the method of dissemination and the date of first dissemination ; 
(b) ensure that advertising of medicinal products by their undertaking or not -for-
profit entities  conforms to the requirements of this Chapter ; 
(c) verify that medical sales representatives employed by their undertaking or not -
for-profit entities  have been adequately trained and fulfil the obligations 
imposed upon them by Article 18 2, paragraphs 2 and 3 ; 
(d) supply the competent  authorities of the Member States  or bodies responsible 
for monitoring advertising of medicinal products with the information and 
assistance they require to carry out their responsibilities ; EN 162  EN (e) ensure that the decisions taken by the competent  authorities of the Member 
States  or bodies re sponsible for monitoring advertising of medicinal products 
are immediately and fully complied with.  
3. The Member States shall not prohibit the co -promotion of a medicinal product by the 
marketing authorisation holder s and one  or more companies nominated by them . 
Chapter XIV 
Supervision  and controls  
SECTION  1 
SUPERVISION  
Article 188  
System of supervision  and inspections  
1. The competent authority of the Member State concerned shall, in cooperation with 
the Agency and where relevant, other Member States , ensure compliance with the 
rules of this D irective, namely the principles of good manufacturing practice and 
good distribution practice s referred to in Article s 160 and 161. 
For the purposes of the first subparagraph, the competent authority of the Member  
State  shall have in place a system of supervision that shall include the following 
measures:  
(a) announced and , where appropriate , unannounced  on-site inspections;  
(b) remote inspections, whe re justified;  
(c) compliance control measures;  
(d) the effectiv e follow -up of the measures referred to in points (a), (b) and (c) . 
2. The competent authorit ies of the Member State concerned, and the Agency shall 
exchange  information on the inspections  referred to in paragraph  1, second 
subparagraph,  point s (a) and (b) , that are planned or that have been conducted and 
shall cooperate in the coordination of such inspections.   
3. The competent authority of the Member State shall ensure that the measures referred 
to in paragraph 1, second subparagraph , are carried out by the official representatives  
of the competent authority of the Member State : 
(a) at an appropriate  frequency based on risk, at the premises or on the activities of  
manufacturers of medicinal products , located in the Union or in third countries, 
including wh ere appropriate at central or decentralised site(s), and at the 
premises or on the activities of  wholesale distributors of medicinal products 
located in the Union ; 
(b) at an appropriate frequency based on risk, at the premises or on the activities  of 
the manufacturers of active substances located in the Union or in third 
countries and at the premises or on the activities of importers , or distributors of 
active substances, located in the Union .  
4. To determine the appropriate frequency based on ris k referred to in paragraph 3, 
point (b) , the competent authority of the Member State may:  EN 163  EN (a) rely on inspecti on reports from trusted non -Union  regulatory authorities;  
(b) take into account whether the manufacturer of active substance is located in a 
third  country included in the list referred to in Article 159(2). 
5. Whe re the competent authority of the M ember State  considers it necessary, in 
particular whe re there are grounds for suspecting non -compliance with the rules of 
this Directive, including with the principles of good manufacturing practice and good 
distribution practices , referred to in Article s 160 and 161, it may have its official 
representatives carry  out the measures referred to in paragraph 1, second 
subparagraph  at the premises or on the activities  of: 
(a) manufacturers or importers of medicinal products applying for a manufacturing 
import authorisation or wholesale distributors applying for a wholesale 
distribution authorisation;  
(b) manufacturers of active substance applying for a regist ration or manufacturing 
sites applying for a registration as decentralised sites;  
(c) marketing authorisation holders;  
(d) distributors of  medicinal products or  active substances located in third 
countries;  
(e) manufacturers of excipients, functional excipients, starting materials or 
intermediate  product s located in its territory or in a third country;  
(f) importers of excipients , functional excipients, starting materials or intermediate  
product s located in its territory;  
(g) persons  broker ing medicina l products located in its territory . 
6. The measures referred to in paragraph  1, second subparagraph,  may also be carried 
out at the request of a competent authority of a Member State, the Commission or the 
Agency  in the Union or in third countries or, where appropriate, by asking an 
Official Medicines Control Laboratory or a laboratory that Member State has 
designated for that purpose to carry out tests on samples.  
7. Each Member State shall ensure  that official representatives  of its competent 
authorities are  empowered and required to carry out one or more of the following 
activities:  
(a) inspect the manufacturing or commercial establishments of manufacturers of 
medicinal products, of active substances or of excipients, and any laboratories 
employed  by the manufacturing authorisation holder  to carry out verifications 
and controls  pursuant to Article 8 ; 
(b) take samples during an inspection or request samples as part of the measures 
referred to in paragraph  1, second subparagraph,  including any required 
essential testing material or reagent  with a view to independent tests being 
carried out by an Official Medicines Control Laboratory or a laboratory that a 
Member States has  designated for that purpose;  
(c) inspect the premises, rec ords, documents and pharmacovigilance system master 
file of the marketing authorisation holder or any undertaking  employed by the 
marketing authorisation holder to perform the activities described in  Chapter 
IX. EN 164  EN 8. Inspections referred to in paragraph  1, second subparagraph,  points (a) and (b) , shall 
be carried out in accordance with the principles  referred to in  Article  190. 
9. After every inspection carried out  in accordance with paragraph s 3 and  5, the 
competent authority of the Member State  concerned  shall issue a report on the 
compliance  of the manufacturing activities inspected  with the good  manufacturing 
practice and good distribution practices referred to in Article s 160 and 161, as 
applicable.  
10. The competent authority  of the Member State  that had its official representatives  
carry  out inspections  in accordance with  paragraphs 3  and 5, shall share its draft 
report with  the inspected entity.  
11. Before adopting the  report, the competent authority of the Member State  shall give 
the inspected entity the opportunity to submit comments.  
12. Without prejudice to any arrangements that may have been concluded between the 
Union and third countries, a Member State, the Commission or the Agency may 
require a manufacturer of a medicinal product or of an active substance  established in 
a third country to submit to an inspection as referred to in this Article.  
13. Within 90 days of the conclusion of  an inspection carried out in accordace with  
paragraph s 3 and 5 the competent authority of the Member State  concerned  shall 
issue to the inspected entity  a certificate of compliance of  good manufacturing 
practice or good distribution practices if the outcome of that inspection shows that 
the inspected entity  complies with the principles of good manufacturing practice or 
good distribution practices referred to in Article s 160 and 161 . 
14. If the outcome of the inspection carried out in accordance with paragraph 3, 4 and 5  
shows that the inspected entity does not comply with the principles of good 
manufacturing practice or good distribution practices as referred to in Articles  160 
and 161, the competent authority of the Member State  concerned  shall issue a 
statement of non -compliance.  
15. The competent authority of the Member State  shall enter the certificates of good 
manufacturing practice or good distribution practices in the relevant  Union database 
managed by the Agency on behalf of the Union. Pursuant to Article 157, the 
competent autho rity of the  Member States shall also enter information in that 
database regarding the registration of importers, manufacturers and distributors of 
active substances and decentralised sites performing decentralised manufacturing 
activities , including their respective  database link to the manufacturing authorisation 
of the central site . 
16. If the outcome of the inspection carried out in accordance with paragraph  5 is that the 
inspected entity does not comply with the legal requirements or the principles of 
good manufacturing practice or good distribution practices as referred to in Article s 
160 and 161 the information shall be entered in the Union database as referred to  in 
paragraph  15. 
17. If the outcome of the activity carried out  in accordance with  paragraph  7, point (c) , is 
that the marketing authorisation holder does not comply with the pharmacovigilance 
system as described in the pharmacovigilance system master file and with Chapter 
IX, the competent authority of the Member State c oncerned shall bring the 
deficiencies to the attention of the marketing au thorisation holder and give the 
marketing authorisation holder  the opportunity to submit comments.  EN 165  EN In such case the Member State concerned shall inform the other Member States, the 
Agency and the Commission  accordingly . 
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  as laid down in Article  206. 
Article 189  
Cooperation on inspections  
1. Upon  request by one or more competent authorities, inspections referred  to in Article 
188, paragraphs 3 and 5, may be carried out by official representatives  from more 
than one Member State, together with the inspectors of the Agency in accordance 
with Article  52(2), point (a)  of [revised Regulation  (EC) 726 /2004 ] (‘the joint 
inspection ’). 
The competent authority of the Member State receiving a request for a j oint 
inspection, shall make all reasonable efforts to accept such a request, and coordinate 
and support that joint inspection, where:  
(a) it is demonstrated, or there are reasonable ground for suspecting, that the 
activities carried out on the territory of the Member State receiving the request 
pose a risk to the safety and quality in the Member State  of the competent 
authority requesting the joint inspection ; 
(b) competen t authorities of the Member State requesting the joint inspection 
require specialist technical expertise available in the  Member State receiving 
the joint inspection request ; 
(c) the competent authority of the Member State receiving the request agrees that  
there are other reasonable grounds such as training of inspectors, sharing of 
good practice, for for conducting a joint inspection . 
2. The competent authorities participating in a joint inspection shall conclude an 
agreement prior to the inspection that  defines at least the following:  
(a) the scope and obj ective of the joint inspection;  
(b) the roles of the participating inspectors during and following the inspection, 
including the designation of an authority leading the inspection;  
(c) the powers and res ponsibilities of each of the competent authorities.  
3. The competent authorities participating in the joint inspection shall commit 
themselves in that agreement to jointly accept  the results of the inspection.  
4. Whe re the joint inspection is conducted in one of the Member States, the competent 
authority leading the joint inspection shall ensure that the joint inspection  is carried 
out in accordance with the national legislation of the Member State in which th e joint 
inspection takes place.  
5. Member States may set up joint inspection programmes to facilitate routine joint 
inspections. Member States may operate such programmes under a agreement as 
referred to in paragraph s 2 and  3. 
6. A competent authority of a Member St ate may request another competent authority 
to take over one of its  inspections referred to in Article 188, paragraphs 3 and 5 . EN 166  EN 7. The other competent authority of the Member State  shall communicate to the 
requesting competent authority whether it accepts the request to conduct the 
inspection within 10 days. Where it accepts, it shall be responsible as the competent 
authority to carry out the inspections pursuant to this Section . 
8. For the purposes of paragraph  6, and when the request is agreed , the requesting 
competent authority shall, in a timely manner, submit the relevant information 
necessary to conduct the inspection to the competent authority of the Member State 
that accept ed the request.  
Article 190 
Inspection guidelines  
1. The Commission may adopt implementing acts to lay  down the principles applicable 
to: 
(a) the system of supervision referred to in Article 188(1); 
(b) the joint inspections referred to in  Article 189(1); 
(c) the exchange of information and cooperation in the coordination of inspections 
in the system of supervision between the Member States and the Agency; and 
(d) trusted non -Union  regulatory authorities . 
The implementing  acts referred to in the first subparagraph  shall be adopted in 
accordance with the procedure referred to in Article 214(2) . 
2. Member States shall, in cooperation with the Agency, establish the form and content 
of the manufacturing  authorisation referred to in Article 142(1) and of the  wholesale 
distribution authorisation referred to in Article 16 3(1), of the report referred to in 
Article 188 , of the certificates of good manufacturing practice and of the certificates 
of good distribution practices referred to in  Article 188(13). 
SECTION  2 
CONTROLS  
Article 191 
Controls on medicinal products  
Member States shall take all appropriate measures to ensure that the marketing authorisation  
holder  for a medicinal product and, where appropriate, the manufacturing authorisation  
holder , furnish proof of the controls carried out on the medicinal product or the ingredients 
and of the controls carried out at an intermediate stage of the manufacturing process, in 
accordance with the methods laid down in Annex I. 
Article 192 
Submission of co ntrol reports  for immunological medicinal products  
For the purpose of implementing Article 19 1, Member States may require manufacturers of 
immunological products to submit to a competent authority  of the Member States  copies of all 
the control reports signed by the qualified person in accordance with Article 15 3. EN 167  EN Article 193 
Batch control  of specific medicinal product by Member States  
1. Where it considers it necessary in the interests of public health, a Member State may 
require the marketing  authorisation holder of : 
(a) live vaccines , 
(b) immunological  medicinal products used in the primary immunisation of infants 
or of other groups at risk,  
(c) immunological medicinal products used in public health immunisation  
programmes,  
(d) new immunological medicinal products or immunological medicinal products 
manufactured using new or altered kinds of technology or new for a particular 
manufacturer, during a transitional period normally specified in the marketing 
authorisation , 
to submit samples from each batch of the bulk or the medicinal product for 
examination by an Official Medicines Control Laboratory or a laboratory that a 
Member State has designated for that purpose before release on to the market unless 
the competent authority of another Member State has previously examined the batch 
in question and declared it to be in conformity with the approved specifications. In 
such a case the declaration of conformity issued by another Member States shall be 
directly recognised. Member States shall ensure that any such examination is 
completed within  30 days of the receipt of the samples.  
2. Where, in the interests of public health, the laws of a Member State so provide, the 
competent authorities  of the Member State  may require the marketing authorisation 
holder for medicinal products derived from human blood or human plasma to submit 
samples from each batch of the bulk or the medicinal product for testing by an 
Official Medicines Control Laboratory or a laboratory that  a Member State has 
designated for that purpose before being released into free circulation, unless the 
competent authorities of another Member State have previously examined the batch 
in question and declared it to be in conformity with the approved speci fications. 
Member States shall ensure that any such examination is completed within 60 days 
of the receipt of the samples.  
Article 194 
Processes for the preparation of medicinal products derived from human blood or human 
plasma  
1. Member States shall take all necessary measures to ensure that the manufacturing 
and purifying processes used in the preparation of medicinal products derived from 
human blood or human plasma are properly validated, attain batch -to-batch 
consistency and guarantee, insofar as the s tate of technology permits, the absence o f 
specific viral contamination.  
2. To this end manufacturers shall notify the competent authorities of the Member 
States  of the method used to reduce or eliminate pathogenic viruses liable to be 
transmitted by medic inal products derived from human blood or human plasma. The 
competent authority  of the Member State  may submit samples of the bulk or the 
medicinal product for testing by a State laboratory or a laboratory designated for that EN 168  EN purpose, either during the exa mination of the application pursuant to Article 29, or 
after a marketing authorisation  has been granted.  
Chapter XV 
Restrictions of marketing authorisations  
Article 195 
Suspending, revoking or varying the terms of marketing authorisations  
1. The competent authorities  of the Member State s or, in the case of centralised 
marketing authorisation, the Commission  shall suspend, revoke or vary a marketing 
authorisation if the view is taken that the medicinal product is harmful or that it lacks 
therapeutic efficacy, or that the benefit -risk balance is not favourable, or that its 
qualitative and quantitative compositi on 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.  
2. The competent authorities  of the Member States  or, in the case of centralised 
mark eting authorisation, the Commission  may suspend, revoke or vary a marketing 
authorisation if a serious  risk to the environment or public health has been identified 
and not sufficiently addressed by the marketing author isation holder.  
3. A marketing authorisation may also be suspended, revoked or varied where the 
particulars supporting the application as provided for in Article s 6, 9 to 14 or 
Annexes I  to V are incorrect or have not been amended in accordance with Article 
90, or where any conditions referred to in Articles 44 , 45 and 87 have not been 
fulfilled or where the controls referred to in  Article 191 have not been carried out.  
4. Paragraph 2 also applies in cases where the manufacture of the medicinal product is 
not carried out in compliance with the particulars provided pursuant to Annex I, or 
where controls are not carried out in compliance with the control methods described 
pursuant to Anne x I. 
5. The competent  authoriti es of the Member State  or, in the case of centralised 
marketing authorisation, the Commission  shall suspend or revoke the marketing 
authorisation for a category of preparations or all preparations where any one of the 
requirements laid down in  Article 143 is no longer met.  
Article  196 
Prohibition of supply or withdrawal of a medicinal product from the market  
1. Without prejudice to the measures provided for in Article 195 , the competent 
authorities  of the Member States  and, in the case of centralised marketing 
authorisation, the Commission  shall take all appropriate steps to ensure that the 
supply of the medicinal product is prohibited and the medicinal product withdrawn 
from the market, if the view is taken that:  
(a) the medicinal product is harmful;  
(b) it lacks therapeutic efficacy;  
(c) the benefit -risk balance is not favourable;  
(d) its qualitative and quantitative composition is not as declared;  EN 169  EN (e) the controls on the medicinal product or on the ingredients and the controls at 
an intermediate stage of the manufacturing process have not been carried out or 
if some other requirement or obligation relating to the grant of the 
manufacturing authorisation has not been fulfilled ; or 
(f) a serious risk to the environment or to public health via the environment has 
been identified and not sufficiently addressed by the marketing authorisation 
holder.  
2. The competent authority  of the Member State  or, in the case of centralised marketing 
authorisation, the Commission  may limit the prohibition to supply the product, or its 
withdrawal from the market, to those batches that are the subject of dispute.  
3. The competent authority  of the Member State  or, in the case of centralised marketing 
authorisation, the Commission  may, for a medicinal product for which the supply has 
been prohibited or that has been withdrawn from the market in accordance with 
paragraph s 1 and 2, in exceptional circumstances during a transitional period allow 
the supply  of the medicinal product to patients who are already being treated with the 
medicinal product . 
Article  197 
Suspected falsified medicinal products and medicinal products with suspected quality defects  
1. Member States shall have a system in place that aims  at preventing medicinal 
products that are suspected to present a danger to health from reaching the patient.  
2. The system referred to in paragraph 1 shall cover the receipt and handling of 
notifications of suspected falsified medicinal products as well a s of medicinal 
products with  suspected quality defects. The system shall also cover recalls of 
medicinal products by marketing authorisation holders or withdrawals of medicinal 
products from the market ordered by competent authorities  of the Member States  or, 
in the case of centralised marketing authorisation, the Commission  from all relevant 
actors in the supply chain both during and outside normal working hours. The system 
shall also make it possible to recall, where necessary with the assistance of healt h 
professionals, medicinal products from patients who received such products.  
3. If the medicinal product in question is suspected of presenting a serious risk to public 
health, the competent authority of the Member State in which that product was first 
identified shall, without undue  delay, transmit a rapid alert notification to all Member 
States and all actors in the supply chain in that Member State. In the event of such 
medicinal products being deemed to have reached patients, urgent public 
announcement s shall be issued within 24 hours in order to recall those medicinal 
products from the patients. Those announcements shall contain sufficient information 
on the suspected quality defect or falsification and the risks involved.  
Article 198 
Suspending  or revoking manufacturing  authorisation  
In addition to the measures specified in  Article 196, the competent authority of the Member 
State  may suspend manufacture or imports of medicinal products coming from third 
countries, or suspend or revoke the manufacturing authorisation  for a category of preparations 
or all preparations where Articles 144 , 147, 153 and 191 are not complied with.  EN 170  EN Artic le 199 
Refusal, suspension or revocation within the limits of the Directive  
1. An authorisation to market a medicinal product shall not be refused, suspended or 
revoked except on the grounds set out in this Directive.  
2. No decision concerning suspension of manufacture or of importation of medicinal 
products coming from third countries, prohibition of supply or withdrawal from the 
market of a medicinal product may be taken except on the grounds set out in Article s 
195(5) and 196. 
Chapter XVI 
General provisions  
Article 200 
Competent authorities of the  Member States  
1. Member States shall designate the competent authorities to carry out tasks under this 
Directive . 
2. Member States shall ensure that adequate financial resources are available to provide 
the staff and other resources necessary for the competent authorities to carry out the 
activities required by this Directive and [revised Regulation (EC) No 726/2004] . 
3. The competent authorities of the Member States shall cooperate with each other and 
with the Agency and the Commission in the performance of their tasks under this 
Directive and [revised Regulation (EC) No 726/2004] to ensure proper application 
and due enf orcement. The competent authorities of the Member States  shall transmit 
to each other all necessary information.  
4. The competent authority of the Member State may process personal health data from 
sources other than clinical studies  to support their publi c health tasks and, in 
particular, the evaluation and monitoring to medicinal products, for the purpose of 
improving the robustness of the scientific assessment or verifying claims of the 
applicant or marketing authorisation holder.  
Processing of personal data under this Directive  shall be subject to Regulations (EU) 
2016/679 and (EU) 2018/1725, as applicable.  
Article  201 
Cooperation with other  authorities  
1. Member  States, in applying this Directive , shall ensure that when  questions arise 
with regard to the regulatory status of a medicinal product, in relation to their link to 
substances of human origin as referred to in Regulation (EU) No [ SoHO Regulation ], 
the competent authorities of the Member States  shall consul t the relevant authorities 
established under  that Regulation . 
2. Member  States, in applying this Directive, shall take the necessary measures to 
ensure cooperation between competent authorities for medicinal products and 
customs authorities.  EN 171  EN Article  202 
Mem ber States exchange of information of manufacturing  or wholesale distribution 
authorisations of medicinal products  
1. Member States shall take all appropriate measures to ensure that the competent 
authorities of the Member States  concerned communicate to each other such 
information as is appropriate to guarantee that the requirements placed on the 
authorisations referred to in Article s 142 and 163, on the certificates referred to in 
Article 188 (13) or on the marketing authorisatio ns are fulfilled.  
2. Upon reasoned request, Member States shall send electronically the report  referred to 
in with Article 188  to the competent authorities of another Member State or to the 
Agency.  
3. The conclusions reached in accordance with Article s 188(13) or 188( 14) shall be 
valid throughout the  Union . 
4. However, in exceptional cases, if a Member State is unable, for reasons relating to 
public health, to accept the conclusions reached following an inspection under 
Article 188 (1), that Member State sha ll without undue delay  inform the Commission 
and the Agency. The Agency shall inform the Member States concerned.  
5. When the Commission is informed of these divergences of opinion, it may, after 
consulting the Member States concerned, ask the inspector wh o performed the 
original inspection to perform a new inspection; the inspector may be accompanied 
by two other inspectors from Member States that are not parties to the disagreement.  
Article 203 
Information on prohibition of supply or other action on a marketing authorisation  
1. Each Member State shall take all the appropriate measures to ensure that decisions 
granting  marketing  authorisation , refusing or revoking a marketing authorisation , 
cancelling a decision refusing or revoking a marketing authorisa tion, prohibiting 
supply, or withdrawing a product from the market, together with the reasons on 
which such decisions are based, are brought to the attention of the Agency without 
undue delay . 
2. In addition to the notification made pursuant to Article 116 of [revised Regulation 
(EC) No 726/2004] , the marketing authorisation holder shall declare without undue 
delay  if such notified  action is based on any of the grounds set out in  Article s 195 or 
196(1). 
3. The marketing authorisation holder shall also make the notification pursuant to 
paragraph  2 in cases where the action is taken in a third country and where such 
action is based on any of the grounds set out Article s 195 or 196(1). 
4. The marketing authorisation holder shall furthermore notify the Agency wh ere the 
action referred to in paragraphs 2  or 3 is based on any of the grounds referred to in 
Article s 195 or 196(1). 
5. The Agency shall forward notifications received in accordance with paragraph 4 to 
all Member States without undue delay.  
6. Member States shall ensure that appropriate information about action taken pursuant 
to paragraph s 1 and 2 that may affect the protection of public  health in third countries EN 172  EN is without undue delay  brought to the attention of the World Health Organization, 
with a copy to the Agency.  
7. Each year, the Agency shall make public a list of the medicinal products for which 
marketing authorisations have been refused, revoked or suspended in the Union, 
whose supply has been prohibited or that have been withdrawn from  the market, 
including the reasons for such action.  
Article 204 
Notification of decisions related to marketing authorisations  
1. Every decision referred to in this Directive that is taken by the competent authority 
of a Member State shall state in detail the reasons on which it is based.  
2. Such decision shall be notified to the party concerned, together with information as 
to the redress available to them  under the laws in force and of the time  limit allowed 
for access to such redress.  
3. Decisions to grant or revoke a marketing authorisation shall be made public ly 
available.  
Article 205 
Authorisation of a medicinal product on public health grounds  
1. In the absence of a marketing authorisation or of a pending application for a 
medicinal product authorised in another Member State in accordance with Chapter 
III, a Member State may for justified public health reasons authorise the placing on 
the market of  the said medicinal product.  
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 Chapters IV, VI, IX, XIII and XI V, and Article 206. 
Member States may decide that Article  74, paragraphs 1 to 3, shall not apply to 
medicinal products authorised under paragraph  1. 
3. Before granting such a marketing authorisation, a Member State:  
(a) shall notify the marketing authorisation holder, in the Member State in which 
the medicinal product concerned is authorised, of the proposal to grant a 
marketing authorisation under this Article in respect of the medicinal product 
concerned ; 
(b) may request the competent a uthority in that Member State to submit copies of 
the assessment report referred to in Article 43 (5) and of the marketing 
authorisation in force in respect of the medicinal product concerned. If so 
requested, the competent authority in that Member State sh all supply, within 30 
days of receipt of the request, a copy of the assessment report and the 
marketing authorisation in respect of the medicinal product concerned.  
4. The Commission shall set up a public ly available  register of medicinal products 
authoris ed under paragraph  1. Member States shall notify the Commission if any 
medicinal product is authorised, or ceases to be authorised, under paragraph  1, 
including the name or corporate name and permanent address of the marketing  
authorisation holder. The Com mission shall amend the register of medicinal products 
accordingly and make this register available on their website.  EN 173  EN Article 206 
Penalties  
1. Member States shall lay down the rules on penalties applicable to infringements of 
national provisions adopted pursuant to this Directive and shall take all measures 
necessary  to ensure that they are implemented. The penalties must be effective, 
proportion ate and dissuasive. Member States shall, without delay, notify the 
Commission of those rules and of those measures and shall notify without delay of 
any subsequent amendment affecting them.  
Those penalties shall not be inferior to those applicable to infri ngements of national 
law of similar nature and importance.  
2. The rules referred to in paragraph 1, first subparagraph,  shall address, inter alia, the 
following:  
(a) the manufacturing, distribution, brokering, import and export of falsified 
medicinal produ cts, as well as sale at distance  of falsified medicinal products to 
the public;  
(b) non-compliance with the provisions laid down in this Directive on 
manufacturing, distribution, import and export of active substances;  
(c) non-compliance with the provision s laid down in this Directive on the use of 
excipients ; 
(d) non-compliance with the provisions laid down in this Directive on 
pharmacovigilance;  
(e) non-compliance with the provisions laid down in this Directive on advertising.  
3. Where relevant, the penal ties shall take into account the risk to public health 
presented by the falsification of medicinal products.  
Article 207  
Collection of unused or expired medicinal products  
Member States shall ensure that appropriate collection systems are in place for medicinal 
products that are unused or have expired.  
Article 208 
Declaration of interests  
1. In order to guarantee independence and transparency, the Member States shall ensure 
that members of staff of the competent authority responsible for granting 
authorisations, rapporteurs and experts concerned with the authorisation and 
surveillance of medic inal products have no financial or other interests in the 
pharmaceutical industry that could affect their impartiality. These persons shall make 
an annual declaration of their financial interests.  
2. In addition, the Member States shall ensure that the com petent authority makes 
public ly available  its rules of procedure and those of its committees, agendas for its 
meetings and records of its meetings, accompanied by decisions taken, details of 
votes and explanations of votes, including minority opinions.  EN 174  EN Chapter XVII  
Specific provisions concerning Cyprus , Ireland , Malta  and the 
United K ingdom in respect of Northern  Ireland  
Article  209 
Provisions relevant to the United Kingdom in respect of  Northern Ireland  
1. By way of derogation from Article 5 , the competent authorities of the United 
Kingdom in respect of Northern Ireland may temporarily authorise the supply to 
patients in Northern Ireland of a medicinal product belonging to the categories 
referred to in Article  3, paragraphs 1 and 2  of [revise d Regulation (EC) No 
726/2004]  provided that all of the following conditions are fulfilled:  
(a) the medicinal product concerned has been granted a marketing authorisation by 
the competent authority of the United Kingdom for parts of the United 
Kingdom othe r than Northern Ireland;  
(b) the medicinal product concerned is only made available to patients or end -
consumers in the territory of Northern Ireland and is not made available in any 
Member State.  
The maximum validity of the temporary authorisation shall b e six months.  
Notwithstanding the specified validity, the temporary authorisation shall cease to be 
valid if the medicinal product concerned has been granted a marketing authorisation 
in accordance with Article 13  of [revised Regulation (EC) No 726/2004 ], or if such 
marketing authorisation has been refused in accordance with that Article.  
2. By way of derogation from Article 56 (4), marketing authorisations may be granted 
by the competent authorities of the United Kingdom in respect of Northern Ireland:  
(a) to applicants established in parts of the United Kingdom other than Northern 
Ireland;  
(b) to marketing authorisation holders established in parts of the United Kingdom 
other than Northern Ireland , in accordance with the mutual recognition or the 
decentrali sed procedure laid down in Chapter III, Sections 3 and 4 . 
The competent authorities of the United Kingdom in respect of Northern Ireland may 
extend marketing authorisations already granted prior to 20 April 2022 to marketing 
authorisation holders establish ed in parts of the United Kingdom other than Northern 
Ireland.  
3. By way of derogation from Article  33, paragraphs 1, 3 and 4 and Article 35(1) , if an 
application for marketing authorisation is submitted in one or more Member States 
and in the United Kingd om in respect of Northern Ireland, or if an application for 
marketing authorisation is submitted in the United Kingdom in respect of Northern 
Ireland for a medicinal product that is already being examined or has already been 
authorised in a Member State, t he application regarding the United Kingdom in 
respect of Northern Ireland shall not have to be submitted in accordance with 
Chapter III, Sections 3 and 4 , provided that all of the following conditions are 
fulfilled:  
(a) the marketing authorisation for the  United Kingdom in respect of Northern 
Ireland is granted by the competent authority for the United Kingdom in EN 175  EN respect of Northern Ireland in compliance with Union law, and such 
compliance with Union law is ensured during the period of validity of that 
marketing authorisation;  
(b) the medicinal products authorised by the competent authority for the United 
Kingdom in respect of Northern Ireland are made available to patients or end -
consumers only in the territory of Northern Ireland, and they are not made 
available in any Member State.  
4. The marketing authorisation holder of a medicinal product for which a marketing 
authorisation has already been granted for the United Kingdom in respect of 
Northern Ireland in accordance with Chapter III, Sections 3 and 4 , before 20 April 
2022 shall be allowed to withdraw the marketing authorisation for the United 
Kingdom in respect of Northern Ireland from the mutual recognition or the 
decentralised procedure and to submit an application for a marketing authorisation 
for th at medicinal product to the competent authorities of the United Kingdom with 
respect to Northern Ireland in accordance with paragraph  1. 
5. With regard to quality control testing referred to in Article 8 carried out in parts of 
the United Kingdom other tha n Northern Ireland regarding medicinal products 
included in the list referred to in Article 21 1(9) other than those authorised by the 
Commission, the competent authorities of the United Kingdom in respect of 
Northern Ireland may consider that there is a ju stifiable case within the meaning of 
Article 8 , point (b), without carrying out a case -by-case assessment provided that:  
(a) each batch of the medicinal products concerned is released by a qualified 
person on a site in the Union or in Northern Ireland or b y a qualified person on 
a site in parts of the United Kingdom other than Northern Ireland applying 
quality standards that are equivalent to those laid down in Article  153; 
(b) the establishment designated by the third party conducting the quality control 
testing is supervised by the competent authority of the United Kingdom, 
including by performing on -the-spot checks;  
(c) where the batch release is carried out by a qualified person who resides and 
operates in parts of the United Kingdom other than Northern Ireland, the 
manufacturing authorisation holder declares that it does not have at its disposal 
a qualified person who resides and operates in the Union on 20 April 2022.  
6. By way of derogation from Article 142(1), the competent authorities of the United 
Kingdom in respect of Northern Ireland shall allow medicinal products to be 
imported from parts of the United Kingdom other than Northern Ireland by a 
wholesale distribution authorisation holders  as referr ed to in Article 163 (1) that are 
not in possession of a relevant manufacturing authorisation provided that all of the 
following conditions are fulfilled:  
(a) the medicinal products have undergone quality control testing either in the 
Union, as provided for in Article 153 (3), or in parts of the United Kingdom 
other than Northern Ireland in compliance with Article 8 , point (b);  
(b) the medicinal products have been subject to batch release by a qualified person 
in the Union in accordance with  Article 153(1) or, for medicinal products 
authorised by the United Kingdom in respect of Northern Ireland, in parts of 
the United Kingdom other than Northern Ireland applying quality standards 
that are equivalent to those laid down in  Article 153(1); EN 176  EN (c) the marketing authorisation for th e medicinal product concerned has been 
granted in accordance with Union law, by the competent authority of a 
Member State or by the Commission or, as regards medicinal products placed 
on the market in Northern Ireland, by the competent authority of the Uni ted 
Kingdom in respect of Northern Ireland;  
(d) medicinal products are only made available to patients or end -consumers in the 
Member State into which the medicinal products are imported, or, if imported 
into Northern Ireland, are only made available to pa tients or end -consumers in 
Northern Ireland;  
(e) the medicinal products bear the safety features referred to in Article 67 . 
7. For batches of medicinal products that are exported to parts of the United Kingdom 
other than Northern Ireland from a Member State and subsequently imported into 
Northern Ireland, the controls upon importation referred to in Article 153 (1), first 
and second subparagraphs , shall not be required , provided that those batches have 
undergone such controls in a Member State prior to being exported to parts of the 
United Kingdom other than Northern Ireland and that they are accompanied by the 
control reports referred to in Article 153(1), third subpar agraph . 
8. Where the manufacturing authorisation is granted by the competent authority of the 
United Kingdom in respect of Northern Ireland, the qualified person referred to in 
Article 151(1) may reside and operate in parts of the United Kingdom other than  
Northern Ireland. This paragraph shall not apply where the manufacturing 
authorisation holder already has at its disposal a qualified person who resides and 
operates in the Union on 20 April 2022.  
9. By way of derogation from the Article 99(5), where the marketing authorisation is 
granted by the competent authority of United Kingdom in respect of Northern 
Ireland, the qualified person referred to in Article 99(4), point (a) , may reside and 
operate in parts of the United Kingdom other than Northern Ireland.  This paragraph 
shall not apply where the marketing authorisation holder already has at its disposal a 
qualified person who resides and operates in the Union on 20 April 2022.  
10. The competent authorities of the United Kingdom in respect of Northern Irela nd 
shall publish on their website a list of medicinal products to which they have applied 
or intend to apply the derogations as set out in this Article  and shall ensure that the 
list is updated and managed in an independent manner, at least on a six -monthl y 
basis.  
Article 210 
Regulatory functions carried out in the United Kingdom  
1. The Commission shall continuously monitor developments in the United Kingdom 
that could affect the level of protection regarding the regulatory functions referred to 
in Article 99(4), Article 151(3), Article 211, paragraphs 1, 2, 5  and 6 , Article 209, 
paragraphs 6 and 7 , that are carried out in parts of the United Kingdom other than 
Northern Ireland taking into account, in particular, the following elements:  
(a) the rules governing the granting of marketing authorisations, the obligations of 
the marketing authorisation holder, the granting of manufacturing 
authorisations, the obligations of the manufacturing authorisation holder, the EN 177  EN qualified persons and their obligations,  quality control testing, batch release 
and pharmacovigilance as laid down in United Kingdom law;  
(b) whether the competent authorities of the United Kingdom ensure the effective 
enforcement within their territory of the rules referred to in point (a), by means 
of, inter alia, inspections and audits of marketing authorisation holders, 
manufacturing authorisation holders and wholesale distributors located in their 
territories, and on -the-spot checks at their premises regarding the exercise of 
the regulatory functions referred to in point (a).  
2. Where the Commission finds that the level of protection of public health ensured by 
the United Kingdom through rules governing the production, distribution and use of 
medicinal products as well as the effective enforc ement of those rules is no longer 
essentially equivalent to that guaranteed within the Union, or where sufficient 
information is not available to the Commission to enable it to establish whether an 
essentially equivalent level of protection of public healt h is ensured by the United 
Kingdom, the Commission shall inform the United Kingdom through a written 
notification of that finding and of the detailed reasons therefor.  
For a period of six months following the written notification made pursuant to the 
first subparagraph, the Commission shall enter into consultations with the United 
Kingdom with a view to remedying the situation giving rise to that written 
notification. In justified cases, the Commission may extend that period by three 
months.  
3. If the situa tion giving rise to the written notification made pursuant to paragraph  2, 
first subparagraph, is not remedied within the time  limit referred to in paragraph  2, 
second subparagraph, the Commission shall be empowered to adopt a delegated act 
amending or sup plementing  the provisions among those referred to in paragraph 1 
whose application shall be suspended.  
4. Where a delegated act pursuant to paragraph 3 has been adopted, the provisions 
referred to in the introductory sentence of paragraph  1 as specified in  the delegated 
act shall cease to apply on the first day of the month following the entry into force of 
the delegated act.  
5. Where the situation giving rise to the adoption of the delegated act pursuant to 
paragraph  3 has been remedied, the Commission shall adopt a delegated act 
specifying those suspended provisions that shall apply again. In that case, the 
provisions specified in the delegated act adopted pursuant to this paragraph shall 
apply again on the first day o f the month following the entry into force of the 
delegated act referred to in this paragraph.  
Article 211 
Provisions relevant to Cyprus, Ireland and Malta and applicable until 31 December 2024  
1. By way of deroga tion from  Article 56(4), marketing authorisations may  be granted  in 
accordance with the mutual recognition or the decentralised procedure laid down in 
Chapter I II, Sections 3 and 4 , to marketing authorisation holders established in parts 
of the United Kingdom other than Northern Ireland.  
Until 31 December 2024, the competent authorities of Cyprus, Ireland and Malta 
marketing authorisations already granted prior to 20 April 2022 may be extended to  EN 178  EN marketing authorisation holders established in parts of the United Kingdom other 
than Northern I reland.  
The marketing authorisations granted or extended by the competent authorities of 
Cyprus, Ireland or Malta in accordance with the first and second subparagraph s shall 
cease to be valid at the latest on 31 December 2026.  
2. With regard to quality control testing referred to in Article 8  carried out in parts of 
the United Kingdom other than Northern Ireland regarding medicinal products 
included in the list referred to in  paragraph 9, other than those authorised by the 
Commission, and, until 31 December 2024, the competent authorities of Cyprus, 
Ireland and Malta may consider that there is a justifiable case within the meaning of 
Article 8 , point (b), without carrying out a case -by-case assessment provided that:  
(a) each batch of the medicinal products concerned is released by a qualified 
person on a site in the Union or in Northern Ireland or by a qualified person on 
a site in parts of the United Kingdom other than Northern Ireland app lying 
quality standards that are equivalent to those laid down in  Article 153(1); 
(b) the establishment designated by the third party conducting the quality control 
testing is supervised by the competent authority of the United Kingdom, 
including by perfor ming on -the-spot checks;  
(c) where the batch release is carried out by a qualified person who resides and 
operates in parts of the United Kingdom other than Northern Ireland, the 
manufacturing authorisation holder declares that it does not have at its disp osal 
a qualified person who resides and operates in the Union on 20 April 2022.  
3. By way of derogation from Article 142 (1), the competent authorities of Cyprus, 
Ireland and Malta shall allow medicinal products to be imported from parts of the 
United Kingd om other than Northern Ireland by  wholesale distribution authorisation 
holders  as referred to in Article 163 (1) that are not in possession of a relevant 
manufacturing authorisation provided that all of the following conditions are 
fulfilled:  
(a) the medicinal products have undergone quality control testing either in the 
Union, as provided for in Article 153 (3), or in parts of the United Kingdom 
other than Northern Ireland in compliance with  Article 8 , point (b);  
(b) the medicinal products have bee n subject to batch release by a qualified person 
in the Union in accordance with  Article 153(1) or, for medicinal products 
authorised by the competent authorities the United Kingdom in respect of 
Northern Ireland, in parts of the United Kingdom other than Northern Ireland 
applying quality standards that are equivalent to those laid down in Article 
153(1); 
(c) the marketing authorisation for the medicinal product concerned has been 
granted in accordance with Union law, by the competent authority of a 
Member State or by the Commission or, as regards medicinal products placed 
on the market in Northern Ireland, by the competent authority of the United 
Kingdom in respect of Northern Ireland;  
(d) medicinal products are only made available to patients or end -consum ers in the 
Member State into which the medicinal products are imported, or, if imported 
into Northern Ireland, are only made available to patients or end -consumers in 
Northern Ireland;  EN 179  EN (e) the medicinal products bear the safety features referred to in Article 67 . 
Article 166 (1), point (b),  shall not apply to imports that fulfil the conditions laid 
down in the first subparagraph.  
4. For batches of medicinal products that are exported to parts of the United Kingdom 
other than Northern Ireland from a Member State and subsequently imported until 31 
December 2024  into Cyprus, Ireland or Malta, the controls upon importation referred 
to Article 153(1), first and second subparagr aphs, shall not be required, provided that 
those batches have undergone such controls in a Member State prior to being 
exported to parts of the United Kingdom other than Northern Ireland and that they 
are accompanied by the control reports referred to in Article 153 (1), third 
subparagraph.  
5. By way of derogation from  Article 20 5(1) until 31 December 2024, in the absence of 
a marketing authorisation or of a pending application for a marketing authorisation 
the competent authorities of Cyprus and Malta may authorise for justified public 
health reasons the placing on their national mar ket of a medicinal product authorised 
in parts of the United Kingdom other than Northern Ireland.  
The competent authorities of Cyprus and Malta may also maintain in force or, until 
31 December 2024, extend marketing authorisations that were granted pursuan t to 
Article 205(1) before 20 April 2022  and that authorise the placing on their national 
market of a medicinal product authorised in parts of the United Kingdom other than 
Northern Ireland.  
Authorisations that are granted, extended or maintained in force pursuant to the first 
or second subparagraph s shall not be valid after 31 December 2026.  
6. By way of derogation from  Article 56 (4), the competent authorities of Malta and 
Cyprus may grant marketing authorisations as referred to in paragraph  5 to marketing  
authorisation holders established in parts of the United Kingdom other than Northern 
Ireland.  
7. Where the competent authorities of Cyprus or Malta grant or extend a marketing 
authorisation as referred to in paragraph  5, they shall ensure compliance with the 
requirements of this Directive.  
8. Before granting a marketing authorisation pursuant to paragraph  5, the competent 
authorities of Cyprus or Malta:  
(a) shall notify the marketing authorisation holder in parts of the United Kingdom 
other than Northern I reland of the proposal to grant a marketing authorisation 
or to extend a marketing authorisation under paragraph s 5 to 8 in respect of the 
medicinal product concerned;  
(b) may request the competent authority in the United Kingdom to submit the 
relevant inf ormation regarding the marketing authorisation of the medicinal 
product concerned.  
9. The competent authorities of Cyprus, Ireland, Malta shall publish on their website a 
list of medicinal products to which they have applied or intend to apply the 
derogati ons as set out in this Article  and shall ensure that the list is updated and 
managed in an independent manner, at least on a six -monthly basis.  EN 180  EN Article 2 12 
Derogations for medicinal products place d on the markets of Cyprus, Ireland, Malta or 
Northern Ireland  
The derogations set out in Article 211, paragraphs 1 and 6 , Article 8 , Article 209, paragraphs 
6 and 7 , Article 153 (3), Article 99 (4) and Article 211(5) shall not affect the obligations of the 
marketing authorisation holder to ensure the quality, safety and efficacy of the medicinal 
product placed on the markets of Cyprus, Ireland, Malta or Northern Ireland laid down in this 
Directive.  
Chapter XVIII  
Final provisions  
Article 2 13 
Amendment to the Annexes  
The Commission is empowered to adopt delegated acts in accordance with  Article 215 
amending Annex es I to VI in order to adapt them to scientific and technical progress  and 
amend Article 22  with regard to the ERA requirements set  out in paragraphs 2, 3, 4 and 6  of 
that Article . 
Article 21 4 
Standing Committee on Medicinal Products for Human Use  
1. The Commission shall be assisted by the Standing Committee on Medicinal Products 
for Human Use. That Committee shall be a committee within the meaning of 
Regulation (EU) No 182/2011.  
2. Where reference is made to this paragraph, Article 5 of Regulation (EU) No 
182/2011  shall apply.  
3. Where the opinion of the Committee is to be obtained by written procedure and 
reference is made to thi s paragraph, that procedure shall be terminated without result 
only when, within the time  limit for delivery of the opinion, the chair of the 
Committee so decides.  
4. The rules of procedure of the Standing Committee on Medicinal Products  shall be 
made public ly available . 
5. The Standing Committee on Medicinal Products for Human Use shall ensure that its 
rules of procedure are adapted to the need to make medicinal products swiftly 
available to patients and take account of the tasks incumbent upon it unde r Chapter 
III and the procedure set out in Article  42. 
Article 215 
Exercise of the delegation s 
1. The power to adopt delegated acts is conferred on the Commission subject to the 
conditions laid down in this Article.  
2. The power to adopt delegated acts referred to in Articles 4(2), 24(5), 25(9), 26(3) , 28, 
paragraphs 2 and 3 , 27(3), 63(5), 65(2), 67(2), 88(1), 92(4), 126(1), 150(3), 153(4), 
161, 210(4)  and 213 shall be conferred on the Commission for a period of five years EN 181  EN from [OP please insert the date of the entry into force of this Directive] . The 
Commission shall draw up a report in respect of the delegation of power not later 
than nine months before the end of the five -year period. The delegation of power 
shall be tacitly extended for periods of an identical duration, unless the European 
Parliament or the Council opposes such extension not later than three months before 
the end of each period.  
The power to adopt delegated acts referred to in  Article 210, paragrap hs 3 and 5 , 
shall be conferred on the Commission for an indeterminate period of time from [OP 
please insert the date = the date of the entry into force of this Directive] . 
3. The delegation of power referred to in Articles 4(2), 24(5), 25(9), 26(3), 27(3), 28, 
paragraphs 2 and 3,  63(5),  65(2), 67(2), 88(1), 92(4), 126(1), 150(3), 153(4), 161, 
210(4) and 213 may be revoked at any time by the European Parliament or by the 
Council. A decision to revoke shall put an end to the delegation of the power 
specified in that decision. It shall take effect the day following the public ation of the 
decision in the Official Journal of the European Union  or at a later date specified 
therein. It shall not affect the validity of any delegated acts already in force.  
4. Before adopting a delegated act, the Commission shall consult experts designated by 
each Member State in accordance with the principles laid down in the 
Interinstitutional Agreement of 13 April 2016 on Better Law -Making.  
5. As soon as it adopts a delegated act, the Commission shall notify it simultaneously to 
the European Parliament and to the Council.  
6. A delegated act adopted pursuant to  Articles 6 (2),  26(3), 24(5), 28, paragraphs 2 and 
3, 27(3),  63(5), 65(2), 67(2), 88 (1), 92(4), 126(1), 150(3), 153 (4), 161, 210 (4) and 
213 shall enter into force only if no objection has been expressed either by the 
European Parliament or by the Council within a period of two months of notification 
of that act to the European Parliament and the Council or if, before the e xpiry of that 
period, the European Parliament and the Council have both informed the 
Commission that they will not object. That period shall be extended by two months 
at the initiative of the European Parliament or of the Council.  
Article 2 16 
Report  
By [OP please insert the date = 10 years following 18 months after the date of entering into 
force of this Directive ], the Commission shall present a report to the European Parliament and 
the Council on  the application of this Directive , including an assessmen t of the fulfilment of 
its objectives and the resources required to implement it.  
Article 2 17 
Repeal s 
1. Directive 2001/83/EC is repealed  with effect from [OP please insert the date = 18 
months after the date of entering into force of this Directive ].  
2. Directive 2009/35/EC  is repealed  with effect from [OP please insert the date = 18 
months after the date of entering into force of this Directive ].  EN 182  EN 3. References to the repealed Directives 2001/83/EC and 2009/35/EC shall be 
construed as references to this  Directive. References to the repealed Directive 
2001/83/EC shall be read in accordance with the correlation table in Annex VIII . 
Article  218 
Transitional provisions  
1. The procedures concerning the applications for marketing authorisations for 
medicinal products validated in accordance with Article 19 of Directive 2001/83/EC 
before [ OP please insert the date = 18 months after the date of entering into force of 
this Directive ] and that were pending on  [OP please insert the date = the day befo re 
18 months after the date of entering into force of this Directive ] shall be completed in 
accordance with  Article 29. 
2. Procedures initiated on the basis of Articles  29, 30, 31, and 107i of Directive 
2001/83/EC before [ OP please insert the date = 18 months after the date of entering 
into force of this Directive ] and that were pending on [OP please insert the date = the 
day before 18 months after the date of entering into force of this Directive ] shall be 
completed in accordance with Article s 32 to 34 or Article 107k,  as appropriate,  of 
that Directive  as applicable on [OP please insert the date = the day before 18 months 
after the date of entering into force of this Directive ]. 
3. This Directive shall also apply to medicinal products authorised  in accordance with 
Directive 2001/83/EC before [OP please insert the date = 18 months after the date of 
entering into force of this Directive ]. 
This Directive shall also apply to  registrations of homeopathic medicinal products 
and traditional herbal medic inal products carried out in accordance wit h Directive 
2001/83/EC before [OP please insert the date = 18 months after the date of entering 
into force of this Directive ]. 
4. By way of derogation from  Chapter VI , the m edicinal products placed on the market 
in accordance with Directive 2001/83/EC before [OP please insert the date = 18 
months after the date of entering into force of this Directive ] may continue to be 
made available on the market until [ OP please insert the date = five years after 18 
months after the date of entering into force of this Directive ], provided that they 
comply with the provision on labelling and package leaflet set out in Title V of 
Directiv e 2001/83/EC as applicable on [OP please insert the date = the day before 18 
months after the date of entering into force of this Directive ]. 
5. By way of derogation from Article 81, reference medicinal products for which the 
application for  marketing authorisation has been  submitted before [ OP please insert 
the date = 18 months after the date of entering into force of this Directive ] shall be 
subject to the  provisions on data protection periods set out in A rticle 10  of Directiv e 
2001/83/EC as applicable on [OP please insert the date = 18 months after the date of 
entering into force of this Dire ctive ] until [OP please insert the date = 18 months 
after the date of entering into force of this Directive ]. 
6. By way of derogation from paragraph 3, the reporting  obligations as ref erred to in 
Article 57, shall n ot apply with regards to  medicinal products authorised in 
accordance with Directive 2001/83/EC before [OP please insert the date = 18 months 
after the date of entering into force of this Directive ]. EN 183  EN Article 2 19 
Transposition   
1. Member States shall bring into force the laws, regu lations and administrative 
provisions to comply with this Directive by [18 months after the date of entering into 
force  of this Directive ]. They shall immediately communicate the text of those 
measures to the Commission.  
2. When Member States adopt those measures, they shall contain a reference to this 
Directive or be accompanied by such reference on the occasion of their official 
public ation. They shall also include a statement that references in existing laws, 
regulations a nd administrative provisions to the Directives repealed by this Directive 
shall be construed as references to this Directive. Member States shall determine how 
such reference is to be made and how that statement is to be formulated.  
3. Member States shall  communicate to the Commission the text of the main measures 
of national law that they adopt in the field covered by this Directive.  
Article  220 
Entry into force  
This Directive shall enter into force on the twentieth day following that of its public ation in 
the Official Journal of the European Union . 
Article  221 
Addressee s 
This Directive is addressed to the Member States.  
Done at Brussels,  
For the European Parliament  For the Council  
The President  The President