marketing authorisations in the european union
TRANSCRIPT
MARKETING AUTHORISATIONS IN THE
EU: THE CENTRALISED PROCEDURE
October 2016
François MAIGNEN
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
THE STARTING POINT OF REGULATION OF
MEDICINES IN EUROPE
Frances Oldham
Kelsey (FDA)
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)
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
THE EU INSTITUTIONS
HISTORY OF THE AGENCY SINCE 1995 ...
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)
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
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)
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.
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.
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
THE COMMON TECHNICAL DOCUMENT:
DIRECTIVE 2001/83/EC, AS AMENDED
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
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
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
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)
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
SIGNAL DETECTION TO
DECISION MAKING
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)
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
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/
MAIN EU LEGISLATION
Regulation (EC) 726/2004 consolidated versionhttp://ec.europa.eu/health/files/eudralex/vol-1/reg_2004_726_cons/reg_2004_726_cons_2013_en.pdf
Directive 2001/83/EC consolidated versionhttp://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 therapieshttp://ec.europa.eu/health/files/eudralex/vol-1/reg_2007_1394/reg_2007_1394_en.pdf
Regulation (EC) No 141/2000 Orphan drugshttp://ec.europa.eu/health/files/eudralex/vol-1/reg_2000_141/reg_2000_141_en.pdf
Regulation (EC) No 1901/2006 Paediatricshttp://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf
Regulation (EU) No 712/2012 Variationshttp://ec.europa.eu/health/files/eudralex/vol-1/reg_2012_712/reg_2012_712_en.pdf