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European Medicines Agency (EMEA

)

European Medicine
Strategy and Liver
Diseases/Hepatitis
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
http://ec.europa.eu/enterprise/pharmaceuticals/index_en.htm

2.EMEA: European Medicines Agency
http://www.emea.europa.eu

3.NCA: National competent authorities
http://www.hma.eu

4.CHMP:
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
pharmaceuticals
• Protect and promote public and animal
health
• Facilitate availability to patients of new
medicines
• Same product information for
professionals and for patients
• Benefit European R&D pharmaceutical
industry
The European system – How?

• “One European system: two procedures”
− Centralised procedure
− Mutual recognition and decentralised
procedures
• EMEA is focal point of the centralised
procedure
• 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
adopted
• 1985 – ‘1992 Single Market’ project launched
• 1993 - Council Regulation No 2309/93
adopted
• 1995 - EMEA officially opens and new
European
system comes into operation
• 2001 - Commission proposes ‘Review’
package
A networking decentralised
agency
• Member States have pooled their
sovereignty for authorisation of
medicines
• EMEA is designed to coordinate the
existing scientific resources of Member
States
• EMEA is not intended to replace national
authorities, but to be a partner in the
system
• A ‘virtual’ agency, providing an interface
EMEA and its Europartners

• Some 45 national competent authorities
(dealing with human and veterinary
medicines)
• Network of over 4,500 European experts
• EU institutions: European Commission,
European Parliament, other EU agencies
(EMCDDA, EFSA, ECDC, Translations
Centre)
• European Pharmacopoeia (Council of
Europe)
• 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
authority
• 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
opinion
EMEA – a dynamic
agency
• 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
medicines
• Stimulation of innovation
• The European medicines network
• Transparency, communication and
provision of information
• International regulatory activities
Structure of EMEA

Management Executive
Board Director

Financial
CHMP CVMP COMP HMPC PedCom
Controller

EMEA Secretariat
Administration Evaluation of Technical Evaluation of
Medicines for Co Medecines for
…… Human Use Ordination Veterinary
Pre- / Post - Use
……. Authorization Inspections
Units …. …….
5/15
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
(CHMP/BPWG/4222/02)
Actual from November 2006

● Guideline on the core SPC for human plasma derived
hepatitis-B immunoglobulin for intravenous use
(CHMP/BPWG/4207/02
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
disease.
● 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
monotherapy)

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
(CPMP/EWP/6172/03)
» 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)
Scope
● 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.
Background
● 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)
Topics
● 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

http://www.emea.europa.eu/pdfs/human/ewp/3003908en.pdf