BEIJING
BRUSSELS
CHICAGO
DALLAS
FRANKFURT GENEVA
HONG KONG
LONDON
LOS ANGELES
NEW YORK
SAN FRANCISCO
SHANGHAI
SINGAPORE
TOKYO
WASHINGTON, D.C.
The Future of Pharmacovigilance:
Hot Issues on the Horizon in the EU
Maurits Lugard, Partner
November 8, 2007
Overview Presentation
• What’s on the Horizon for
the EU PV System
• a New EU Council
Regulation?
• New EU PV Requirements
(Volume 9A)
• New EU Penalties
Regulation
Overview Presentation
• What’s on the Horizon
for the EU PV System
• a New EU Council
Regulation?
• New EU PV Requirements
(Volume 9A)
• New EU Penalties
Regulation
EU PV System Re-design
• The Commission recently announced that it intends to
re-design the EU PV system
• Follows an open consultation from Spring 2006
• Commission’s primary goals:
– Achieve a better implementation of the current PV
system
– Introduce changes to the legal framework to clarify
and simplify standards and reporting requirements
EU PV System Re-design
• 2004
Commission launches call for proposals for
independent study of strengths and
weaknesses of current system
• 2005
Study conducted by
Fraunhofer Institute & University of
Tűbingen
• 2006
Public consultation on outcome study
• 2007
New strategy announced by
Commissioner Verheugen & impact
assessment
• 2008
New legal proposal adopted by
Commission
Some Key Weaknesses in EU PV Regime:
• Legal framework is complex and difficult to rapidly
understand
• Implementation is not the same in all MS
• Complex system with many players
• Frequent duplication of work
• Quality management is lacking
• Resources vary considerably
– 50 persons in Germany; a handful in some new Member States
• Funding is problematic
• Decision-making can be slow, especially at EU level
Better Implementation of Current EU PV
System
• Commission will:
– Fund studies into both the safety of medicines and
general methodologies used to conduct PV
– Make efforts for the EU Member States to resolve
implementation issues (reporting)
– Ensure the EMEA has a stronger coordinating role in the
overall process
• Including better use of the Eudravigilance database
Anticipated Changes to the PV Legal
Framework
• Minimize duplications between Member States and the
EMEA
• Strengthen rules on transparency relating to PV data,
assessment and decision-making
• Involve stakeholders in the processes (patient groups)
• Establish clear standards (Good Vigilance Practices)
• Simplify reporting of ADRs
• Establish a clear legal requirement to conduct postauthorization safety studies (PASS)
• BIG OPEN QUESTION: Entirely new legal framework??
Overview Presentation
• What’s on the Horizon for
the EU PV System
• a New EU Council
Regulation?
• New EU PV Requirements
(Volume 9A)
• New EU Penalties
Regulation
Instruments for Regulating PhV in the EU
• Council Regulation
• EU Directives
• EU Guidances
• National legislation
• International fora
Council Regulation
• Adopted by the Council and the European
Parliament based on a proposal from the European
Commission
• Directly applicable in EU Member States
• Consistency of law throughout the EU territory is
safeguarded - “no discrepancies”
• Published in the Official Journal
• Available in all official languages
• Full legal certainty
-
Council Regulation 726/2004 (for central
authorization – in force since 20 November 2005)
EU Directives
• Adopted by the Council and the European Parliament based
on a proposal from the European Commission
• National implementation is required – “not directly
applicable”
• Discrepancies in national implementing laws
• Published in the Official Journal
• Available in all official languages
• Legal certainty, but no EU uniform regime
- Directive 2001/83/EC (for national authorization and
mutual recognition – important amendments were to be
implemented by EU Member States by 30 October 2005)
EU Guidances
Commission guidances
• Drafted by DG Enterprise in consultation with EMEA and
other experts
• No systematic input from other Commission services
• No input from EU institutions, e.g. Council or European
Parliament
• Legally binding?
• Sometimes ambiguous provisions
• Available only on Internet (DG Enterprise website) and in
English
- Eudralex Volume 9A
EU Guidances
EMEA guidance documents
• Drafted by Pharmacovigilance Working Party
• Not adopted through a legislative process
• Legally binding?
- EMEA/CHMP/313666/05 Note for Guidance on the
Exposure to Medicinal Products during Pregnancy: Need for
Post-Authorisation Data (Adopted November 2005)
- EMEA/115735/2004 Note for Guidance on the Electronic
Data Interchange (EDI) of Individual Case Safety Reports
(ICSRS) and Medicinal Product Reports (MPRS) in
Pharmacovigilance during the Pre-and Post-Authorisation
Phase in the European Economic Area (EEA)
(EudraVigilance TIG adopted September 2004)
National legislation
• Country specific
• Exists side-by-side with EU PhV legislation
• Complex network of 27 national rules in
national languages
• Harmonization does not mean uniformity rules are transposed differently and at
different speeds in different Member States
• Necessary to comply with different national
obligations, including reporting
requirements and timeframes
• Duplication of national efforts ties up
resources that could be better spent on
drug safety
International Agreements
• International Conference
on Harmonization (‘ICH’)
• Council for International
Organizations of Medicinal
Sciences (‘CIOMS’)
A PhV Council Regulation could address
(certain) weaknesses in EU PV System
• Detailed clear and concise provisions
• Directly applicable in EU Member States
• Eliminates national discrepancies
• Prepared with input from all interested parties
• Legally binding on all interested parties
• Published in the Official Journal in all official
languages
Overview Presentation
• What’s on the Horizon for
the EU PV System
• a New EU Council
Regulation?
• New EU PV
Requirements (Volume
9A)
• New EU Penalties
Regulation
Volume 9A: Guidelines on
Pharmacovigilance
• Published January 25, 2007
• Took effect immediately
• Applies to medicinal products for human use
authorized in the EU
• New content compared to Volume 9
– Revised guidelines on previously covered topics
– New guidelines on new topics
– Collection of other guidelines in one document
Part I, Section 1.2.1 – Role &
Responsibilities Of The QPPV
• Two types of responsibilities:
(1) those that cannot be delegated and for which there is
“direct responsibility” by the QPPV
(2) those that can be delegated, but for which the QPPV
must maintain “oversight responsibility”
Part I, Section 1.2.1 – Role &
Responsibilities Of The QPPV
• QPPV’s direct responsibilities are:
1. establish/maintain/manage MAH PV system
2. have overview of safety profiles and emerging safety
concerns for all products for which the MAH holds
authorization
3. be single contact point for Competent Authorities (24
hours!)
Part I, Section 1.2.1 – Role &
Responsibilities Of The QPPV
• QPPV’s oversight responsibilities are:
• ensure collection of adverse reactions at one point in
the EU
• ensure preparation of ICSRs, PSURs, reports on PASSs
• ensure continuous overall post-authorization PV
evaluation
• ensure that requests from CAs are answered fully &
promptly
• ensure that CAs are provided with any other relevant
information re: risk-benefit, including information on
PASS and data from sources related to reporting in
special situations
Part I, Section 1.2.1 – Role &
Responsibilities Of The QPPV
• QPPV also has oversight responsibility to cover the
functioning of the PV system in all relevant aspects
including:
• quality control and assurance procedures
• SOPs
• database operations
• contractual arrangements
• compliance data
• audit reports
• PV training of personnel
Part I, Section 1.2.2 – Role &
Responsibilities Of The MAH v. QPPV
• Pharmaceutical groups with
more than 1 PV system can
have more than 1 QPPV
– “Each company (i.e.
Applicant/MAH or group of
MAHs using the same PV
system) should appoint 1 QPPV
responsible for overall PV for all
medicinal products…”
Part I, Section 1.3 – Contractual
Arrangements
• New section
• MAH may transfer any and all its PV tasks,
including those of QPPV, to others
(person/organization), but ultimate responsibility
always remains with MAH
• MAH must have “detailed and clear
documented contractual arrangements” in
place to meet PV obligations
• MAH must provide authorities with “information
on such arrangements”
Part I, Section 4 Requirements for
Expedited Reporting of Individual Case
Safety Reports
• Clock for expedited reporting: starts (“day 0”) as
soon as the minimum information has been brought
to the attention of:
– Any personnel of the MAH or
– An organization having a contractual arrangement with
the MAH, including medical representatives
Overview Presentation
• What’s on the Horizon for
the EU PV System
• a New EU Council
Regulation?
• New EU PV Requirements
(Volume 9A)
• New EU Penalties
Regulation
Penalties Regulation
• Commission Regulation (EC) No 658/2007 of 14 June 2007
concerning financial penalties for infringement of certain
obligations in connection with marketing authorisations granted
under Regulation (EC) No 726/2004 of the European Parliament
and of the Council, OJ L 155, 15.6.2007, p. 10.
• Effective from July 5, 2007
• Top line:
– applies to centrally authorized products
– lays down rules concerning the imposition of financial
penalties to MAHs in respect of 17 infringements,
including re: PV obligations
– financial risk associated with non-compliance: up to
5% of total EU annual turnover
Infringements covered
•
17 different types of infringement, which can be
divided into four main categories:
I.
completeness and accuracy of submissions to EMEA
(article 1.1)
II. breach of the conditions and restrictions imposed in
the marketing authorization re safe and effective use
(articles 1.2 to 1.3)
III. breach of post-marketing obligations (articles 1.4 to
1.11)
IV. infringement of PV rules, including: QPPV, AE
reporting, communication (articles 1.12 to 1.17)
Enforcement procedures
Two stages:
I.
investigation stage by
EMEA (to report within 18
months)
II. decision-making stage by
the Commission
Enforcement procedures
Investigation stage (I):
● By who? To be initiated by EMEA (article 5) either

at its own initiative; or

at the request of the European Commission; or

at the request of an EU Member State.
● When? In cases where the infringement concerned
•
may have significant public health implications in the
Community, or
•
where it has a Community dimension by taking place or
having its effects in more than one Member State, or
•
where interests of the Community are involved
Enforcement Procedures
Investigation stage (II)
•
Third parties have no formal right to request an
investigation by way of complaint
•
EU Member States and MAHs are required to
cooperate with EMEA in its request for information
• failure to do so by MAH may result in fines up to
0.5% EU annual turnover, and periodic penalty
payments per day of up to 0.5% of MAH’s daily
EU turnover in case of continuous noncooperation
•
MAH has right of access to the file
•
MAH has right to submit written observations prior to
adoption of EMEA report
Enforcement Procedures
•
Decision-making stage:
•
Controlled by European Commission
•
Based on EMEA report, the Commission will decide
whether to continue procedure
•
If so, it sends out Statement of Objections to MAH
(with allegations and notice that fines may be imposed)
•
MAH has right to submit comments in writing
•
Right to request oral hearing, with legal representation
Forms of Penalties
• Financial penalties can
take two forms:
– a fine of up to 5% of
the MAH’s annual EU
turnover; and
– periodic penalty
payments per day of
up to 2.5% of
average EU daily
turnover in case of
continuous
infringement
Determination level of financial penalty
• Which level of fine is appropriate?
– European Commission has broad discretion
– Principles of “effectiveness, proportionality and dissuasiveness”
– taking into account a long list if circumstances
 seriousness and effects of infringement;
 presence or absence of good faith or evidence of willful deceit;
 degree of diligence and cooperation or any obstruction by MAH;
 need to adopt provisional measures as a matter of urgency;
 repetition, frequency or duration of infringement;
 prior sanctions imposed on MAH;
 turnover of medicinal product concerned.
Questions?
Thank you!
Maurits J.F. Lugard
Partner
Sidley Austin LLP
Square de Meeûs 35
B–1000 Brussels, Belgium
Tel: + 32 2 504 64 17
E-mail: [email protected]
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European Enforcement of Pharmacovigilance and …