E-business
en de nieuwe farmacovigilantie wetgeving
12 maart 2013
Anja van Haren
Disclaimer
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
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1. Introduction
2. PSUR and RMP
3. Reporting of suspected Adverse Drug Reactions
4. Art 57(2) / IDMP
5. Closure
Pharmacovigilance:
Regulatory framework
Bijeenkomst Jaarbeurs Utrecht 2013
Regulation (EU) 1235/2010
Directive 2010/84/EU
Nationale wet
EC Implementing Regulations
GVP
(Good Pharmacovigilance Practice)
replace Volume 9A
Questions & Answers
Geneesmiddelenwet
Staatsblad (Stb. 2013, 67)
Implementation new legislation
Bijeenkomst Jaarbeurs Utrecht 2013
New pharmacovigilance legislation entered into force
in July 2012
Stepwise implementation
Criteria for prioritisation:
1. public health activities
2. transparency and communication activities
3. simplification activities
New PV legislation: 4 topic areas
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Impact beyond pharmacovigilance
ICT related changes
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ENCEPP
EMA Web Site
ENCEPP
WCMS
CorGxP (EudraGMP?)
ENCEPP User
E-PSUR
Redirects
Art 57(2)
EMA Data Manager
(“Kinapse”)
CorpGxP
(EudraGMP?)
Procedures
Siamed
Queries on structured product and substance info
List of Substance – Rapporteur
<To be completed with the other info >
EU Medicines Web
Portal
Audit system
Redirects
General
Public
Product and
Substance Data
Management Tool
Other Web Sites
(NCAs, …)
E-RMP
Web ICSR Reporting
Tool
EudraVigilance
DD Tool
Product info
Substance info
SRS
Duplicate Detection
Engine
ISO ICSR
NCA + EMA
EV Registration
System
Fees
Contact info
SSI Tool
Repositories
ISO standards
SSI XML
EV Web
ISO
ICSR
EVPRM+
ICSR
(lit. art. attached)
MAH
Product info
Substance infoOrganisation info
eCTD PSUR
EVPRM+
Ack (EVPRM+)
Loader
Validator
WHO &
EMCDDA
extracts
ECD
ISO
ICSR
MAH
EVPRM+
ISO ICSR
EVPRM+
eCTD IDMP+S
Product info
Substance info
ISO
ICSR
eCTD RMP (incl Annex 1)
Ack (ISO ICSR)
Auditors
Recoding
BFC
E2B
ICSR
Email System
User & Organisation
Registration
Alerting Tool
(NarrcowCast)
ISO ICSR
EV 7/8
Eudra Gateway
Medicines Web Portal
ISO ICSR
Re-route
Lit Art
(Web) RMP Reporting
Tool
Gateway adaptation
Substance
Monitoring
ISO
ICSR
Logon
DWH
Product info
Substance info
ETL
EudraCT
Document
Repository
eCTD RMP
(the NH tool?)
BI Tool
Rapporteur Substance
eCTD
PSUR
Web PSUR Reporting
Tool
IDMP+S
Loader
Validator
IDMP+S
Product info
EUTCT
eCTD
RMP (incl Annex 1)
eCTD
PSUR
Fee collection
Substance info
PAS Registry
Re-routed ISO ICSR
Loader
Validator
Rapporteur
info
NCA Multi-Purpose
Tool
PSUR
& RMP
RMP (incl Annex 1)
NCA
EPITT (Rename?)
NCA (Org)
Loader
Validator
pragmatic use of existing systems
until budget available
EURS
PSUR
EPITT
Support PRAC
NCA (Rep)
7
Pharmacovigilance legislation
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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)
Implementing Regulation
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Legally binding
no need to transpose into
national legislation
Bijeenkomst Jaarbeurs Utrecht 2013
1. Introduction
2. PSUR and RMP
3. Reporting of suspected Adverse Drug Reactions
4. Art 57(2) / IDMP
5. Closure
Risk Management Plan (RMP)
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Implementing Regulation
GVP
Module V
Periodic Safety Update Report (PSUR)
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Implementing Regulation
GVP
Module VII
PSUR vs PBRER
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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
E-PSUR and E-RMP
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• Electronic format not part of ICH PSUR/PBRER work
• HL7 project to define electronic format for PSUR & RMP
- utilizes modular structure
How to submit PSUR?
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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?
Bijeenkomst Jaarbeurs Utrecht 2013
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_
and_procedural_guideline/2012/05/WC500127658.pdf
How to submit PSUR?
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PSUR Repository
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PSURs + Assessment Reports + comments
Status: Requirements gathering
PDF-based?
New HL7 format?
Bijeenkomst Jaarbeurs Utrecht 2013
1. Introductie
2. PSUR and RMP
3. Reporting of suspected Adverse Drug Reactions
4. Art 57(2) / IDMP
5. Closure
Implementing Regulation (EU) 520/2012
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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 279532:2011)
From ICH E2B (R2) to ICH E2B(R3)
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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
ISO ICSR/ICH E2B (R3)
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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
22
ICH E2B (R2) vs E2B (R3)
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• 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
23
Message structure:
ICH E2B (R2) vs E2B (R3)
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E2B(R2)
E2B(R3)
EU Implementation Guide
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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
Testing E2B(R3)
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• 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/ftpare
a/esubmitter/platforms/Windows/IncludeJvm/jinstall
_CBER_ICSR.zip
26
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27
Simplified routing ADR reporting
- Future
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Own
products
all
MAH
Domestic
NCA..1
Domestic
NCA..2
Domestic
NCA..28
Transitional period
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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 period
Annex to GVP Module VI
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Lareb reports
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In the near future Lareb cases will be sent to
MAHs only via:
- gateway, E2B(R2) format
- e-mail (XML-file + html file)
Bijeenkomst Jaarbeurs Utrecht 2013
1. Introduction
2. PSUR and RMP
3. Reporting of suspected Adverse Drug Reactions
4. Art 57(2) / IDMP
5. Closure
Article 57(2)
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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) implementation
Bijeenkomst Jaarbeurs Utrecht 2013
Phase 1
Phase 2
Notification of
electronic
submission format
(July 2011, revised
March 2012)
Electronic
submission & data
processing
xEVMPD update,
guidances,
controlled vocs,
Q&As
By 2 July 2012
Phase 3
Initiation of quality
review and
maintenance of Art
57(2) data
Phase 4
Update in
compliance with
ISO IDMP
standards
xEVPRM format
will be replaced
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 IDMP standards
(final Oct 2012)
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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 Medicinal
Products (IDMP) standard ‘Data elements and structures for unique
identification and exchange of units of measurement’
Implementation ISO IDMP standards
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1.
Information model
2. Messaging
HL7 (SPL)
XML
xEVPRM
3. Terminologies
Maintenance
Organisation(s)
Article 57(2) implementation
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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)
Bijeenkomst Jaarbeurs Utrecht 2013
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/g
eneral/general_content_000496.jsp&mid=WC0b01ac05803bf141&js
enabled=true
Bijeenkomst Jaarbeurs Utrecht 2013
1. Introduction
2. PSUR and RMP
3. PASS
4. Reporting of suspected Adverse Drug Reactions
5. Art 57(2)
6. Closure
Closure
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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
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Thank you for your attention
Abbreviations
Bijeenkomst Jaarbeurs Utrecht 2013
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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
43
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Back-up slides
Additional Monitoring
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Additional Monitoring
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GVPs available
Bijeenkomst Jaarbeurs Utrecht 2013
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
XV
Safety Communication
(public consultation closed, expected Q1/Q2 2013)
GVPs under development
Bijeenkomst Jaarbeurs Utrecht 2013
Release public
consultation
No
Module title
XI
Public participation in pharmacovigilance
XII
Continuous pharmacovigilance, ongoing benefitrisk evaluation, regulatory action and planning Q1 2013
of public communication
XIV
International cooperation
Q2 2013
XVI
Risk-minimisation measures: selection of tools
and effectiveness indicators
Q1 2013
Q2 2013
‘Special’ GVPs
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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
•……
Post Authorisation Safety Studies (PASS)
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Implementing Regulation
GVP
Module VIII
Post Authorisation Safety Studies (PASS)
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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 entered
prior to the start of data collection into the
electronic register of non-interventional PASS
EU PAS Register
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Before the EU PAS register is fully operational, studies should be registered
in the ENCePP E-register of studies
EMA Q&A document - PASS
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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.
Submission of PASS
Bijeenkomst Jaarbeurs Utrecht 2013
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_gui
deline/2012/02/WC500123204.pdf
Further guidance documents PASS
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