e-business en de nieuwe farmacovigilantie wetgeving 12 maart 2013 anja van haren

E-business en de nieuwe farmacovigilantie wetgeving

12 maart 2013

Anja van Haren

Bijeenkomst Jaarbeurs Utrecht 2013

• The information contained in these slides is for general purposes only and presents the state of knowledge at 12 March 2013

• No rights can be derived from this information

• The Medicines Evaluation Board accepts no liability for direct or consequential damage resulting from the use of, reliance on or action taken on the basis of this information provided during this session

2

Disclaimer


1. Introduction

2. PSUR and RMP

3. Reporting of suspected Adverse Drug Reactions

4. Art 57(2) / IDMP

5. Closure


Regulation (EU) 1235/2010

Directive 2010/84/EU

EC Implementing Regulations

GVP(Good Pharmacovigilance Practice) replace Volume 9A

Questions & Answers

Pharmacovigilance: Regulatory framework

Nationale wet

GeneesmiddelenwetStaatsblad (Stb. 2013, 67)


Implementation new legislation

New pharmacovigilance legislation entered into force in July 2012

Stepwise implementation

Criteria for prioritisation:1.public health activities2.transparency and communication activities3. simplification activities


New PV legislation: 4 topic areas

Impact beyond pharmacovigilance


7

NCA Multi-Purpose Tool

GeneralPublic

EMA Web Site WCMS

EU Medicines Web Portal

Redirects

Redirects

Other Web Sites(NCAs, …)

Web ICSR Reporting Tool

SSI Tool

EV Web

SSI XML

Eudra Gateway

EVPRM+

LoaderValidatorEVPRM+

ICSR (lit. art. attached)

EV 7/8

ISO ICSR

EVPRM+

Ack (EVPRM+) Re-route ISOICSR

ISO ICSR

NCA (Org)

Re-routed ISO ICSR

BFC

ISO ICSR

ISOICSR

ISO ICSR

E2B ICSR

DocumentRepository

Lit Art

Product and Substance Data

Management Tool

EMA Data Manager (“Kinapse”)

Product infoSubstance info

SRS

Recoding

ISO ICSR

Duplicate Detection Engine

ISO ICSR

DD Tool

EUTCT



Ack (ISO ICSR)

LoaderValidatorIDMP+S IDMP+S

EudraCT

eCTD RMP (incl Annex 1)

LoaderValidator RMP (incl Annex 1)

(Web) RMP Reporting Tool

(the NH tool?)

eCTD RMP

eCTD PSUR

eCTDPSUR

LoaderValidator PSUR

Web PSUR Reporting Tool

eCTDPSUR

Substance Monitoring

EPITT (Rename?)

ECD

Rapporteurinfo

Rapporteur - Substance

User & OrganisationRegistration

EV Registration System Fees

ENCEPP User

ENCEPPENCEPP

ETLDWH

BI Tool

Alerting Tool (NarrcowCast)

MAH

NCA

Logon

Email System


WHO &EMCDDAextracts

NCA + EMA

CorGxP (EudraGMP?) CorpGxP(EudraGMP?) SiamedProcedures

Queries on structured product and substance infoList of Substance – Rapporteur

<To be completed with the other info >

EURS

PSUR& RMP

Auditors

Audit system

eCTD IDMP+S

eCTDRMP (incl Annex 1)

Product info

Substance info

MAH

EVPRM+

EPITT

NCA (Rep)

Contact info

Organisation info

E-PSUR

E-RMP

Repositories

PAS Registry

Medicines Web Portal

EudraVigilance

Fee collection

ISO standards

Support PRAC

Art 57(2)

Gateway adaptation

pragmatic use of existing systems until budget available

ICT related changes


References use of internationally agreed terminology, formats and standards(Dir 2010/84/EU Art. 108, Reg.1235/2010 Art. 87a)

Further specified in Implementing Regulation: – Periodic Safety Update Report (E)- Risk Management Plan (E)- Study protocol, abstract and end-of-study report

(for Post Authorisation Safety Studies - PASS)- Suspected Adverse Drug Reactions (E)- Medicinal Product Information (E)

Pharmacovigilance legislation


Implementing Regulation

Legally binding

no need to transpose into national legislation


1. Introduction

2. PSUR and RMP


4. Art 57(2) / IDMP

5. Closure


Risk Management Plan (RMP)


GVPModule V


Periodic Safety Update Report (PSUR)


GVP Module VII


PSUR vs PBRER

ICH E2C(R1) ‘PSUR’ is replaced by ICH E2C(R2) ‘PBRER’• PSUR: Periodic Safety Update Report • PBRER: Periodic Benefit Risk Evaluation Report

Different mindset: From periodic review to cumulative review benefit-risk

•EU legislation: ‘PSUR’•Format of PSURs follows structure described in Implementing Regulation•ICH E2C(R2) principles implemented in GVP Module VII


• Electronic format not part of ICH PSUR/PBRER work• HL7 project to define electronic format for PSUR & RMP

- utilizes modular structure

E-PSUR and E-RMP


EMA shall set up and maintain a repository for PSURs and the corresponding assessment reports [Reg. Art. 25a]

MAHs shall submit PSURs electronically to EMA [Dir. Art. 107b]

Transitional provisions in Dir. 2010/84: till 12 months after the PSUR repository is fully operational PSURs will be sent directly to the MSs where the products/substances are authorised

How to submit PSUR?


How to submit PSUR?

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127658.pdf


How to submit PSUR?


PSUR Repository

PSURs + Assessment Reports + comments

Status: Requirements gathering

PDF-based? New HL7 format?


1. Introductie

2. PSUR and RMP


4. Art 57(2) / IDMP

5. Closure


Implementing Regulation (EU) 520/2012

Specifies internationally agreed formats for transmission of suspected adverse drug reactions:

•ICH E2B(R2) ‘Maintenance of the ICH guideline on clinical safety data management: data elements for transmission of Individual Case Safety Reports’

•ICH M2 standard ‘Electronic Transmission of Individual Case Safety Reports Message Specification’

From 1 July 2016:•ISO 27953-2:2011 Health Informatics, Individual case safety reports (ICSRs) in pharmacovigilance — Part 2: Human pharmaceutical reporting requirements for ICSR (ISO 27953- 2:2011)


From ICH E2B (R2) to ICH E2B(R3)

ICH has developed an Implementation Guide (IG) on how to use this ISO ICSR standard: ICH E2B(R3)

Will replace the current ICH E2B(R2) message

Final ICH E2B(R3) package to be published on ICH website March/April 2013


22

ISO ICSR/ICH E2B (R3)

ICH E2B(R3) package:

ICH E2B(R3) Implementation Guide (IG)

- Appendix I (A) ICH ICSR schemas- Appendix I (B) Backwards & Forwards Compatibility (BFC)

(convert R2 into R3 message and vice versa) - Appendix I (C) Schema files- Appendix I (D) Reference instances for XML-files (ICSR and ACK)- Appendix I (E) Example instances of report cases- Appendix I (F) ICH E2B code lists - Appendix I (G) Technical Information- Appendix I (H) SGML & XML conversion


23

ICH E2B (R2) vs E2B (R3)

• Fields removed or updated (size increased, new values)

• Some fields are repeatable (“r”) (indication)

• New concepts introduced by:– Adding new fields– New values for existing fields

• Improved user instruction for fields

• Some changes capture information differently-seriousness at event level-country of occurrence at event level


E2B(R3)

E2B(R2)

Message structure: ICH E2B (R2) vs E2B (R3)


EU Implementation Guide

ICH E2B(R3) Implementation Guide (IG)to be complemented by EU Regional Implementation Guide

Under preparation by EudraVigilance Expert Working Group

Will address:•Business Rules•Additional ISO/HL7 data fields (drug section)•Integration with ISO IDMP standards•ICSR classification•Use of standard terminologies•What to do in system failure•…

Expected delivery in 2013, will be subject to public consultation


• FDA-EU joint pilot testing - will assist in defining requirements for future EudraVigilance enhancements and drafting of EU regional implementation guide

• FDA test tool

http://www.accessdata.fda.gov/esubmissions/ftparea/esubmitter/platforms/Windows/IncludeJvm/jinstall_CBER_ICSR.zip

26

Testing E2B(R3)


27


NCA..1

NCA..2

NCA..28

MAH

Domestic

all

Domestic

Domestic

Own products

Simplified routing ADR reporting - Future


Transitional period

Transitional Period; submit to MS and/or EV:-obligation to submit non-serious varies between MS

Direct reporting by NCAs and MAHs to EV will apply after successful audit of EV system:-Comply with ISO ICSR/IDMP standards-Re-routing of ICSRs to NCAs-Support signal detection activities-Access to EV- reporting of ICSRs to WHO (on behalf of member states)

-Exchange with EMCDDA-…


Interim periodAnnex to GVP Module VI


Lareb reports

In the near future Lareb cases will be sent to MAHs only via: - gateway, E2B(R2) format- e-mail (XML-file + html file)


1. Introduction

2. PSUR and RMP


4. Art 57(2) / IDMP

5. Closure


EMA to create a list of all medicinal products authorised in the EU regardless of licensing procedure

• Coordinate the regulation, safety-monitoring and pharmacovigilance activities of medicines across the EU

• Identify medicines accurately, especially in ICSRs

• Facilitate the international harmonisation activities

Article 57(2)


Notification of electronic

submission format (July 2011, revised

March 2012)

xEVMPD update, guidances,

controlled vocs, Q&As

Electronic submission & data

processing

Initiation of quality review and

maintenance of Art 57(2) data

Update in compliance with

ISO IDMP standards

By 2 July 2012xEVPRM format will

be replaced

Article 57(2) implementation

This obligation does not involve traditional herbal medicinal products (Chapter 2a of Directive 2001/83/EC) , homeopathic medicinal products registered according to the simplified registration procedure (Article 14 of Directive 2001/83/EC)


ISO 11615:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard ‘Data elements and structures for unique identification and exchange of regulated medicinal product information’

ISO 11616:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard ‘Data elements and structures for unique identification and exchange of regulated pharmaceutical product information’

ISO 11238:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard ‘Data elements and structures for unique identification and exchange of regulated information on substances’

ISO 11239:2012, Health Informatics, Identification of Medicinal Products (IDMP) standard ‘Data elements and structures for unique identification and exchange of regulated information on pharmaceutical dose forms, units of presentation, routes of administration and packaging’

ISO 11240:2012, Health Informatics, Identification of MedicinalProducts (IDMP) standard ‘Data elements and structures for uniqueidentification and exchange of units of measurement’

ISO IDMP standards (final Oct 2012)


Implementation ISO IDMP standards

1. Information model

2. MessagingXML

HL7 (SPL)

xEVPRM

3. Terminologies

Maintenance Organisation(s)


Art 57 Joint Implementation Working Group(18 October 2012, 24 January 2013)

Discussion:

- Further defining requirements for data maintenance (e.g. handling of variations, migration of data, controlled vocabularies)

- Submission of structured substance information (SSI)

- Implementation of ISO IDMP standards(XEVRPM to be replaced by new message format)

Article 57(2) implementation


http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000496.jsp&mid=WC0b01ac05803bf141&jsenabled=true


1. Introduction

2. PSUR and RMP

3. PASS


5. Art 57(2)

6. Closure


Simplification: budget and technology limitations

ICT-changes essential for efficient compliance with pharmacovigilance obligations

No ‘short-term’ electronic formats expected for PSUR, RMP

EMA is in a process to develop roadmap towards implementation of ISO IDMP/ICSR standards in the EU- 2016; subject to available budget

Some changes not only IT systems, but also impact your current business process

Closure


Thank you for your attention


43

• ADR = Adverse Drug Reaction• EMA = European Medicines Agency• EV = EudraVigilance• GVP = Good Vigilance Practice• HL7 = Health Level 7 • ICSR = Individual Case Safety Report• IDMP = Identification of Medicinal Products• ISO = International Organization for Standardization• MA = Marketing Authorisation• MAH = Marketing Authorisation Holder• MS = Member State• NCA = National Competent Authority• PASS = Post Authorisation Safety Study• PBRER = Periodic Benefit Risk Evaluation Report • PRAC = Pharmacovigilance Risk Assessment Committee• PSUR = Periodic Safety Update Report• RMP = Risk Management Plan• XEVMPD = Extended EudraVigilance Medicinal Product Dictionary• XEVPRM = Extended EudraVigilance Product Report Message

Abbreviations


Back-up slides


Additional Monitoring


GVPs available

No Module title

I Pharmacovigilance Systems & Quality Systems

II Pharmacovigilance System Master File

III Pharmacovigilance Inspections

IV Pharmacovigilance Audits

V Risk Management Systems

VI Management & Reporting of Adverse Reactions to Medicinal Products

VII Periodic Safety Update Report

VIII Post-Authorisation Safety Studies

IX Signal Management

X Additional Monitoring (public consultation closed, expected Q1/Q2 2013)

XV Safety Communication


No Module titleRelease public consultation

XI Public participation in pharmacovigilance Q2 2013

XIIContinuous pharmacovigilance, ongoing benefit-risk evaluation, regulatory action and planning of public communication

Q1 2013

XIV International cooperation Q2 2013

XVIRisk-minimisation measures: selection of tools and effectiveness indicators

Q1 2013

GVPs under development


Considerations for product- and population-specific pharmacovigilance

P I - Vaccines (revision of previous guideline) Public consultation scheduled for Q1 2013

More planned:• Biological medicinal products• Pregnancy • Children• Elderly•……

‘Special’ GVPs



GVPModule VIII

Post Authorisation Safety Studies (PASS)


Post Authorisation Safety Studies (PASS)

EMA to make public protocols and public abstracts of (non-interventional) PASS falling within the scope of the new procedures involving the PRAC

MAHs should have information on the study enteredprior to the start of data collection into the electronic register of non-interventional PASS


EU PAS Register

Before the EU PAS register is fully operational, studies should be registered in the ENCePP E-register of studies


4.8. Is the ENCePP website amenable to receiving an Extensible Markup Language (XML) file that encodes the values for the fields required for registration? (New November 2012)

The ENCePP E-Register of studies must be populated via the data entry form and it does not accept XML files for upload.

EMA Q&A document - PASS


Requirements for the registration of PASS is available in GVP Module VIII - chapter VIII.B.4

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/02/WC500123204.pdf

Submission of PASS


Further guidance documents PASS

e-business en de nieuwe farmacovigilantie wetgeving 12 maart 2013 anja van haren

Documents

regulation eu

new pv legislation

study report

medicines evaluation

ebusiness en

structured product

topic areasimpact

agreed terminology