Update on new pv legislation plg june2012

Consulting and
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for Life Sciences

Update on the New
Pharmacovigilance Legislation

June 2012

06/07/2012 www.productlife‐group.com 1

Agenda

• Timelines
• Introduction to New PV Legislation
• Good Pharmacovigilance Practices
• GVP Modules
• Transitional Measures
• Article 57(2): XEVMPD

www.productlife‐group.com

Timelines

• 10 December 2008: Commission published proposals to amend
EU PV legislation contained in Directive 2001/83/EC &
Regulation 726/2004/EC
• 22 September 2010: Final text approved by EU Parliament
• 29 November 2010: Final approval by EU Council
• 31 December 2010: Final texts published in Official EU Journal
• 22 February 2012: Seven GVP modules released for public
consultation (ended 18 April 2012)
• July 2012: New legislation comes into force, first set of GVP
modules to be finalised


New PV Legislation

• The incoming legislation is outlined in Regulation (EU) No
1235/2010 (amending No 726/2004/EC) and Directive
2010/84/EU (amending 2001/83/EC).
• The legislation is the biggest change to the regulation of human
medicines in the European Union (EU) since 1995.
• It has significant implications for applicants and holders of EU
marketing authorisations (MAs).


Aim of New PV Legislation

• The legislation aims to:
• make roles and responsibilities clear
• minimise duplication of effort
• free up resources by rationalising and simplifying adverse
reaction (AR) reporting and periodic safety update report (PSUR)
reporting
• establish a clear legal framework for
post‐authorisation monitoring


Good Pharmacovigilance Practices

• Good Pharmacovigilance Practices (GVP) is a set of measures
drawn up to facilitate the performance of pharmacovigilance in
the EU.
• They apply to marketing authorisation holders, the European
Medicines Agency (EMA) and Competent Authorities in EU
Member States.
• The overall aim is to improve safety for patients by
strengthening pharmacovigilance across the EU.
• GVP covers medicines authorised centrally as well as medicines
authorised at national level.


GVP Modules

• There will be a total of 16 GVP modules, which the EMA anticipate
will be finalised by early 2013.
• First set of 7 modules were released on
22 February for public consultation.
• Public consultation ended 18 April.
• Remaining 9 modules to be released later in 2012.


Draft GVP Modules Released
February 2012
• Module I: Pharmacovigilance systems & their quality systems
• Module II: Pharmacovigilance system master files
• Module V: Risk management systems
• Module VI: Management and reporting of adverse reactions to
medicinal products
• Module VII: Periodic safety update reports
• Module VIII: Post‐authorisation safety studies
• Module IX: Signal management


Final GVP Modules Released
25th June 2012
• Module I: Pharmacovigilance systems & their quality systems
• Module II: Pharmacovigilance system master files
• Module V: Risk management systems
• Module VI: Management and reporting of adverse reactions to
medicinal products
• Module VII: Periodic safety update reports
• Module VIII: Post‐authorisation safety studies + annex
• Module IX: Signal management


Final GVP Modules Released
25th June 2012


Important to Note
• The information provided in the following slides is taken from
the draft GVP modules; these are subject to change before
finalisation, following the recent public consultation.
• When reading the GVP modules:
• All applicable legal requirements are referenced as explained in
the GVP Introductory Cover Note and are usually identifiable by
the modal verb “shall”.
• All guidance for the implementation of legal requirements is
provided using the modal verb “should”.


GVP Module I: PV Systems & Their
Quality Systems
• Guidance for the establishment and maintenance of quality
assured pharmacovigilance systems for MAHs, competent
authorities of Member States and the Agency
• The interactions of the systems of these organisations while
undertaking specific pharmacovigilance processes is described in
each respective Module of GVP


Quality Systems
• Overall quality objectives for pharmacovigilance
• Principles for good pharmacovigilance practices
• Responsibilities
• Training
• Facilities and equipment
• Compliance management


Quality Systems
• Record management
• Documentation
• Critical pharmacovigilance processes
• Monitoring performance and effectiveness
• Preparedness planning


Quality Systems
• MAHs shall also document
• their resource management
• job descriptions defining the duties of the managerial and
supervisory staff
• an organisation chart defining the hierarchical relationships of
managerial and supervisory staff
• arrangements for record management for the documentation of
the pharmacovigilance system and documents relating to
authorised medicinal products, including the location of the
records


Quality Systems
• PV Responsibilities of the MAH
• Responsibilities of the MAH in relation to the EU QPPV
• Qualifications of EU QPPV
• Role of EU QPPV – defines responsibilities
• Operation of the EU Network – section present in most GVP
modules


Quality Systems
• Specific quality system processes of the MAH
• includes requirement to continuously check the European
medicines web‐portal for any relevant updates, including
consultations and notifications of procedures to ensure product
information is kept up to date
• monitoring the use of terminology, with data entry staff being
instructed in the use of terminology and their proficiency
verified


GVP Module II: PV System Master File

• The PV System Master File (PSMF) is a legal requirement
• The PSMF replaces the Detailed Description of PV Systems (DDPS)
• Provides an overview of the PV system
• An MAH may have more that one PSMF
• PSMF must be maintained in real time and must be available to
Competent Authorities upon request
• No template available at this time



• Content
• Details relating to qualified person responsible for
pharmacovigilance (QPPV)
• Organisational structure of the marketing authorisation holder
relevant to PV
• Sources of safety data
• Computerised systems and databases



• Content
• Processes
• Monitoring of PV system performance
• Quality system



• Content
• Annex containing
– A list of Marketing Authorisations covered by the PSMF
– A list of contractual agreements covering delegated tasks
– A list of tasks that have been delegated by the QPPV
– A list of all completed audits, for a period of ten years, and a
list of audit schedules
– A list of performance indicators in accordance with the
Commission Implementing Regulation on the Performance
of Pharmacovigilance Activities Provided for in Regulation
(EC) No 726/2004 and Directive 2001/83/EC
– Where applicable, a list of other PSMFs held by the same
MAH
– A ‘logbook’ for recording changes to the PSMF



• Marketing Authorisation Application (MAA)
• The PSMF is not included in the MAA but may be requested by
Competent Authorities during assessment
• A summary of the applicant’s PV system should be included in the
MAA
– proof that the applicant has at his disposal a QPPV
responsible for PV
– the Member States in which the QPPV resides and
carries out his/her tasks
– the contact details of the QPPV
– a statement signed by the applicant to the effect that
the applicant has the necessary means to fulfil the
tasks and responsibilities listed in Title IX
– a reference to the location where the PSMF for the
medicinal product is kept



• Location
• Must be within the EU
• At the site where the main pharmacovigilance
– activities are performed
• or
• At the site where the EU QPPV operates



• Maintenance
• No variations required when updating PSMF
• Variations will be only required for changes to the PV system
summary submitted with the MAA
• Changes to the PSMF must be recorded in a ‘logbook’


GVP Module V: Risk Management
Systems
• A Risk Management Plan (RMP) is now required to be submitted
with each MAA
• RMP consists of seven parts, with some parts divided into
modules
• RMP is a dynamic, stand alone document which should be
updated throughout the life‐cycle of the product. For products
requiring periodic safety update reports (PSURs), certain (parts
of) modules may be used for both purposes


Systems
• RMP should be proportionate to risks
• New section on plans for post authorisation efficacy studies.
These can now be a condition of the MA in addition to post
authorisation safety studies
• Section VI of RMP includes a summary of safety concerns in lay
language
• Includes guidance for RMP requirements for specific situations


Systems


GVP Module VI: Management and
Reporting of Adverse Reactions to
Medicinal Products
• Summarises all legal requirements and guidelines applicable to
Competent Authorities, MAHs and the EMA with regard to the
collection, data management and reporting of
unsolicited/solicited cases of suspected adverse reactions
associated with medicinal products for human use authorised in
EU reported by healthcare professionals, patients or consumers


Medicinal Products
• Replaces Volume 9A:
• Chapter I.4: Requirements for expedited reporting of ICSRs
• Chapter I.5: Requirements for reporting in special situations
• Chapter II.1.3: Management of spontaneous reporting
programmes
• Part III: Electronic exchange of pharmacovigilance information in
EU


Medicinal Products
• Electronic reporting is now mandatory –
non‐adherence constitutes non‐compliance with EU legislation
• Reportable cases include healthcare professional and non‐
healthcare professional valid ICSRs
• Cases are considered valid if they contain the following:
– An identifiable reporter (primary source)
– An identifiable patient
– At least one suspected substance/medicinal product
– At least one suspected adverse reaction


Medicinal Products
• Interim arrangements – in place until the functionalities of the
EudraVigilance database specified in [Reg Art 24(2)] are
established
• Defined for MAHs and Competent Authorities


Medicinal Products
Interim arrangements for MAHs


Medicinal Products
• Final arrangements – will be in place within 6 months of the
announcement by the Agency of the establishment of the
appropriate functionality in EudraVigilance
• Defined for MAHs and Competent Authorities


Medicinal Products
Final arrangements for MAHs


Medicinal Products
• Requirement for weekly literature search remains – this module
contains a detailed guidance on monitoring scientific and
medical literature developed by the EMA
• EMA will monitor some publications for some products but list is
yet to be published
• Until list is published, MAHs must monitor literature for all
authorised products


Medicinal Products
• Module also contains
• Guidance on nullification of cases
• Business process maps and descriptions relating to
– Identification of biological medicinal products,
– Modalities for expedited reporting during interim and final
arrangements,
– Transmission and rerouting to NCAs of ICSRs submitted to
EudraVigilance by MAHs in final arrangements
– Transmission of ICSRs to WHO collaborating centre
– Data quality monitoring of ICSRs transmitted electronically
– Duplicate detection and management of ICSRs


GVP Module VII: Periodic Safety
Update Reports

• Change to format
• Publication of List of Union Reference Dates (replaces PSUR
Work‐sharing & Synchronisation Lists)
• Change to frequency of preparation ‐ periodicity is defined on
the basis of a risk‐based approach
• No PSURs required for some generic products
• New timelines for submission
• Single assessment


Update Reports - Format

• Modular structure including common modules with Risk
Management Plan (RMP)



• Template available ‐ list of sections and appendices prescribed
in GVP Module VII with details of information to be included in
each
• No line listings (may be requested during assessment)
• Emphasis on risk‐benefit evaluation



• Includes cumulative data starting from the granting of the
marketing authorisation with the focus on new information
emerging in the period since the DLP of the last PSUR
• A comprehensive and critical analysis of the risk‐benefit balance
of the medicinal product taking into account new or emerging
information, in the context of cumulative information


Update Reports
• List of Union Reference Dates (EURD)
• Objectives:
• Harmonisation of data lock point (DLP) & frequency of
submission of PSURs for the same active substance/
combination of active substances
• Optimisation of the management of PSURs & PSURs
assessments within the EU
• Single EU assessment & reassessment of the risk‐benefit
balance of an active substance based on all available safety data


Update Reports

• Draft list released for public consultation on
4 April 2012
• Consultation ends 4 June 2012
• The following information is included for each active substance:

Are PSURs required for
Names of active substances or European Union Proposed PSUR Proposed
Generics?
combinations of active substances reference date (EURD) Submission Frequency DLP
Yes/No


Update Reports
• Overrules the submission schedule described in [DIR Art 107c
(2)] & any conditions related to the frequency of submission of
PSURs included in the Marketing Authorisation
• As a result of the publication of the EURD list, any changes to
the PSUR submission frequency and dates of submission / DLP
will trigger the obligation of the MAHs to submit a variation for
the products where contradictory requirements are specified in
the Marketing Authorisation


Update Reports
• Timelines for submission
• Within 70 calendar days of the data lock point (DLP) for PSURs
covering intervals up to 12 months
• Within 90 calendar days of the DLP for PSURs covering intervals
in excess of 12 months
• Ad hoc PSURs requested by Competent Authorities: timelines
will normally be specified in the request, otherwise they should
be submitted within 90 days of the DLP


Update Reports
• Submission
• The EMA will set up a repository for submission of PSURs
• The repository shall undergo an independent audit before the
functionalities are announced by the EMA
• Until repository is ready (12 months after functionality has been
announced), all PSURs must be submitted to all Member States
where MA is held
• For substances with an EU reference date ‐ the PSURs should be
also sent to the EMA


Update Reports
• Single assessment
• Timelines for procedure defined in legislation
• Pharmacovigilance Risk Assessment Committee (PRAC)
involvement
• Outcome of PSUR assessment is legally binding and can result in
the marketing authorisations of the concerned medicinal
products being varied, suspended or revoked


GVP Module VIII: Post-Authorisation
Safety Studies
• Purpose of module:
• Provide general guidance and requirements for the conduct of
any non‐interventional PASS conducted by MAHs
• Provide general guidance and requirements for the protocol
oversight and reporting and transparency of results of any
non‐interventional PASS


Safety Studies
• Purpose of module:
• Describe the procedure whereby competent authorities may
impose an interventional or non‐interventional PASS to a MAH
as a condition of the MA
• Focusses mainly on non‐interventional studies – if PASS is a
clinical trial must comply with Directive 2001/20/EC and Volume
10 of The Rules Governing Medicinal Products in the European
Union


Safety Studies
• General principles
• Study protocol
• Reporting PV data
• Publication of study results
• Data protection
• Quality systems, audits and inspections
• Study registration
• Impact on the risk management system


Safety Studies
• If a PASS is condition of MA, must be described in RMP and
results included in next PSUR
• In an RMP does not exist then one must be prepared to describe
the PASS
• If results have an impact on MA then MAH must submit an
appropriate variation


GVP Module IX: Signal Management

• Objectives
• To provide general guidance and requirements on structures
and processes involved in signal management
• To describe how these structures and processes are applied in
the setting of the EU pharmacovigilance and regulatory network
in order to detect whether there are new risks or whether risks
have changed



• Describes signal management steps:
• Signal detection
• Signal validation
• Signal analysis and prioritisation
• Signal assessment
• Recommendation for action
• Exchange of information



• Refers to methods of signal detection described in ‘Report of
CIOMS Working Group VIII on Practical Aspects of Signal
Detection in Pharmacovigilance’
• Quality requirements include tracking, systems and
documentation, and training



• EMA have a significant role in signal management, including
publication of a list of products for work‐sharing of monitoring
EudraVigilance (EV) with Competent Authorities
• EV monitoring will be monthly, with more frequent reviews for
products subject to additional monitoring
• PRAC will be involved in validated signal assessment
• PRAC assessments and recommendations will be published on
European Medicines web‐portal



• MAH Responsibilities:
• Shall monitor all available data and information for signals
• Shall monitor the data in EV to the extent of their accessibility.
The frequency of the monitoring should be at least once
monthly and shall be proportionate to the identified risk, the
potential risk and the need for additional information
• Shall monitor all emerging data and perform worldwide signal
detection activities



• MAH Responsibilities:
• Shall validate any detected signal and shall forthwith inform the
responsible competent authority in line with the work‐sharing
list as published by the Agency
• Should notify as an Emergency (Emerging?) Safety Issue (see
Module VI) any safety issue arising from its signal detection
activity
• Should collaborate with the PRAC for the assessment of the
signals by providing additional information upon request
• Should keep an audit trail, via a tracking system, of their signal
detection activities


GVP Annex 1: Definitions

• Also released for consultation in February 2012
• Comprehensive list of PV related definitions
• Will be useful reference to ensure consistent standard across all
PV stakeholders
• Will be finalised by July 2012


Anticipated Timelines for Release of
Remaining GVP Modules
Date of release for
Module number Module title
public consultation

III Pharmacovigilance inspections Q3 2012
IV Pharmacovigilance system audits Q3 2012
X Additional monitoring Q2 2012
XI Public participation in pharmacovigilance Q4 2012
Continuous pharmacovigilance, on‐going benefit‐risk
XII evaluation, regulatory action and planning of public Q4 2012
communication
Incident management (to be confirmed if to be included
XIII Q4 2012
in Module XII)
Referral procedures for safety reasons (to be confirmed
XIV Q3 2012
if part of GVP or in Notice to Applicants)
XV Safety communication Q3 2012
Risk minimisation measures: selection of tools and
XVI Q3 2012
effectiveness indicators


Transitional Measures

• Apply to
• PSMF
• RMPs
• PSURs
• PASS
• Renewals

• The EMA have published a Q and A document, available at
• http://ec.europa.eu/health/files/pharmacovigilance/2012_02_q
a_phv.pdf


Transitional Measures

• No need to ‘upgrade’ pending Marketing Authorisation
Applications
• DDPS to PSMF by July 2015 – at renewal or by variation
• RMP – must include with all new applications. Authorities may
request RMP for existing MAs in justified cases
• PSURs – new format and submission in line with EURD from July
2012


Article 57(2): XEVMPD

• All MAHs must provide details of all their authorised products
to be included in the Extended EudraVigilance Medicinal
Product Dictionary (XEVMPD) by 02 July 2012 and on an on‐
going basis
• Training is required before MAHs can provide these details
• A web portal is available for small companies


Contacts

Your contact:
Dr Erick J. Gaussens (CSO)
Tel : +33 1 414 422 11 – Mob : +33 6 030 215 84
Mail : egaussens@productlife-groupe.com


Update on new pv legislation plg june2012

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