New European Pharmacovigilance Legislation on Risk Management

October 22, 2013

Henri CAPLAIN, MD, MS

Associate Vice-President

Head Risk Management Center of Excellence

Global Pharmacovigilance & Epidemiology

Sanofi

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Disclaimer

The views and opinions expressed in this

presentation are solely those of the presenter and

do not necessarily reflect those of Sanofi, or any

of its affiliated organizations.

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Implementing Regulation520/2012

198/2013 ()

Good Pharmacovigilance Practices (GVP)

Regulatory & procedural guidance

EMA Information & Communication

EU Pharmacovigilance Legislation

Applies on 21-Jul-2012

Applies on 2-Jul-2012

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

Promote and protect public health by reducing burden of Adverse Drug Reactions (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-PV Legislation:

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

EMA website European Commission website

Applies on 31-Dec-2013.

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Good pharmacoVigilance Practice (GVP)

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•Self-standing guidance on pharmacovigilance replacing Volume 9A

•Addressed to EU Marketing Authorisation Holders, Competent Authorities in Member States and Agency

•Developed within EU network

•8 weeks public consultation

•2 types of ‘Chapters’:

•Modules for major processes

•Product or populations specific (P)

•GVP structure:

•A: Introduction

•B: Structures and processes

•C: Operation of the EU network

Good pharmacoVigilance

Practice (GVP)

Module IPharmacovigilance systems and their quality systems

Module IIPharmacovigilance system master file

Module IIIPharmacovigilance

inspections

Module IVPharmacovigilance

audits

Module VRisk management

systems

Module VIManagement and reporting of ADRs

Publication of Revision 1 as final Q4 2013

Module VIIPeriodic safety update

reportsPublication of Revision 1

as final Q4 2013

Module VIIIPost-authorisation

safety studies

Module IXSignal management

Module XAdditional monitoring

Module XIPublic participationPublic consultation

Q2 2014

Module XIIContinuous

pharmacovigilancePublic consultation

Q1 2014

Module XIVInternational cooperation

Public consultation Q1 2014

Module XVSafety

communication

Under development

Public consultation

Published

P I – VaccinesPublication as final

Q4 2013

Module XVIRisk minimisation

measuresPublication as final

Q4 2013

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Beyond 2013…what still needs to be done

Topics Activities

Literature monitoring EMA service to industry for population of EudraVigilance with

case reports of old substances.

EudraVigilance Delivery of enhanced functionalities and Information

Technology (IT) system audit results in centralised reporting for

industry

Article 57(2) data

submission and handling

Updates (variations) to the data can be submitted by industry

and data fully used to support regulation, safety and

stakeholder needs.

Periodic Safety Update

Reports

Delivery of PSUR repository and single PSUR assessment

process for National Application Procedures (NAPs) allowing

centralised reporting for industry and faster warnings for NAPs

Risk Management

System

Implement risk-based system for measuring the effectiveness

of risk minimisation

Transparency and

communication

Delivery of EU Medicines web-portal and public hearings.

EU GVP Module VRisk management systems

● GVP* are a set of measures drawn up to facilitate the performance

of pharmacovigilance (PV) in the EU

● Apply to Marketing Authorization (MA) holders, the EMA and

medicines regulatory authorities in EU Member States (MSs). They

cover medicines authorized centrally via the Agency & medicines

authorized at national level.

● Replace “Rules Governing Medicinal Products in the European Union”

(Volume 9A)

● Effective since July 2, 2012

● New format/template* required since January 10, 2013

● To be used for new submissions & RMP updates

*Guideline on good pharmacovigilance practices (GVP). Module V – Risk management systems - EMA/838713/2011

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EU GVP Module VMajor components of the RMP (EU)● Safety Specifications: what is and is not known about safety of a drug

● Important identified and potential risks, missing information

● PV Plan = Risk Assessment Activities● Routine PV Practices

• Activities outlined in your PV System Master File (PSMF)

• Periodic Reports (e.g. PSUR)

• Enhanced PV Activities (additional monitoring)

● Additional PV Activities• Non-clinical studies

• Clinical trials

• Non-interventional studies (PASS)

● Risk Minimization Measures● Routine Measures

• Labeling (SPC, package leaflet)

• Packaging (size and design)

• Legal (prescription) status of the product

● Additional Risk Minimization Measures• Educational program / tools (checklist, brochure, poster, patient alert card)

• Controlled access program

● Other Risk Minimization Measures• Pregnancy prevention program

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Risk Management Plan Template: New format (EU)

Part I Product(s) overview

Part II Safety specification

• SI Epidemiology of the indication(s) and target population(s)

• SII Non-clinical part of the safety specification

• SIII Clinical trial exposure

• SIV Populations not studied in clinical trials

• SV Post-authorisation experience

• SVI Additional EU requirements for the safety specification

• SVII Identified and potential risks

• SVIII Summary of the safety concerns

Part III Pharmacovigilance plan

Part IV Plans for post-authorisation efficacy studies

Part V Risk minimisation measures (including evaluation of the effectiveness of

risk minimisation measures)

Part VI Summary of the risk management plan

Part VII Annexes

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EU-RMP Annexes

List of Annexes

Annex 1 Interface between EU-RMP and Eudravigilance

Annex 2 Current (or proposed if product is not authorised), SPC, Package Leaflet

Annex 3 Worldwide marketing authorisation by country (including EEA)

Annex 4 Synopsis of ongoing and completed clinical trial programme

Annex 5 Synopsis of ongoing and completed pharmacoepidemiological study programme

Annex 6 Protocols for proposed and ongoing studies in RMP part III (Pharmacovigilance

Plan)

Annex 7 Specific adverse event follow-up forms

Annex 8 Protocols for proposed and ongoing studies in RMP part IV (Plans for post-

authorisation efficacy studies)

Annex 9 New available study reports

Annex 10 Details of additional risk minimisation activities (if applicable)

Annex 11 Mock-up of proposed additional risk minimisation measures (if applicable)

Annex 12 Other supporting data (including referenced material)26

Tracked change versions, version control is key

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New Template

Part I - Product(s) overview

Part II - Safety specification

SI: Epidemiology of the indication(s) and target

population(s)

SII: Non-clinical part of the Safety Specification

SIII: Clinical trial exposure

SIV: Populations not studied in clinical trials

SV: Post-Authorisation Experience

SVI: Additional EU requirements for the Safety

Specification

SVII: Identified and potential risks

SVIII: Summary of the safety concerns

Part III - Pharmacovigilance plan

Part IV - Plans for post-authorisation efficacy

studies

Part V - Risk minimization measures

Part VI - Summary of the RMP

Part VII - Annexes

Past and present EU-RMP

Previous Template

Product information

Safety specification

Non-clinical

Limitations of the human safety database

Populations not studied in the pre-authorisation

phase

Post Marketing Experience

Adverse Events/Adverse Reactions

Identified and potential interactions including food-

drug and drug-drug interactions

Epidemiology of the indication and safety concerns

Pharmacological class effects

Additional EU requirements

Summary on ongoing safety concerns

Pharmacovigilance plan

Evaluation of the need for risk minimisation activities

Risk minimisation plan

Summary of the EU-RMP

Annexes

Part I

Part II

Part IV - Plans for post-authorisation efficacy

studies

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GVP Module VRequirement for an EU-RMP

● For all new marketing applications

● For applications involving a significant change to an existing

marketing authorisation (MA)

● New dosage form, route of administration, manufacturing process of a

biotechnologically-derived product

● Paediatric indication

● Other significant change in indication (e.g. new disease area, age group

or a more severe disease to a less severely affected population).

● At the request of the Agency (EMA) or national Competent Authority

(NCA) when there is a concern about the risk-benefit balance

● At the time of the renewal of the MA if the product has an existing

RMP

● An updated EU-RMP should always be submitted if there is a

significant change to the benefit-risk balance of one or more medicinal

products included in the RMP

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Update: Changes to RMPs (August 2013)

● There is no longer an automatic requirement to update RMPs on a

fixed-time basis. The Agency and the NCAs are now adopting a

risk-based approach to RMP updates.

● An updated RMP should now be submitted:

● at the request of the Agency or an NCA;

● whenever the risk-management system is modified, especially as the

result of new information being received that may lead to a significant

change to the benefit-risk profile or as a result of an important

pharmacovigilance or risk-minimisation milestone being reached.

● When justified by risk, the competent authority may still specify a date

for submission of the next RMP as a condition of the marketing

authorisation in exceptional cases.

● If the date for the submission of a periodic safety update report

(PSUR) and the need to update a RMP coincide, both can be

submitted at the same time.

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Update: Changes to RMPs (August 2013)

● Changes to 'important missing information‘: The word 'important' has

been removed from the phrase 'important missing information' within

risk-management documents defining what constitutes a safety concern in

an RMP.

● Safety concerns are now classified as:

● important identified risks;

● important potential risks;

● missing information.

● Previously, International Conference on Harmonisation (ICH) of

Technical Requirements for Registration of Pharmaceuticals for

Human Use E2E and all EU risk-management documents used the

terms 'important identified risks', 'important potential risks' and'

important missing information' to define safety concerns in RMPs.

● The concept of a safety concern has not changed; it is still missing

information that could be clinically important and that needs to be

captured. The only change is the way that this concept is expressed.

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EU GVP Module VRequirements for new marketing applications

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Common Sections Between the New EU-RMP and PSUR / PBRER

● The PSUR and RMP modular format is intended to minimize duplication by enabling common

(sections of) modules to be utilized interchangeably across both reports

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PRAC (PV Risk Assessment Committee) Highlights

● EMA 7th scientific Committee (Replacing the PhVWP)

• Composed of EU National Agencies representatives, 6 independent scientific experts,

Healthcare Professionals and Patient associations representatives (2 each)

• Key role in PV assessments: mandatory or consultative role

• Referrals (Art 20, 31, 107i)

• PSUR/PBRER

• PASS protocols and results

• Signal detection

• Safety communication

• EURD lists

• Safety concerns

• Rapid risks evaluation in the context of the identified benefits

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

Additional monitoring

RMPs

Renewals & annual assessment

Type II safety variations

PV audits, inspections requests & results

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Membership of PRAC

Appointed by

each Member

State:

Appointed by

European

Commission:

1 member + alternate

28 + EEA countries non

voting members

6 members - relevant expertiseincluding clinical pharmacology

and pharmacoepidemiology

1 member/alternate representing patient organizations

1 member/alternate representing healthcare professionals

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RMP data

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RMP Data

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● Views of patient,

consumer and healthcare

professional

organisations were

pivotal to choice of

inverted black triangle as

symbol

● Additional monitoring list

now published from April

2013

▼ This medicine is subject

to additional monitoring. This will allow quick identification of new safety information

You can help by reporting any side effects you may get

See the end of section 4 for how to report side effects

Additional Monitoring

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Additional monitoring list

Monthly review by

PRAC of proposals

for additions to the

list

Communications

campaign starting

1 October 2012

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Further legislation…

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Publication of RMP summaries

●Pilot phase to be initiated in October 2013.

•Summary (Part VI.2 of RMP) to be published at the time of the EPAR

publication.

•Summary to be updated in case of important changes to RMP.

•Summary is aligned with other information (European Public

Assessment Reports (EPAR) summary, product information).

•For all newly - authorized Centralized Application Procedures (CAPs);

•For other (not newly authorised) CAPs, RMP summary to be published

when RMP is updated.

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● VI.2.4: Summary of safety concerns

● Safety concerns in lay language

Important identified risk

Risk What is known Preventability

Risk 1 Frequency and severity

Important potential risk

Risk What is known

Risk 1 Reason why it is thought to be a potential risk along with

uncertainties

Missing information

Risk What is known

Risk 1 State risk has not been studied, the relevance to the target

population and what the recommendations are

Part VI.2: Elements for a public summary

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Conclusion

Risk management is fluid and continuous

Global responsibility

Benefit/Risk

● Pharmacovigilance legislation is

continually evolving and a work-in-

progress

● Safety principles remain relatively

constant

● Main change in the RMP – Addition

of benefit/risk evaluation

● More details about planned

efficacy studies

● Opportunity to design efficacy /

safety studies in post-marketing

setting

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