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