Implementation and Impact of the PV Regulations - how are we

doing? Sue Rees Eisai Europe Ltd. &

John Barber, Dr Reddy's Laboratories

Agenda

• PSMF

• PSURs

• Solicited sources

• RMPs

• Inspections

• Signal detection

• Impact on Resources

Ground Rules

• Session Leaders to give an overview of status and issues / challenges

• Delegates to give their experiences, pose questions, challenge assumptions etc

– Confidential sharing of experiences

• Session leader briefly summarise discussion

• Move on to next topic

• General Q&A at the end if time

PV SYSTEM MASTER FILE

Status

• Commission Implementing Regulation finalised 19 June 2012

• GVP Module II issued 22 June 2012

• Required by July 2015 or with first MAA / Renewal after 2 July 2012

• No template but lots of guidance

• Summary only to be submitted – must be available in 7 days

Summary of PSMF

Challenges - Structure

PSMF Summary

PSMF Master Document

PSMF Annexes

Only when QPPV changes

Only when major changes to PV system

Dynamic and constantly changing 1 person or multi-input?

Challenges – Information gathering

• Global information – not just from PV

• Organisational structure including FTEs

– Local affiliates with multi-faceted roles

• List of products and contacts in all countries

– CAPs not marketed in countries with no affiliate

• Full list of organised data collection schemes

• SOPs for all critical processes – easier if you have global processes

Challenges – Co-marketing MRP

• Whose PSMF?

Response from MHRA:

“You would be required to submit each PSMF to all concerned member states, much in the same way that you would have to submit a batch release site to all member states, even though it may only be used in a single country.

Each PSMF will require its own variation, therefore a group application should be submitted. “

Other challenges / discussion points?

PSURS

PSURs

• Status

– GVP Module VII issued June 2012

– EURD list not finalised until October 2012

– New format mandatory from 10 January 2013

– Critical evaluation of benefit: risk required from July 2013

– EURD list mandatory from 1 April 2013

– Best practice guidelines on submission of renewals issued September 2013

PSURs

• Issues – Phased implementation – 3 phases – EURD list and harmonisation with global requirements – Impact on global requirements

• 60 days RoW vs 70/90 days in Europe • Formatting differences • SBRs no longer accepted

– Impact on generic sector • PSURs no longer routinely required for generics • Competent authorities not following the EURD list • What are the safety issues requiring a generic PSUR? • Different requirements within a product class

PSURs

• Issues – Impact on innovators

• Significant increase in workload

– Benefit assessment

– Benefit:risk assessment

– Single assessment – when?

– Addendum to the clinical overview • Almost a PSUR but not quite

– New renewal requirements effective from April or September 2012?

Other challenges / discussion points?

SOLICITED SOURCES OF DATA

Status

• GVP Module VI is clear

– All data from organised data collection schemes is solicited (except some named patient or compassionate supply where AEs are not actively sought)

• EMA Q&A July 2012

– All adverse events should be collected by the MAH and assessed as to whether or not they are suspected adverse reaction

Causality assessments

• EMA Q&A July 2012

– MAH should exercise due diligence in asking the primary source for their opinion on causality

• Even if the primary source is the patient

– Where causality is missing MAH should exercise judgement on whether the report is a valid ICSR which should be reported

Recent developments

• Efpia position paper on PSPs and MR

– Clearer definition of PSP

– Propose some reports are classified Spontaneous

– Plan to generate further data

• Correspondence from Peter Arlett that further guidance is being developed and will be subject to consultation shortly

Challenges - Different interpretations

• Only collect non-serious (events ? reactions?) if protocol specified

• Change all protocols to specify collection of non-serious

• All new protocols to specify collection of non-serious

Challenges – Causality

• Who makes causality / serious assessment

– Global drug safety team

– Local Safety officer

– CRO

– Reporter

Challenges – Safety database

• Will you add all events (including non-serious events) to your global safety database?

• Translation burden (some Japanese PMS have 5000 events reported)

• How will you factor in to signal detection?

• Do all ODCS, globally for products authorised in EU have a process for collecting adverse reactions?

Other challenges / discussion points?

RMPS

RMPs

• Status

– GVP Module V issued June 2012

– Templates issued November 2012

– Mandatory of all new applications from July 2012

– New format mandatory from 10 January 2013

– Modular format, compatible with PSUR sections

– Lay summary required

– Updates required, annual for 3 years then 3 yearly

RMPs

• Issues

– Phased implementation

– Impact on generic sector

• Access to innovator’s RMP

– Impact on innovators

– Preparation of lay summary

– Updates – when and how

– No/limited assessment experience

Other challenges / discussion points?

AUDIT AND INSPECTION

Status

• GVP Module I – PV Systems and their Quality Systems

• GVP Module II – PV System Master File • Came in to effect 2 July 2012

• GVP Module III – Pharmacovigilance

Inspections • GVP Module IV – Pharmacovigilance Audits • Came in to effect 13 December 2012

Audit Strategy and Planning

Strategic level audit planning

• An audit strategy over 2-5 years which should be endorsed by upper management

Tactical level audit

planning

• A 1 years audit programme, setting audit objectives, and the extent and boundaries of the audits in that programme

Operational level audit planning

• An audit plan for individual audit

Audit Strategy and Planning

Strategic level audit

planning

• Our 5 years strategy is to

• Conduct PV audits of the affiliates based on the results of an annual risk based questionnaire

• All offices will be audited at least every 3 years

• All distributors collecting AE reports will also be in scope for audits

• All PV global centres will be audited at least annually

Tactical level audit

planning

• In 2013 a full PV system audit will be conducted at the EU PV centre

• Affiliate audits of Germany, Spain and Belgium will be conducted

• Distributors X & Y will be audited in line with SDEA

• Audit scope will include key interface departments

Operational level audit planning

• The audit on France will take place in May

• Company Z has been engaged to conduct the audit

• The agenda for the audit will cover the following areas

• etc

Reporting Audit Findings

• The audit process should include communicating the audit findings to the auditee and to management and allow feedback

• Issues that need to be urgently addressed should be communicated in an expedited manner to management and senior management

• QPPV should receive relevant audit reports • Audit findings should be graded in order to indicate their

relative risks impacting the pharmacovigilance system • The grading system should be defined in the description of

the quality system for pharmacovigilance • Critical and major findings must be reported in the PSMF

until resolved

Preparing for an Inspection

• DDPS or PV System Master File? – Whichever is in place and up to date! – Don’t claim to have a PSMF if you don’t have one!

• May still have to produce specific listings or questionnaires for Inspectors – May sure it is checked and that those who will be at the

forefront of the Inspection know what is in it!

• Understand the Transitional Arrangements – When should you change and when will you change?

• Ensure Core processes are documented • NB: GVP Module I has no transition timeframe!

Hot Topics – Events of Interest

• Off label use with no adverse event

• Occupational Exposure

– How are you collecting?

– Has everyone been trained?

– How are you reviewing for signal detection?

• How are you following up pregnancy reports?

Hot Topics – Third Parties

• Are your agreements comprehensive and up to date with new legislation?

– Consider simple agreement to cover additional requirements in interim

• Do you have plans in place to audit your third parties?

• What level of training have they had?

January 2013

Hot Topics - Processes

• Are your processes well documented and up to date – Changes in ICSR reporting – PSUR production (inc training and QC) – Signal detection – Responding to regulatory requests (including

assessment reports)

• What processes do you have to ensure Quality? – ICSRs – PSURs – Translations

January 2013

Other challenges / discussion points?

SIGNAL DETECTION

Signal Detection

• Status

– GVP Module IX issued June 2012

Signal Detection

• Issues

– No clear and unequivocal guidance on what should be done and when

– More robust processes required?

– Access to EudraVigilance data, when and what?

– Role of the PRAC

Other challenges / discussion points?

IMPACT ON RESOURCES

Resource Challenge Manage PSMF

PBRER / PSUR complexities

RMPs for generics

Lay summary in RMP

Non-serious ICSR reporting

Collecting non-serious solicited events

Collecting off label use with no ADR

Fewer PSURs for established products (only in EU)

Eventual EV reporting

Less country specific ‘gold plating’?

Fewer variations related to DDPS

“Judge a man by his questions – not his answers” Voltaire