1. E-business en de nieuwe farmacovigilantie wetgeving 12 maart 2013 Anja van Haren

2. 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

3. Bijeenkomst Jaarbeurs Utrecht 2013 1.Introduction 2.PSUR and RMP 3.Reporting of suspected Adverse Drug Reactions 4.Art 57(2) / IDMP 5.Closure

4. Bijeenkomst Jaarbeurs Utrecht 2013 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 Geneesmiddelenwet Staatsblad (Stb. 2013, 67)

5. Bijeenkomst Jaarbeurs Utrecht 2013 Implementation new legislation 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

6. Bijeenkomst Jaarbeurs Utrecht 2013 New PV legislation: 4 topic areas Impact beyond pharmacovigilance

7. Bijeenkomst Jaarbeurs Utrecht 2013 7 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

8. Bijeenkomst Jaarbeurs Utrecht 2013 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

9. Bijeenkomst Jaarbeurs Utrecht 2013 Implementing Regulation Legally binding no need to transpose into national legislation

10. Bijeenkomst Jaarbeurs Utrecht 2013 1.Introduction 2.PSUR and RMP 3.Reporting of suspected Adverse Drug Reactions 4.Art 57(2) / IDMP 5.Closure

11. Bijeenkomst Jaarbeurs Utrecht 2013 Risk Management Plan (RMP) Implementing Regulation GVP Module V

12. Bijeenkomst Jaarbeurs Utrecht 2013 Periodic Safety Update Report (PSUR) Implementing Regulation GVP Module VII

13. Bijeenkomst Jaarbeurs Utrecht 2013 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

14. Bijeenkomst Jaarbeurs Utrecht 2013 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

15. Bijeenkomst Jaarbeurs Utrecht 2013 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?

16. Bijeenkomst Jaarbeurs Utrecht 2013 How to submit PSUR? http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_ and_procedural_guideline/2012/05/WC500127658.pdf

17. Bijeenkomst Jaarbeurs Utrecht 2013 How to submit PSUR?

18. Bijeenkomst Jaarbeurs Utrecht 2013 PSUR Repository PSURs + Assessment Reports + comments Status: Requirements gathering PDF-based? New HL7 format?

19. Bijeenkomst Jaarbeurs Utrecht 2013 1.Introductie 2.PSUR and RMP 3.Reporting of suspected Adverse Drug Reactions 4.Art 57(2) / IDMP 5.Closure

20. Bijeenkomst Jaarbeurs Utrecht 2013 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)

21. Bijeenkomst Jaarbeurs Utrecht 2013 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. Bijeenkomst Jaarbeurs Utrecht 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. Bijeenkomst Jaarbeurs Utrecht 2013 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

24. Bijeenkomst Jaarbeurs Utrecht 2013 E2B(R3) E2B(R2) Message structure: ICH E2B (R2) vs E2B (R3)

25. Bijeenkomst Jaarbeurs Utrecht 2013 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

26. Bijeenkomst Jaarbeurs Utrecht 2013 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 Testing E2B(R3)

27. Bijeenkomst Jaarbeurs Utrecht 2013 27

28. Bijeenkomst Jaarbeurs Utrecht 2013 NCA..1 NCA..2 NCA..28 MAH Domestic all Domestic Own products Simplified routing ADR reporting - Future

29. Bijeenkomst Jaarbeurs Utrecht 2013 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 -…-…

30. Bijeenkomst Jaarbeurs Utrecht 2013 Interim period Annex to GVP Module VI

31. Bijeenkomst Jaarbeurs Utrecht 2013

32. 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)

33. Bijeenkomst Jaarbeurs Utrecht 2013 1.Introduction 2.PSUR and RMP 3.Reporting of suspected Adverse Drug Reactions 4.Art 57(2) / IDMP 5.Closure

34. Bijeenkomst Jaarbeurs Utrecht 2013 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)

35. Bijeenkomst Jaarbeurs Utrecht 2013 Phase 1Phase 2Phase 3Phase 4 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 2012 xEVPRM 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)

36. Bijeenkomst Jaarbeurs Utrecht 2013 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’ ISO IDMP standards (final Oct 2012)

37. Bijeenkomst Jaarbeurs Utrecht 2013 Implementation ISO IDMP standards 1. Information model 2. Messaging XML HL7 (SPL) xEVPRM 3. Terminologies Maintenance Organisation(s)

38. Bijeenkomst Jaarbeurs Utrecht 2013 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

39. 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

40. 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

41. Bijeenkomst Jaarbeurs Utrecht 2013 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

42. Bijeenkomst Jaarbeurs Utrecht 2013 Thank you for your attention

43. Bijeenkomst Jaarbeurs Utrecht 2013 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

44. Bijeenkomst Jaarbeurs Utrecht 2013 Back-up slides

45. Bijeenkomst Jaarbeurs Utrecht 2013 Additional Monitoring

46. Bijeenkomst Jaarbeurs Utrecht 2013 Additional Monitoring

47. Bijeenkomst Jaarbeurs Utrecht 2013 GVPs available NoModule title IPharmacovigilance Systems & Quality Systems IIPharmacovigilance System Master File IIIPharmacovigilance Inspections IVPharmacovigilance Audits VRisk Management Systems VIManagement & Reporting of Adverse Reactions to Medicinal Products VIIPeriodic Safety Update Report VIIIPost-Authorisation Safety Studies IXSignal Management XAdditional Monitoring (public consultation closed, expected Q1/Q2 2013) XVSafety Communication

48. Bijeenkomst Jaarbeurs Utrecht 2013 NoModule title Release public consultation XIPublic participation in pharmacovigilance Q2 2013 XII Continuous pharmacovigilance, ongoing benefit- risk evaluation, regulatory action and planning of public communication Q1 2013 XIVInternational cooperationQ2 2013 XVI Risk-minimisation measures: selection of tools and effectiveness indicators Q1 2013 GVPs under development

49. Bijeenkomst Jaarbeurs Utrecht 2013 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

50. Bijeenkomst Jaarbeurs Utrecht 2013 Implementing Regulation GVP Module VIII Post Authorisation Safety Studies (PASS)

51. Bijeenkomst Jaarbeurs Utrecht 2013 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 entered prior to the start of data collection into the electronic register of non-interventional PASS

52. Bijeenkomst Jaarbeurs Utrecht 2013 EU PAS Register Before the EU PAS register is fully operational, studies should be registered in the ENCePP E-register of studies

53. Bijeenkomst Jaarbeurs Utrecht 2013 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

54. 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 Submission of PASS

55. Bijeenkomst Jaarbeurs Utrecht 2013 Further guidance documents PASS