update on new pv legislation plg june2012

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Update on the New Pharmacovigilance Legislation

June 2012

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

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Agenda

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


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



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



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



• 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



• 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



• 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



• 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


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


GVP Module VI: Management and Reporting of Adverse Reactions to 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


GVP Module VI: Management and Reporting of Adverse Reactions to 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


GVP Module VI: Management and Reporting of Adverse Reactions to 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


GVP Module VI: Management and Reporting of Adverse Reactions to Medicinal Products Interim arrangements for MAHs


GVP Module VI: Management and Reporting of Adverse Reactions to 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


GVP Module VI: Management and Reporting of Adverse Reactions to Medicinal Products Final arrangements for MAHs


GVP Module VI: Management and Reporting of Adverse Reactions to 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


GVP Module VI: Management and Reporting of Adverse Reactions to 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


GVP Module VII: Periodic Safety 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



• 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



• List of Union Reference Dates (EURD)• Draft list released for public consultation on

4 April 2012• Consultation ends 4 June 2012• The following information is included for each active substance:

Names of active substances or combinations of active substances

European Union reference date (EURD)

Proposed PSUR Submission Frequency

ProposedDLP

Are PSURs required for Generics?Yes/No



• List of Union Reference Dates (EURD)• 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



• 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



• 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



• 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



• 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



• 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



• 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

Module number Module title Date of release for public consultation

III Pharmacovigilance inspections Q3 2012IV Pharmacovigilance system audits Q3 2012X Additional monitoring Q2 2012XI Public participation in pharmacovigilance Q4 2012

XIIContinuous pharmacovigilance, on‐going benefit‐risk evaluation, regulatory action and planning of public communication

Q4 2012

XIII Incident management (to be confirmed if to be included in Module XII) Q4 2012

XIV Referral procedures for safety reasons (to be confirmed if part of GVP or in Notice to Applicants) Q3 2012

XV Safety communication Q3 2012

XVI Risk minimisation measures: selection of tools and effectiveness indicators Q3 2012


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 84Mail : [email protected]

update on new pv legislation plg june2012

Health & Medicine

final gvp modules released25th

riskmanagementsystems

timelines 10december2008

annex moduleix