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European Medicines Agency (EMEA


European Medicine
Strategy and Liver
International Symposium Liver & Drugs 2008 – Viral
Hepatitis – The Health Priority in EU,
September 5, 2008, Bratislava, Slovak Republic

Jan Mazag, CHMP Member, EMEA (London)
Who is who
1.EC: European Commission

2.EMEA: European Medicines Agency

3.NCA: National competent authorities

Committee for Human Medicinal Products
5.VWP: Vaccine Working Party
The European perspective
= 27 Member States plus
2 observers: Ic & No
The European system – Why?
• Complete single EU market for
• Protect and promote public and animal
• Facilitate availability to patients of new
• Same product information for
professionals and for patients
• Benefit European R&D pharmaceutical
The European system – How?

• “One European system: two procedures”
− Centralised procedure
− Mutual recognition and decentralised
• EMEA is focal point of the centralised
• Rapid and EU-wide authorisation after
single evaluation
• No price or reimbursement issues
40 years of harmonisation
• 1965 - First Directive set out basic principles
• 1975 - First pharmaceutical testing Directive
• 1981 - Specific veterinary legislation
• 1985 – ‘1992 Single Market’ project launched
• 1993 - Council Regulation No 2309/93
• 1995 - EMEA officially opens and new
system comes into operation
• 2001 - Commission proposes ‘Review’
A networking decentralised
• Member States have pooled their
sovereignty for authorisation of
• EMEA is designed to coordinate the
existing scientific resources of Member
• EMEA is not intended to replace national
authorities, but to be a partner in the
• A ‘virtual’ agency, providing an interface
EMEA and its Europartners

• Some 45 national competent authorities
(dealing with human and veterinary
• Network of over 4,500 European experts
• EU institutions: European Commission,
European Parliament, other EU agencies
(EMCDDA, EFSA, ECDC, Translations
• European Pharmacopoeia (Council of
• Medicines Control Laboratories Network
EMEA and national authorities
• European experts’ network underpins the
work of the scientific committees and
working parties
• European experts work for EMEA
independently of their nominating
• Scientific competence is guaranteed by
their nominating authority, independence
and integrity assured by public declaration
of interests
EMEA and EU institutions

• EMEA is a decentralised agency of the EU,
not part of the European Commission
• EMEA adopts opinions on basis of
scientific criteria, Commission takes
decisions based on that opinion
• Commission must fully justify decision
when it is not in accordance with EMEA
EMEA – a dynamic
• 2001: Orphan medicines
• 2005 & 2008: Extended mandatory scope
• 2005: ‘Biosimilar’ and generic medicines
• 2005: Herbal medicines
• 2007: Paediatric medicines
• 2008/2009: Advanced therapies
EMEA priorities in 2008
• Our core business
• Safety monitoring of medicines for human
and veterinary use
• Earlier and improved availability of
• Stimulation of innovation
• The European medicines network
• Transparency, communication and
provision of information
• International regulatory activities
Structure of EMEA

Management Executive
Board Director


EMEA Secretariat
Administration Evaluation of Technical Evaluation of
Medicines for Co Medecines for
…… Human Use Ordination Veterinary
Pre- / Post - Use
……. Authorization Inspections
Units …. …….
Vaccines for preventive use

● Problem of immunogenicity of vaccines

● Effectivity of vaccines

● content of organomercuric preservative
mainly used in vaccines (from 1999)
HBV actual guidelines
● Guideline on the core SPC for human plasma derived
hepatitis –B immunoglobulin for intramuscular use
Actual from November 2006

● Guideline on the core SPC for human plasma derived
hepatitis-B immunoglobulin for intravenous use
Actual from November 2006

Coordination role in harmonisation of SPC for products used in
immunopropfylaxis of HBV in non- immunised patients
HCV Infection – European perspective
● HCV infection is the most common infection causing chronic liver
● Prevalence varies by geographic region (about 0.5% in Northern
countries, 2% and higher in Mediterranean countries / Eastern Europe).
● HCV of genotype 1(GT 1) is the predominant genotype.
● 30% (-50%) of HIV-infected patients are co-infected with HCV.
● After about 20 years, around 20–30% of chronic carriers progress to
cirrhosis, 5–10% have end stage liver disease and 4–8% die of liver-
related causes. In patients with cirrhosis, the 5-year risk of hepatic
decompensation is around 15-20% and that of hepatocellular carcinoma
around 10%.
● The current standard-of-care (SOC) is pegylated interferon-alpha 2a or
2b and ribavirin.
● With SOC, around 70-85% of patients infected with HCV genotype 2 and
3 achieve SVR after a 6-month treatment course. In contrast, only half
of patients infected with HCV genotype 1 and 4 reach SVR despite
treatment for one year.
Medicinal products for treatment
of Hepatitis (1/2)
INN Invented Indications (Hepatitis-related only)+ Approval
name route*
Peginterferon alfa-2a Pegasys ● Treatment of hepatitis B in adults CP
● Treatment of chronic hepatitis C in adults (in
combination with ribavirin or exceptionally as monotherapy )

Peginterferon alfa-2b PegIntron ●Treatment of chronic hepatitis C in adults (in CP
combination with ribavirin or exceptionally as monotherapy )

Interferon alfa-2a Roferon-A ●Treatment of chronic hepatitis B in adults MRP
Interferon alfa-2b Intron ●Treatment of chronic hepatitis C in adults# (in CP
combination with ribavirin or exceptionally as monotherapy )

Ribavirin Copegus ●Treatment of chronic hepatitis C in adults (only in MRP
combination with peginterferon alfa-2a or interferon alfa-2a; not as

Rebetol ●Treatment of chronic hepatitis C (only in combination CP
with peginterferon alfa-2b [adults] or interferon alfa-2b [adults,
children, adolescents]; not as monotherapy)

Not reflecting details of the indication wording; * CP = centralised procedure, MRP = Mutual Recognition Procedure;
Intron is also approved for use in children and adolescents
Medicinal products for treatment
of Hepatitis (2/2)

INN Invented Indications (Hepatitis-related only) Approval
name route*
Lamivudine Zeffix ● Treatment of chronic hepatitis B in adults CP
» compensated liver disease (active viral
Adefovir Hepsera CP
replication, elevated ALT, histological evidence of
liver inflammation or fibrosis)
» decompensated liver disease
Telbivudine Sebivo ● Treatment of chronic hepatitis B in adults CP
» compensated liver disease (active viral
Entecavir Baraclude replication, elevated ALT, histological evidence of CP
liver inflammation or fibrosis)
Tenofovir Viread CP
* CP = centralised procedure
EMEA/CHMP Guidelines
● Clinical Evaluation of Medicinal Products
intended for Treatment of Hepatitis B
» In effect since Sep 2006
● Clinical Evaluation of Direct Acting Antiviral
Agents intended for Treatment of Chronic
Hepatitis C (CHMP/EWP/30039/08)
» Release for consultation Apr 2008
Draft HCV Guideline (1/2)
● Guidance on the design of exploratory and confirmatory clinical
studies for the evaluation of direct-acting anti-HCV compounds as
add-on to SOC in different target populations.
● Specifically addressing the constraints caused by the high
mutation rate of HCV.
● Focused on direct-acting anti-HCV compounds.
● Numerous direct acting antivirals from different pharmacological classes
are currently under development for the treatment of chronic Hepatitis C
infection, particularly
» HCV Protease (NS3/4A) inhibitors;
» HCV Polymerase (NS5B) inhibitors.
Draft HCV Guideline (2/2)
● Subject characteristics and selection of subjects.
● Methods to assess efficacy
» HCV genotyping and viral load
» Primary endpoint
» Secondary endpoint
» Liver histology.
● Clinical pharmacology studies
(Pharmacokinetics, Pharmacodynamics).
● Clinical efficacy studies (exploratory studies, confirmatory studies)
● Studies in special populations
» Transplant patients
» Studies in children)
● Clinical safety evaluation
Published Draft