The document provides an overview of the marketing authorisation procedures for medicines in the European Union, with a focus on the centralised procedure. It discusses the historical development of regulation, the roles of the European Medicines Agency and other EU institutions. The centralised procedure is mandatory for certain drug classes and allows for a single marketing authorisation valid across all EU member states. The process involves evaluation of dossier submissions by scientific committees like CHMP and a decision on authorisation by the European Commission. Post-approval obligations include pharmacovigilance and risk management activities.

1. MARKETING AUTHORISATIONS IN THE
EU: THE CENTRALISED PROCEDURE
October 2016
François MAIGNEN

2. STRUCTURE OF THE PRESENTATION
 Historical background
 The marketing authorisation procedures in the EU
 The European Medicines Agency and the EU
institutions
 The centralised procedure: mandatory scope, legal
background
 The CTD
 The CHMP and granting of initial marketing
authorisation in the EU
 Post-authorisation and EudraVigilance

3. THE STARTING POINT OF REGULATION OF
MEDICINES IN EUROPE
Frances Oldham
Kelsey (FDA)

4. HISTORICAL BACKGROUND: MILESTONES
 Rome treaty 1957
 Directive 65/65/EEC principle of granting a Marketing
Authorisation to medicinal products (12 pages)
 Maastrich treaty (TEU) 1992: funding principles of the
European Union
 Directive 2001/83/EC: content and structure of marketing
authorisation dossier (128 pages)
 In the 90s: appearance of the first authorised biotechnology
derived medicinal products
 Council Regulation (EEC) No 2309/93: creation of the
European Medicines Agency (EMEA) (35 pages)
 Regulation (EC) No 726/2004 (68 pages)
 Lisbon treaty 2007 (TFEU)

5. MARKETING AUTHORISATION PROCEDURES IN
THE EUROPEAN UNION
 National procedures
 The marketing authorisation is granted by one National
Competent Authority and valid in only one EU MS
 Decentralised and mutual recognition procedures:
 The MA is evaluated by one EU MS and adopted by other EU MS
 CMD(h)
 Centralised Procedure:
 The marketing authorisation is granted by the European
Commission and is valid in all EU member states
 European Medicines Agency / CHMP

6. THE EU INSTITUTIONS

7. HISTORY OF THE AGENCY SINCE 1995 ...

8. TWO MAIN PIECE OF LEGISLATION
 Directive 2001/83/EC, as amended (126 pages incl.
Annex 1)
 Definitions and scope
 Marketing authorisations (mutual recognition and
decentralised) / referrals
 Labelling, classification, wholesale and advertising
 Human blood products, herbal remedies, homeopathy
 Regulation (EU) 726/2004, as amended (68 pages)
 Definitions and scope
 Authorisation and supervision of human medicines
 Something else (see after)
 European Medicines Agency (tasks, committees,
finances)

9. THE EUROPEAN MEDICINES AGENCY:
A NETWORK (ART. 56 REG 726/2004)
Management
board
Executive
Director
Scientific committees
Agency (roles, resp.)
- Supervisory role with general responsibility
for budgetary and planning matters
- Appointment and removal
of the Executive Director
- Monitoring of the Agency’s performance
Art 64 Art 65-67
Art 61-63
Art 57-60 - Scientific / Public Health missions
- Cooperation with WHO
- Conflicts with other EU auth.
- Database of medicinal products

10. THE AGENCY SEVEN SCIENTIFIC COMMITTEES
 Committee for Medicinal Products for Human
Use (CHMP)
 Pharmacovigilance Risk Assessment Committee
(PRAC)
 Committee for Advanced Therapies (CAT)
 Committee for Orphan Medicinal Products (COMP)
 Paediatric Committee (PDCO) and ...
 Committee for Medicinal Products for Veterinary
Use (CVMP)
 Committee on Herbal Medicinal Products (HMPC)

11. THE EUROPEAN MEDICINES AGENCY
MISSIONS (ART 57 OF REGULATION 726/2004)
 The Agency shall be responsible for coordinating
the existing scientific resources put at its disposal
by Member States for the evaluation, supervision
and pharmacovigilance of medicinal products.
 The Agency shall provide the Member States and
the institutions of the Community with the best
possible scientific advice on any question relating to
the evaluation of the quality, safety and efficacy of
medicinal products for human or veterinary use
which is referred to it in accordance with the
provisions of Community legislation relating to
medicinal products.

12. THE KEY ELEMENTS OF THE MISSION OF
THE AGENCY & OTHER EU INSTITUTIONS
 Broad mission of Public and Animal health
protection in relation to virtually all medicines
authorised in the EU
 Network
 Human and veterinary are interconnected (e.g. MRL,
antibiotic resistance, ERA)
 The European Medicines Agency provides scientific
opinions
 Marketing Authorisations: European Commission
(decision)
 Mission of cooperation: other EU institutions and
Agencies but also world-wide Public Health
organisations e.g. WHO.

13. THE CENTRALISED PROCEDURE: MANDATORY
SCOPE
 Biotechnology derived medicinal products (rDNA,
monoclonal antibodies, ...)
 ATMP (gene and cell therapies) Regulation (EC) No
1394/2007
 New chemical entities in particular medicinal
products intended to treat:
 acquired immune deficiency syndrome and viral diseases,
 cancer,
 neurodegenerative disorder,
 diabetes,
 auto-immune diseases and other immune dysfunctions.
 Orphan drugs

14. THE COMMON TECHNICAL DOCUMENT:
DIRECTIVE 2001/83/EC, AS AMENDED

15. CHMP: INITIAL MARKETING
AUTHORISATION
 Milestones
 D80: (Co)-Rapp assessment
reports
 D120: List of questions
 Approvable
 Non-approvable: major
objections (mostly clinical)
 D150: Joint AR
 D180: List of outstanding
issues
 D210: CHMP OPINION
 D277: Commission decision

16. MARKETING AUTHORISATIONS
 “Full” marketing authorisation
 First granted for 5 years, renewed once then valid
forever (until suspended, withdrawn or revoked)
 Conditional approval
 The MA is granted provided that the MA fulfils some
specific obligations
 Eventually once the SO are fulfilled the MA will become
a “full” marketing authorisation
 Annual reassessment renewal
 MA under exceptional circumstances
 Orphan drugs. This authorisation will remain under
exceptional circumstances
 Annual reassessment renewal

17. POST-AUTHORISATION AND MAINTENANCE
ACTIVITIES
 Post-authorisation commitments: Annex 2
 This will include post-authorisation studies (quality, safety,
efficacy)
 Post-authorisation safety and/or efficacy studies
 Pharmacovigilance (maintenance and inspection of
PhV master file, PhV system, PhV obligations)
 Periodic Benefit-Risk Evaluation Reports (PBER former PSURs)
 Risk management plan and risk minimisation activities
 Submission of ICSRs (individual case safety reports of adverse
drug reactions)
 Signal detection
 Variations to the marketing authorisation

18. PHARMACOVIGILANCE
 Science aimed at detecting, assessing, communicating and
preventing the side-effects associated with medicines.
 Shortcomings of the clinical development of medicines
 Low exposure
 “Law of 3/n”
 Need for a post-authorisation surveillance (active vs passive)
 Methods prone to biases
 Spontaneous reporting
 Registries
 Large interventional or observational studies
 Role of the Pharmacovigilance and Risk Assessment
Committee (July 2012)

19. EUDRAVIGILANCE
 EU database of adverse drug reactions
 Post-authorisation module: spontaneous adverse drug reactions
 Pre-authorisation module: implementation of Directive
2001/20/EC on clinical trials (SUSARs)
 Covers all medicinal products authorised in the EU,
established in 2001. Fully functional in November
2005.
 Approx. 5 million cases (1 million/year) from all over
the world

20. SIGNAL DETECTION TO
DECISION MAKING

21. CONCLUSION
 Almost 20 years after …
 750+ new medicines authorised thorough the European Union
including products which have dramatically changed the
course of some diseases:
 Antiretrovirals (NRTi, NNRTi, PIs)
 Anticancer medicinal products (tyrosine kinase inhibitors
e.g. imatinib)
 Orphan diseases (agalsidase alfa, carglumic acid,
nitisinone, ...)
 Innovation
 Involved in the fighting of major Public Health threats (e.g.
pandemic influenza, antibiotic resistance, bioterrorism)

22. PRESPECTIVES
 Proactive publication of all clinical trials results and
implementation of clinical trials Regulation
 Increased transparency, patients and public
involvement (incl. public hearings)
 Public Health threats (Antimicrobial resistance,
Pandemic influenza, Ebola)
 Access to medicines (Adaptive licensing, Dialogue
with HTAs)
 Special populations (elderly)
 Benefit/risk methodologies

23. FURTHER READINGS
 European Medicines Agency (general and procedural
guidance, EPARs)
 www.ema.europa.eu and @EMA_News
 DG Health and consumers: medicinal products for human use
 http://ec.europa.eu/health/human-use/index_en.htm
 Europa: EU institutions and other bodies
 http://europa.eu/about-eu/institutions-
bodies/index_en.htm
 European Parliament: Environment, Public Health and Food
safety committee
 http://www.europarl.europa.eu/committees/en/envi/hom
e.html
 European Voice
 http://www.europeanvoice.com/

24. MAIN EU LEGISLATION
 Regulation (EC) 726/2004 consolidated version
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2004_726_cons/reg_2004_726_cons_2013_en.pdf
 Directive 2001/83/EC consolidated version
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf
 Regulation (EC) No 1394/2007 advanced therapies
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2007_1394/reg_2007_1394_en.pdf
 Regulation (EC) No 141/2000 Orphan drugs
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2000_141/reg_2000_141_en.pdf
 Regulation (EC) No 1901/2006 Paediatrics
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf
 Regulation (EU) No 712/2012 Variations
http://ec.europa.eu/health/files/eudralex/vol-1/reg_2012_712/reg_2012_712_en.pdf