EU Pharmacovigilance Legislation (EU NL)

• Regulatory Implementation status• Overview and industry challenges

April-2014

QPPV Office Global Pharmacovigilance & EpidemiologySanofi

Anne-Marie De-FerranAssociate VP QPPV OfficeManager QPPV Office&PVPolicyGlobal Pharmacovigilance&Epidemiology

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Applicable to the 28 Member States and

Adopted by Norway, Iceland & Liechtenstein

[European Economic Area (EEA) countries]

EU Legal Framework for Pharmacovigilance

LPC Newcomers – October 14th to 15th – Chilly-Mazarin

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Regulatory Network Key European Authorities in PV

The Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human, examine any question relating to marketing authorisation of a medicinal product in two or more Member States in accordance with the mutual recognition procedure or the decentralised procedure

Executive body of the European Union responsible for proposing legislation, implementing decisions, upholding the Union's treaties and day-to-day running of the EU

Helps protect and promote health in Europe by evaluating medicines for both human and veterinary use

Heatlh Authorities of each Member State

The Committee for Medicinal Products for Human Use is the committee at the EMA that is responsible for preparing opinions on questions concerning medicines for human use.

CHMP

The committee at the EMA that is responsible for assessing and monitoring safety issues for human medicines.

EMA

PRAC

National Competent Authorities (NCA)

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● Regulatory Implementation status

● Overview of Major Regulatory Milestone of the EU Pharmacovigilance Legislation

● Industry Challenges

Agenda

EU PL – REGULATORY IMPLEMENTATION STATUS

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EU Pharmacovigilance Legislation

Applies on 21-Jul-2012

Applies on 2-Jul-2012

Applies on 10-Jul-2012Art.29/ 38 apply on 10 Jan 2013

Promote and protect public health by reducing burden of ADRs and optimising the use of medicines Clear roles and responsibilities Robust and rapid EU decision-making Engage patients and healthcare

professionals Science based - integrate benefit and risk Risk based/proportionate Increased pro activity/planning Reduced duplication/redundancy Increase transparency and provide better

information on medicines

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Regulation 1235/20101027/2012

Directive 2010/84/EU2012/26/EU Applies on 28-Oct-2013

Learn more on EU-PL:

Applies on 5-Jun-2013some articles apply on 4 Dec 2012

EMA website European Commission website

Applies on 31-Dec-2013.

Implementing Regulation520/2012

198/2013 ()

PV fees – Regulation (draft)PAES delegated act (draft)

Good Pharmacovigilance Practices (GVP)

Regulatory & procedural guidance

EMA Information & Communication

Directive 2010/84/EU Transposition in Member States

5 No Draft

● Overview of the transposition status from the Directive 2010/84/EU within each Member State Directive effective date at National Level: 21-July-2012 (MRP/DCP products) National Legislation release date:

26Final

EU NPL Transposition Status in 31 Member States

National Legislation:

Last update: 01-April-2014

EU Member

State

National legislation released date(P=planned)

EU Member State

National legislation released date(P=planned)

AUSTRIA 14-Dec-2012 LATVIA 01-Feb-2013

BELGIUM 10-Jun-2013 LIECHTENSTEIN -

BULGARIA 21-Dec-2012 LITHUANIA Nov-2012

CYPRUS 31-May-2012 LUXEMBOURG -

CROATIA July 2013 MALTA 30-Oct-2012

CZECH REPUBLIC 06-Mar-2013 THE

NETHERLANDS 08-Feb-2013

DENMARK 12-Jul-201201-Aug- 2012

NORWAY -

ESTONIA 23-Jul-2012 POLAND 25-Oct-2013

FINLAND 22-May-2013 PORTUGAL 14-Feb-2013

FRANCE 29-Dec-2011/ 09-Nov-2012

ROMANIA 21-Jul-2012

GERMANY 26-Oct-2012 SLOVAKIA 01-Sept-2012

GREECE Sep-2012 SLOVENIA 07-Mar-2014

HUNGARY 17-Jul-2012 SPAIN 26-Jul-2013

ICELAND - SWEDEN 21-Jun-2012

IRELAND 27-Aug-2012 UNITED KINGDOM 14-Aug-2012

ITALY -

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EU PV legislation status

●Implementation of the Pharmacovigilance legislation in July 2012 March 2014 : In EEA, final transposition of Directive 2012/84/EU into 26 national

legislations (5 missing) Amendment on directive and regulation released in Q3 2012 following “Mediator

stress test”

●The majority of the 15 GVP Modules has been now published, pieces are still expected.

●“Pharmacovigilance” legislation in name only Global impact; leaves virtually no function untouched Massive changes in multiple processes required, new skill sets required.

●Lack of harmonisation with non-EEA countries Increased bureaucratic burden with no contribution towards promoting patient safety.

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Updates to the PV legislation since July 2012

●Amendment of the PV legislation Recent pharmacovigilance incidents in the EU have shown the need to strengthen three

aspects of the pharmacovigilance legislation Release of Dir. 2012/26/EU [25 Oct. 2012] / Reg. (EU) 1027/2012 [14 Nov. 2012] Main focus on:

• In case of urgent safety issue Automatically assessed at European level [Art 107i (Dir.)]• Notification of MA status WW when safety concern [Art 23a (Dir) / Art 13a (Reg) – Art 14b (Reg.) / Art 123 (2) (Dir.) ]

• Art 23 (Reg) (c)-(d)

●GVP modules status 5 New, 3 Revised, 3 Expected

●Implementing Regulation 198/2013 on black symbol of 7 March 2013 Adopt black symbol (▼) to identify medicinal products that are subject to additional monitoring

●PAES Delegated act on PAES - Public consultation conducted from Nov. 2012 till Feb. 2013

●Future PV fees

 • • •

EU NPL – OVERVIEW AND INDUSTRY CHALLENGES

Major Regulatory Milestones

EU PV LegislationOversight by

QPPV

Transparency

PRAC

New PSUR/ PBRER

PASS/ PAES

PSMF

Renewals

RMP

Referral

Signal Detection and Screening

xEVMPD

Additional Monitoring

ICSR Management and Reporting

Fees

WW MA status notification

Transparency and Communication

● Creation of medicines web-portals (EMA and each Member State) PRAC Agenda, Minutes, including signal detection activities List of products subject to additional safety monitoring Summary of RMP for lay public PASS protocols and public abstract of results Community Reference Dates and frequency of PSUR submission Final assessment conclusions of PSUR and Urgent Union Procedure Information on Urgent Union Procedures

● EU coordinated communication about safety issues For products authorised in more than one Member States, EMA responsible for coordination

(timetables) of safety announcements between national Competent Authorities

● Eudravigilance publicly accessible Online publication of suspected side effect reports since May 2012 (Centrally Authorised Products) Information on Medicinal Products (xEVMPD)

Industry challenges

• Keep control over public information when product data is made available on web portals in the EEA, anticipate the consequences in the rest of the world

PRAC (PV Risk Assessment Committee)

● EMA 7th scientific Committee (Replacing the PhVWP) Members: EU National Agencies, HCP and Patients representatives Key role in PV assessments: mandatory or consultative role

• Referrals (Art 20, 31, 107i)• PSUR• PASS protocols and results• Signal detection• Safety communication• EURD lists

● Safety concerns : A major change in EU decision making process for safety issues Rapid risks evaluation in the context of the identified benefits

● Final responsibility for opinion on the risk-benefit remains with CHMP (centralised products) or CMDh (other products)

• Additional monitoring• RMP• Renewals & annual assessment• Type II safety variations• PV audits, inspections requests & results

Industry challenges

• Follow-up PRAC activities, answer all questions, coordinate with other MAHs.• Direct Healthcare Professional Communication (DHPC) & communication plan related to medicinal

products authorised in more than one Member State should be referred to the PRAC / EMA coordination.

PRAC - Responsibilities

● “The Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing all aspects of the risk management of the use of medicinal products [human use] approved in EEA.

● This includes the detection, assessment, minimisation and communication relating to the risk of adverse reactions, having due regard to the therapeutic effect of the medicinal product.

● It is responsible for the design and evaluation of post-authorisation safety studies and pharmacovigilance audit.”

Source: EMA webpage Pharmacovigilance

Risk Assessment Committee (PRAC)

PRAC - Composition

● The PRAC is composed of:

a chair and a vice chair, elected by serving PRAC members;

one member/alternate nominated by each of the 28 Member States;

one member/alternate nominated by Iceland and by Norway;

six independent scientific experts nominated by the EC;

one member/alternate to represent healthcare professionals nominated by the EC;

one member and one alternate to represent patients organisations nominated by the EC.

chair vice chair

June Raine Almaath Spooner

Source: EMA webpage Pharmacovigilance

Risk Assessment Committee (PRAC)

(including MRP & DCP)

PRAC Recommendations – Process Flow

Consensus*

Legallybinding

DECISIONto MSs

Majority Vote*

If at least 1 CAP

Source: www.ema.europa.eu

CHMP

Member States

PRAC

RECOMMENDATION

* If CHMP/ CMDh recommendations differ from those of the PRAC, the CHMP/ CMDh shall provide a detailed explanation of the scientific grounds for the differences with their recommendations.”

• Referrals• PSUR Assessment• PASS Results

Centrally Authorised Products (CAP)

Nationally Authorised Products

OPINION*

PRAC - Volume of main activities[July 2012 July 2013]

Source: PRAC minutes/ 7th EMA stakeholders meeting (June Raine)

Sep-12

Oct-12

Nov-12

Dec-12

Jan-13

Feb-13

Mar-13

Apr-13

May-13

Jun-13

Jul-13

0

20

40

60

80

100

120

140

Number of main agenda topics per meeting

Other CHMP/MSs

Renewals- Conditional Renewals- Annual Reassessments

PASSs

PSURs

RMPs

New Signals

New Referrals

Referrals33%

RMPs19%

PSUR16%

Other14%

Sig-nal

10%

PASS4%

Renewals4%

% of PRAC plenary discussion time 2013

Referral proceduresA new pan-European assessment of safety issues

●New referral procedure ‘Urgent Union Procedure’ (107i) Automatically assessed at European level

• Triggered by a Member State or the European Commission To provide a rapid evaluation of a safety issue linked with a

medicine, regardless of its initial authorisation route of the medicine

Scientific assessment lead by PRAC in collaboration with CHMP and Reference Member State

Public hearing may be organised depending of the seriousness of the issue

Re-examination not possible National temporary measures are possible prior PRAC

assessment Outcome

• No action, MAH further evaluation, PASS, RMP, Suspension of MA, Revocation of MA, No renewal of MA

Industry impacts

• Less national specificities/discrepancies• Learning to cope with public hearing in EU• Possible immediate temporary measures requested by the

European Commission upon PRAC recommendation -Art. 107(i)

● Processes for the management of adverse reaction reports need to be re-engineered and procedures will need to be amended in order to address the new requirements

New definitions, in particular for• Adverse Reaction: A response to a medicinal product which is noxious and unintended.

Includes medication errors and use outside the MA

Direct patient reporting New Reporting arrangements

• All EU and non-EU Serious ADRs to Eudravigilance (EV) only within 15 days , including consumer reports• All EU non-serious reports to EV only within 90 days

EV database is the single point of receipt for expedited reports • Until EMA can “ensure the functionalities of EV“ (not before 2015) - Transitional arrangements:

All national non-serious ADRs to Austria (for products under additional monitoring), Croatia, Denmark, Germany (for Vaccines only), Italy (except literature cases), Poland, and Romania (within 90 days)

Revised obligations for collecting reports in non-interventional/observational studies• All AE (serious or not [for EU at least] in a PV database , to allow reporting of all ADRs.

Literature monitoring (starting 2015)• EMA’s monitoring for a list of product in selected scientific literature • MAH’s monitoring for all other medical literature and other products

ICSR Reporting and Management

Industry challenges• Tracking of off-label use, misuse, abuse, occupational exposure and medication error without AEs• Collection of non-serious cases in post-authorisation non-interventional studies

● Non serious case collection from all PAS: number one concern Dir. Article 107(1) :

• “MAHs shall record all suspected adverse reactions in the Union or in third countries which are brought to their attention, whether reported spontaneously by patients or healthcare professionals, or occurring in the context of a post-authorisation study”. GVP Module VI implies only if actively sought i.e. protocol driven

Q&A (July 2012) citing GVP Module VI: • all adverse events should be collected by the MAH and assessed as to whether or not they are

suspected adverse reactions• Applies to all NIS, even if conducted outside Europe

Significant impact on all non-interventional field studies (NIS) which become more burdensome regarding AE collection than clinical trials.

New orientation: proposal of new requirements on management and reporting of suspected ADR originating in post-authorization studies• Based on feedback received from practical implementation of requirements set out in module VI• Public consultation on revised text S1 2013 - Still level of draft – final requirements may vary

Post Authorisation Studies (PAS)Non-Interventional Studies (NIS)

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● Reports from PSPs / MRs All to be classified as solicited in final GVP Module (July 2012), contrary to

what was proposed in the April 2012 draft Poorly documented reports; impossible to make informed causality

assessment and attempts to follow up nearly always unsuccessful Significant bureaucratic burden with no contribution to patient safety Said to be based on FDA position but not consistent with 1997 guidance

● Industry propose to revert to the April 2012 draft guidance Clarify the definition and allow classifying into those that actively seek

information and those that do not. Actively sought = solicited Others = implied causality Longer term - collect data to assess impact on signal detection

● Workshop conducted in June 2013 (@)

Patient Support Programs (PSP) / Market Research (MR)

● Signal detection in Eudravigilance by the EMA and NCAs (Published and managed by the PRAC)

● Information on “validated” signals, Emerging Safety Issues and the outcome of signal assessments should be exchanged between competent authorities and MAHs.

● Requirements for the MAH To track and document all steps of signal detection and management, To report to competent authorities validated signal detected from Eudravigilance

(2015) and emerging safety issues such as safety issues arising from the signal activity which impact B/R balance and/or have an implication for public health

To monitor Eudravigilance outputs (2015)

Signal Detection and Management

Industry challenges

• Surveillance of web portal of National Competent Authority for any new signal posted.• Integration of the new EV source of signal into signal management process of the company

PRAC - Signal management process

Source: www.ema.europa.eu

Signal detection Validation

Confirmation

(=EPITT)

Analysis / Prioritization Assessment

Recommen-dation for

action

MSsEMA[MAH]

MSsEMA

PRACList of

confirmed signals

publishedn=144

Feb 2014

Decision Opinion Position

CHMP/ CMDhEC

PRAC - Signal / Recommendations

● EMA publications PRAC recommendations on safety signals

• MAHs to keep informed about the PRAC recommendations concerning their products. A cumulative list of all signals per product discussed at the PRAC since September 2012

PRAC SignalRecommendations

Supply Additional Information

actionable directly by the MAHs concerned

Regulatory Action

CHMP Endorsement

MAHs are expected to take action according to the recommendations

CMDhEndorsement

nationally authorised medicines

centrally authorised medicines

Source: EMA webpage – Signal Management

● Scope amended Analysis of the Benefit –Risk (B/R) balance of a medicinal product with cumulative review of

safety issues, rather than a detailed listing of individual case reports in a period.

New concept of ICH E2C(R2) implemented in EEA

● Requirements for PSUR proportional to the risks : Not necessary for low risk products Generics/Well-established use products/ Traditional herbal products

● EU Reference Dates and frequency (EURD) list List of substances and combinations of active substances, identify PSURs to be submitted in

accordance with the EURD as determined by the CHMP and CMDh following consultation with PRAC.

● Frequency of PSUR/ PBRER specified in the Marketing Authorization or in EURD list Variation Required

• in case the PSUR cycle is stated in the MA and to align the MA in line with EURD list• for generics remove a previous standard PSUR statement or to align with EURD list

New PSUR / PBRER – Periodic Benefit Risk Evaluation Report

Industry challenges

• New Benefit sections : Contribution by Medical functions not involved previously • PSUR/ PBRER Planning and organization strategy was revised globally and locally

EU Renewals Addendum to Clinical Overview

Industry challenges• Anticipate the renewal submission package• New systematic requirement of the ACO has led to formalize the ACO management process

Renewal incl. CES+ Renewal incl. ACO with expert statement PSRs* when needed + No more PSRsLiterature ref Literature ref + Summary of PSMF RMP when needed History of PV inspection and summary of non compliance

2/21 Jul 2012

* PSR: considered abbreviation PSR for PSUR, PSUR addendum, Summary Bridging Report and line listing

● Renewal submission at least 9 months before expiry Package consolidated quality, safety and efficacy, including all variations

● Request an Addendum to Clinical Overview (ACO) including an Expert Statement without PSRs* submission Final guidelines on renewal process published in Q2/Q4 2012 Actually content corresponds to a “mini PBRER"

Post-Authorisation Safety Study (PASS)

● ScopeAny study relating to an authorized medicinal product conducted with the aim of identifying, characterizing or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures. When imposed by a competent authority :

As an obligation as part of a marketing authorization or under specific circumstances (well established products)

PRAC or to the competent authority of the concerned member state provide Endorsement/ Objection: Draft protocol /amendment Recommendation: final study reports and abstracts.

When voluntarily initiated by a marketing authorization holder including studies proposed and committed in the Risk management plan (RMP)

Industry challenges

• Governance of PASS as new regulatory obligation • Use of new PASS protocol Template. Binding for imposed PASS.• Communication of PASS findings that might influence the Benefit / Risk

Post-Authorisation Efficacy Studies (PAESs) Objectives

● Studies aimed at determining clinical outcome following initial assessment based on surrogate endpoints

● Studies on combination with other medicinal products● Studies in sub-populations● Studies in the context of the European standard of care● Studies linked to a change in the understanding of the standard of care for

the disease and/or the pharmacology of the medicinal product● Studies aimed at determining the long term efficacy of a medicinal product● Studies in everyday medical practice

Draft Delegated act on PAES

Risk Management Plan (RMP)

● New RMP Template, new requirements Obligation to demonstrate the effectiveness of risk minimization measures contained in the

risk management plans Key measures of RMP will be included in the Marketing Authorizations (MA) as conditions

with deadlines for the fulfilment Publish a summary of RMP in lay language

● Explicit legal basis to request a RMP in an application for Marketing Authorization For all new Marketing Authorizations (including generics) For authorized products if there are safety concerns

Industry challenges

• Monitoring of RMPs in all countries• New RMP requirements cause a steep increase in the number of documents• For products without risk management beyond routine: an administrative burden with no

added value? • How to harmonize RMPs for the same substance across all MAHs?

Product Information change: Additional Monitoring scheme

● List of medicines under additional monitoring – Monthly update since April 2013 Mandatory

• All new active substances (MA from 1-Jan-2011)• All biological products, including biosimilars (MA after 1-Jan-2011)

Following PRAC recommendation• Authorised products subject to Post Authorisation Study• Authorised products with conditions or restrictions for the safe and effective use

Medicines will be removed from the list• 5 years after Union Reference Date • or until all conditions are fulfilled

● SmPC and PIL statement Medicines under additional monitoring

• “This medicinal product is subject to additional monitoring” preceded by a black symbol()+ standardised explanatory sentence

For all other medicinal products • Healthcare professional and patients asked to report any suspected adverse reaction

Industry challenge

• Ensure appropriate update of EU SmPC and EU PIL

● Action/ Information related to Registered medicinal products in the EU

MA refused, revoked or suspended, withdrawn / Supply prohibited / Commercialisation stopped / Non Renewal/ B/R re-assessment (new risk &

change in the existing risk)

MAH notification + reasons

MAH Notification of MA events status Transparency increased Art 23a (Dir) / Art 13a (Reg) – Art 123 (2) (Dir.) / Art 14b (Reg.)

Agency / NCA Publications

EMA website : EMA Annual list

National Agencies websites

NCA and EMA

NCA or EMA

Grounds Art 116/117(i) efficacy, negative B/R,

quali-quantitative composition )WW

Other (i.e Commercial)

EU

MA refused, revoked or suspended Supply prohibited Commercialisation stopped

EU

Same information, in national languages, for the products registered or marketed in the country

+ reasons (e.g. safety, efficacy, quality, commercial )

Industry challenge

• MAHs to devise a Process, challenging for large portfolios

“Article 57” – xEVMPDExtended EudraVigilance Medicinal Product Dictionary

● The objective is to better identify the drugs within the ICSRs -Individual Case Safety Reports Create a list of all medicines authorised and registered in EU Identify medicines accurately, especially medicines included in reports of suspected adverse reactions To improve signal detection accuracy and capabilities

● A number of Data elements/set for medicinal products were required by July 2012. Product Information A description of the strength of the active substance(s) A description of the medical device(s) The pharmaceutical dose form The route(s) of administration An electronic (not a scan) copy, including date of last revision, reference numbers and document

language of SmPC, MAH responsible for batch release

● Maintenance of data to be set up. Mandatory as of June 2014

● Clarification of the language requirements depending on the authorisation procedure : National official languages for National Procedures English text for CP; English Core European text for MRP/DCP

Industry challenge

• Ensure maintenance and Quality Control ( Up-to-date SmPCs, Inform on any change, Translation, QPPV information)

Pharmacovigilance System Master file (PSMF)

● Document describing the company’s PV system Replaces the Detailed Description of the Pharmacovigilance System (DDPS) Presents the management organisation of the Company PV system from a corporate perspective

including its affiliated entities in respect of the applicable regulatory requirements. Includes additional descriptions process (RMP, Safety commitments…) and figures pertaining to the

company portfolio, and results from system audits and Key Performance Indicators.

● Tool for QPPV to maintain oversight with the Pharmacovigilance System in the company.

● Provision of a soft or a hard copy of the PSMF within a 7 day time-frame if requested by an authority or at an inspection. Supervisory authority for PV is the Competent Authority in which the PSMF is located

● PSMF Summary - Key elements of the Pharmacovigilance System To be included in application for any Marketing Authorization (MA), whatever the registration

procedure in module 1.8.1 of the dossier• at the time of the renewal, or through Type IAIN variation not later than July 2015.

Industry challenges

• Ensure that total PSMF contains current information • PSMF summary to be associated to each Marketing Authorization

● The MAH shall have permanently and continuously at its disposal an appropriately Qualified Person responsible for PharmacoVigilance” (QPPV) in the EU.

● The QPPV must be appropriately qualified i.e. adequate knowledge and skills to manage the PV system as well as expertise/access to expertise in the following areas: Medicine, Pharmaceutical Sciences, Epidemiology, Biostatistics

● If the QPPV does not have basic medical training, access to a medically trained person must be available and documented in the PSMF.

● The QPPV must reside in the EU [extended to Norway, Iceland or Liechtenstein (EEA)].

● NCA’s have the option to request the nomination of the PV contact person at national level reporting to the QPPV. A contact person at national level may also act as the QPPV.

The QPPV role: Regulatory backgroundEuropean Legislation [DIR Art 104(3)(a)]

Establish and maintain the MAH’s

PV system

●Have sufficient authority to influence the performance of the quality system and the PV activities

●Promote, maintain and improve compliance with the legal requirements

To be compliant with legislative requirements

Tools and processes:●ICSR reporting and submission data●IT systems (database changes, validation status,

failures during validation etc.)●aggregate report processes●SDEAs ●SOP●Trainings●Compliance evaluation/reporting (ICSR,

document submission, safety variation –labelling update etc. – both global + local )

●Quality of data (PBRER, B/R evaluation –ensuring correctness and completeness of data)

QPPV oversight =The QPPV should know everything (1)

QPPV must have an overview of the safety

profiles and any emerging safety

concerns in relation to the medicinal products

for which the MAH holds authorisations

Products and Processes:●Safety profile of new INNs coming to portfolio

(projects, in-licensing, due diligence)●Be aware of any conditions or obligations as part of

the MAs and other commitments relating to safety or the safe use of the products;

●Signal detection and management●Benefit-risk information●Risk management and risk minimisation measure

e.g. be aware of the content of RMP

● Be aware of PASS requested by a competent authority including the results of such studies

● Be involved in the review and sign-off of protocols of PASS conducted in the EU or pursuant to a RMP

●Risk communication (referrals, Product Alerts, product withdrawal ….)

QPPV oversight =The QPPV should know everything (2)

Acting as a single contact point for

the Competent Authorities on a 24-

hour basis

Must be located in the EEA

●Ensuring response to any request from the CA and the Agency for the provision of additional information necessary for B/R evaluation

●Providing any other information relevant to the benefit-risk evaluation to CA and Agency;

●Providing input into the preparation of Regulatory action in response to emerging safety concerns (e.g. variations, urgent safety restrictions, and communication to patients and healthcare professionals);

●To be contact point for PV inspections

QPPV oversight =The QPPV should know everything (3)

Approval/signatures required●PSMF●PSUR/PBRER approval●RMP approval●PASS approval (QPPV)

Internal audit●Own system●Third parties●External partner audit

PV inspection●Competent authority●EMA

CA or EMA/PRAC negotiation (PBRER, RMP, PASS, DUS etc.)

Joint studies

Audit planPeriodic audit

Compliance data

ComplianceCAPA -follow-up

QPPV oversight =PV System compliance and quality

Fees for PharmacoVigilance● Legal proposal under discussion since June 2012 between European Commission, European Parliament, Member States (MS).

On June 26, 2013 European Commission has adopted a legal proposal (@) In February 2014, EU MS have approved a compromise agreement between with the European Parliament on a draft regulation for establishing the long

overdue EU pharmacovigilance fee regime (@) The final regulation needs to be approved by the Parliament and council once revised by the lawyer linguist.

● Agreement on 2 types of fees charged to marketing authorisation holders:Annual Flat Fee €67 per pharmaceutical form (eg tablets, drops and injectables) of medicinal products authorized at national level. This fee is intended to cover the costs of general pharmacovigilance activities of the EMA, such as safety data management, literature monitoring and

information technology, notably maintenance of the EudraVigilance database.Pharmacovigilance Assessment Procedure Fees The EMA will charge fees for three pharmacovigilance assessment procedures performed at EU level to marketing authorization holders (MAHs) that have at

least one product involved in such a Union-wide PV procedure:

• Assessment of PSUR – €19,500 per procedure, of which €13,100 is for national competent authorities (NCA);• Assessment of PASS – €43,000, of which €18,200 is for NCA; and• Assessments of referrals initiated as a result of PV data – standard fee of €17,9000, which can reach up to €295,000 in exceptional

cases involving five and more active substances. Sharing of the referral fee revenue between the involved authorities: 1/3 for EMA - 2/3 for NCAs .

The payment of the fee is divided between the MAHs, with each of them being charged a share of the fee that is proportionate to their share of products covered by the procedure.

● No double charging - Fees paid at EU level covered by the regulation not charged at national level.● Small and medium-sized enterprises : fee reduction of 40% and micro-enterprises: exempted from any fees. ● Reductions from the annual flat-rate fee : specific types of medicinal products, (e.g generics.)

Industry challenges • Anticipated to budget for the PV fees.

● The 2010 EU PV legislation is a massive undertaking for all parties; it offers opportunities, e.g.: Focus has shift on benefit / risk balance with PBRER concept Modular concept for RMP/PSUR Less PSUR for mature and ‘safe’ products Focus on signal rather than on ICSR evaluation Integrated “signal-to-labeling” approach Major step forward in transparency and stakeholder involvement

● Big step toward harmonised pharmacovigilance processes and product evaluation throughout EU PRAC is central to the EU PV legislation

● …but seems also to generate bureaucracy, e.g.: Complexity of the regulatory text corpus does not go toward simplification AE reporting requirements in NIS go against the objective to develop real-life

studies; AE reporting requirement in PSP is not reasonable PRAC may be overwhelmed by the volume of activity

Conclusion (1)

40

● The concept of risk proportionality is there, but… Visible: new PSUR format with a more thoughtful and evaluative

approach, no more PSURs for mature products, Blurred: massive production of RMPs, logic of signal management at

PRAC● The new framework for PV, based on collecting, reporting and

analysing “non-ICSRs” safety events (signals, regulatory decisions…) is emerging painfully Technology and budget constraints: Art 57 – xEVMPD, EMA website,

PSUR repository, new Eudravigilance functionalities, centralisation of literature safety information…

No standard process/system for exchange of information regarding signals (e.g communication MAH PRAC) and regulatory decisions (art 23)

● Anticipation of Budget increase with PV fees

Conclusion (2)

41

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Basic Legislative Acts Release Date

Regulation (EU) No 1235/2010corrigendum to Regulation 1235/2010

December 2010

Regulation (EU) No 1027/2012 November 2012

Directive 2010/84/EUcorrigendum to Directive 2010/84/EU

December 2010

Directive 2012/26/EU October 2012

available in the 23 official languages of the EU

European Commission Delegated and Implementing Acts

Commission Implementing Regulation (EC) No 520/2012 on the performance of pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC

June 2012

Commission Implementing Regulation (EU) No 198/2013 on the selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional monitoring

March 2013

available in the 23 official languages of the EU

Regulation on fees for pharmacovigilance payable to the European Medicines Agency – Draft legal proposal

June 2013

Draft Concept paper on delegated act on PAES – Draft – Public consultation closed Nov12Feb13

Questions and answers

EC - Questions and Answers on transitional arrangements Rev.1 July 2012

EMA - Questions and Answers on practical transitional measures for the implementation of the pharmacovigilance legislation Rev.3

November 2012

CMDh - Questions & Answers document on the Pharmacovigilance Legislation Rev. 8 Jan 2014

Legislative texts

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Good PharmacoVigilance Practices (GVP)

GVP (@) TITLE STATUS Release Date

MODULE I Pharmacovigilance Systems and their Quality Systems Final Jun 2012

MODULE II Pharmacovigilance System Master File Final. Rev.1 Apr 2013

MODULE III Pharmacovigilance Inspections Final Dec 2012

MODULE IV Audits Final Dec 2012

MODULE V Risk Management Systems Final Jun 2012

MODULE VI Management and Reporting of Adverse Reactions to Medicinal Products Final / (Rev.1- Draft) Jun 2012 / (Jun 2013)

MODULE VII Periodic Safety Update Reports Final Rev.1 Dec 2013

MODULE VIII Post-Authorisation Safety Studies Final Rev.1 Apr 2013

Annex to Module VIII Member States' requirements for transmission of information on non-interventional PASS Final Rev.1 Apr 2013

MODULE IX Signal Management Final Jun 2012

MODULE X Additional Monitoring Final Apr 2013

MODULE XI Public Participation in Pharmacovigilance PC Planned Q2 2014

MODULE XII Continuous PV, Ongoing Benefit-Risk Evaluation, Regulatory Action & Planning of Public Communication PC Planned Q2 2014

MODULE XIII Cancelled Incident Management - All topics originally intended covered in this module to be included in XII. NA

MODULE XIV International cooperation PC planned Q2 2014

MODULE XV Safety Communication Final Jan 2013

MODULE XVI Risk-minimisation measures: selection of tools and effectiveness indicators Final Feb 2014

ANNEX I Definitions Final Rev.2 Jan 2014

ANNEX II Templates: Direct Healthcare Professional Communication (DHPC) Final Jan 2013

ANNEX II Templates: Cover page of periodic safety update report (PSUR) Rev.1 Final Apr 2013

ANNEX III Other Guidance Documents

ANNEX IV ICH Guidelines for pharmacovigilance

ANNEX V Abbreviations Final Apr 2013

P. I Vaccines for prophylaxis against infectious diseases Final Dec 2013

P. II Biological medicinal products PC Planned Q2 014

Replace volume 9A

Latest news since last meeting – GVP module update

• Final - planned 2014• Module VI Rev. 1 – ADR

• Public consultation (PC) - planned 2014• Module XI - Public participation in pharmacovigilance - Q2• Module XII - Continuous pharmacovigilance, ongoing benefit-risk evaluation, regulatory action

and planning of public communication - Q2• Module XIV - International cooperation- Q2• PII – Biological medicinal products - Q2

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ICSR Release Date

EMA - Reporting requirements of ICSRs applicable to MAHs during the transitional period – Rev.8 Nov 2013

EMA - CHMP Guideline on detection and management of duplicate individual cases and ICSRs Jun 2012

PSUR/ PBREREMA - webpage on EURD and submission of PSURs and updates of List and requirements

EMA - List of EU Reference Dates (EURD list) for PSURs Monthly update

CMDh - List of substances under PSUR Work Sharing scheme and other substances contained in NAPs with DLP synchronised Monthly update

EMA - Periodic safety update reports: questions and answers Rev. Feb. 2014

CMDh - Best Practice Guide for Transitional Arrangements for PSUR Work Sharing Rev.3 Jan 2014

CMDh - Q&A transitional arrangements for PSURs for nationally authorised products Rev.2 Jun 2013

EMA - First information day on periodic safety update reports (PSURs) Jun 2013

EMA - Template- Request for amendments of or addition of active substances/ combinations of active substances to the EURD list Rev.1 May 2013

EMA - How to submit PSURs for EU Single Assessment of substances contained in both CAPs and NAPs to the EMA May 2013

EMA - NCA requirements for PSUR submission during the transitional period Rev. 7 Nov 2013

HMA - Changes applied to the PSUR Work Sharing and Synchronisation Lists Mar 2013

EMA - PSUR assessment based on active substances in both centrally and nationally authorised medicines Mar 2013

EMA - PSUR Assessment Report template Rev. July 2013

EMA- CHMP approved ICH guideline E2C (R2) Dec 2012

ICH - ICH guideline E2C (R2) - Periodic benefit-risk evaluation report (PBRER) – Step 4 Nov 2012

EMA - Timetable Periodic Safety Updated Reports (PSURs) Rev.1 Sep 2012

Regulatory and procedural guidelines

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EU PV REFERENCETEXTS

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QPPV OfficeVersion as March 2014

Signal Release Date

EMA - Signal management web page

EMA - PRAC recommendations on safety signals: monthly overviews Monthly Update

EMA - List of signals discussed at the PRAC since September 2012 Monthly Update

EMA - Questions & answers on signal management Oct 2013

EMA - Standard operating procedure for signal management for centrally authorised products Mar 2013

EMA - List of active substances subject to worksharing for signal management Nov 2012

EMA - Work instructions Screening electronic reaction monitoring reports (eRMR) for new signals Sep 2012

RMPEMA - RMP webpage

EMA - First summary for the public of the risk-management plan (RMP) of a newly authorized medicine Mar 2014

EMA - Changes to RMPs (RMP Update/ Changes to 'important missing information‘) Aug 2013

EMA - Guidance on format of the risk-management plan in the European Union – in integrated format Rev. 1 Aug 2013

EMA - Guidance on format of the risk-management plan in the European Union for generics Rev. 1 Aug 2013

EMA - Format for risk-management-plan submissions Jan 2013

PASSEMA – PASS webpage Feb 2014

EMA - Template PRAC assessment report of an non-interventional imposed PASS final study report Feb 2014

EMA - Guidance for the format and content of the final study reports for non-interventional PASS Rev.1 Aug 2013

EMA - Post-authorisation safety studies: questions and answers Jul 2013

ENCEPP - Guide on Methodological Standards in Pharmacoepidemiology Rev.2 June 2013

EMA - PRAC Rapporteur PASS protocol assessment report Dec 2012

EMA - Guidance for the format and content of the protocol of non-interventional PASS Oct 2012

EMA – Timetable PASS Protocols (CAPs and NAPs) Jul 2012

Regulatory and procedural guidelines

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xEVMPD Release date

EMA - Electronic submission of information on medicines webpage

EMA - Documents for electronic submission of information on medicines webpage

Renewal (including Addendum to Clinical Overview)

CMDh - Best Practice Guide On The Processing Of Renewals In The Mutual Recognition And Decentralised Procedures rev. 9 Apr 2013

CMDh - Q&A Renewals Nov 2012

EMA - Guideline on the processing of renewals in the centralised procedure rev.4 Jul 2012

Additional MonitoringEMA - Medicines under additional monitoring webpage

EMA - List of medicines under additional monitoring webpage

EMA - List of medicinal products under additional monitoring Monthly update

EC - Medicines undergoing additional monitoring: Video and leaflet to explain new symbol Oct 2013

EMA- Implementation plan for the introduction of the new pharmacovigilance legislation requirements into the product information of centrally approved medicinal Products

Mar 2013

European Medicines Agency updates product information template to label medicines subject to additional monitoring and encourage adverse-reaction reporting

Mar 2013

QRDEMA - Quality Review of Documents human product-information annotated template (English) v9 Mar 2013

EMA - Appendix V - ADR reporting details Rev. 4 Jun 2013

Regulatory and procedural guidelines

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Referrals (incl. Urgent Union procedure) Release date

EMA – Webpage on Referral status per medicinal product

EMA - Template and Explanatory Notes of the letter of representation for Referral procedure under Article 31 of Directive 2001/83/EC Feb 2014

EMA – Questions and answers: Article 31 pharmacovigilance referral Feb 2014

EMA- Questions and answers: Urgent Union procedure (Article 107i) Rev. Feb 2014

EMA - Timetable: Safety referral (Art 107i, urgent Union procedure) Sep 2012

EMA - SOP Article 107 procedures Pharmacovigilance urgent measures Jun 2012

Variation

CMDh - Q&A for the submission of variations according to Regulation (EC) 1234/2008 Rev.25 Jan 2014

EMA - Practical questions and answers to support the implementation of the variations guidelines in the centralised procedure Rev. 2 Feb 2014

European Commission -Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products

May 2013

Regulation (EU) No 712/2012 amending Regulation (EC) No 1234/2008 Aug 2012

Other Regulatory and Procedural guidanceEMA - Marketing and cessation notification: questions and answers Oct 2013

EMA - Questions and answers on variations to an existing pharmacovigilance system as described in the DDPS Aug 2013

EMA - Post-authorisation measures: questions and answers Jul 2013

EMA - Pharmacovigilance system: questions and answers Mar 2013

Regulatory and procedural guidelines

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PRAC Release Date

EMA - PRAC webpage

PRAC - Draft agenda, highlights and minutes of meetings Monthly update

PRAC - Rules of Procedure Mar 2013

PRAC - Elects chair and vice-chair Sep 2012

PRAC - Countdown to July 2012 July 2012

Commission Decision appointing independent scientific experts to the PRAC Official Journal of the EU, 23 official languages of the EU June 2012

CMDh

CMDh - Draft agenda, minutes meetings Monthly update

Medication ErrorEMA – Medication Error webpage

Tackling medication errors: European Medicines Agency workshop calls for coordinated EU approach Mar 2013

EMA - Position paper on potential medication errors in the context of B-R balance and risk minimisation measures – PC closed Jun-Nov 2012

WorkshopsEMA- Workshop on methods for efficacy studies in everyday medical practice Oct 2013

EMA - EMA explores ways to further involve patients in the benefit-risk assessment of medicines Sep 2013

EMA - Workshop on patient-support programmes (PSPs) and market-research programmes (MSP) – Jun 2013

TransparencyEMA Stakeholder meetings: 2010 pharmacovigilance legislation Sep 2013

EMA - Transparency: questions and answers Mar 2013

EMA boosts EU transparency with online publication of suspected side effect reports in 23 EU official languages

May-June 2012

FeesEuropean Commission- Concept Paper on the introduction of Fees to be charged by the EMA for Pharmacovigilance - Outcomes of PC JunJul 2012

European Commission- Proposal for a Regulation Of The European Parliament and of The Council Expected Jun 2013

EMA Information & Communication

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PAES

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2/21 Jul 20122015Nov. 2012 10 Jan 2013

PRAC

New PSUR format Submission / PBRERPBRER format Preparation

Direct ICSR (incl.non serious ) submission to EV

ImplementationPRAC inaugural Meeting 19 July

PRAC Meeting 3-5 September

PRAC Monthly Meeting

New CTDRenewal when required

PSMF

+ MAH EV monitoring

PASS study protocol abstract, study report new format

Submission of new RMP format Effectiveness of Risk minimisation measures

Preparation of new RMP format

PASS study protocol, abstract, study report : no strong format

associated to ICSR submission

+ Monitor List

XEVMPD

Signal detection and management

EU PL - Major Regulatory Milestones

EV functionalities implementation + 6 monthsJun 2013

DDPS

Products subject to additional monitoring

Oct 2013

Transparency and Communication of EMA/NCA/MAH

ADR management and reporting (ICSR submission – Interim Arrangements)

Products subject to additional monitoring

Audit strategy/ Inspection Readiness Readjustment Audit strategy/ Inspection Readiness

Dec. 2012