E-business en de nieuwe farmacovigilantie wetgeving

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

2. Disclaimer • 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

3. Introduction • PSUR and RMP • Reporting of suspected Adverse Drug Reactions • Art 57(2) / IDMP • Closure

4. Pharmacovigilance: Regulatory framework Regulation (EU) 1235/2010 Directive 2010/84/EU Nationale wet EC Implementing Regulations GeneesmiddelenwetStaatsblad (Stb. 2013, 67) GVP(Good Pharmacovigilance Practice) replace Volume 9A Questions & Answers

5. Implementation new legislation New pharmacovigilance legislationenteredinto force in July 2012Stepwiseimplementation Criteria forprioritisation: • public health activities • transparency and communication activities 3. simplification activities

6. New PV legislation: 4 topic areas Impact beyond pharmacovigilance

7. ICT related changes E-PSUR Art 57(2) EudraVigilance E-RMP Repositories ISO standards Medicines Web Portal Gateway adaptation Fee collection PAS Registry pragmatic use of existing systems until budget available Support PRAC

8. References use of internationally agreed terminology, formats and standards (Dir2010/84/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. Implementing Regulation Legally bindingno need to transpose into national legislation

10. Introduction • PSUR and RMP • Reporting of suspected Adverse Drug Reactions • Art 57(2) / IDMP • Closure

11. Risk Management Plan (RMP) Implementing Regulation GVPModule V

12. Periodic Safety Update Report (PSUR) Implementing Regulation GVP Module VII

13. 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. E-PSUR and E-RMP • Electronic format not part of ICH PSUR/PBRER work • HL7 project to define electronic format for PSUR & RMP- utilizes modular structure

15. How to submit PSUR? 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

16. How to submit PSUR? http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC500127658.pdf

17. How to submit PSUR?

18. PSUR Repository PSURs + Assessment Reports + comments Status: Requirements gatheringPDF-based? New HL7 format?

19. Introductie • PSUR and RMP • Reporting of suspected Adverse Drug Reactions • Art 57(2) / IDMP • Closure

20. 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. ICH has developedanImplementation Guide (IG) on how to usethis ISO ICSR standard: ICH E2B(R3) Will replace the current ICH E2B(R2) message Final ICH E2B(R3) package to bepublishedonICH website March/April 2013 From ICH E2B (R2) to ICH E2B(R3)

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 22

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 23

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

25. 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. Testing E2B(R3) • 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

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

29. 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. Interim periodAnnex to GVP Module VI

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. Introduction • PSUR and RMP • Reporting of suspected Adverse Drug Reactions • Art 57(2) / IDMP • Closure

34. Article 57(2) 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

35. Article 57(2) implementation Notification of electronicsubmission format (July 2011, revisedMarch 2012) 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 willbereplaced xEVMPD update, guidances, controlledvocs, Q&As 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. ISO IDMP standards (final Oct 2012) 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’

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

38. Article 57(2) implementation 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)

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

40. Introduction • PSUR and RMP • PASS • Reporting of suspected Adverse Drug Reactions • Art 57(2) • Closure

41. 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

42. 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 43

44. Back-up slides

45. Additional Monitoring

46. Additional Monitoring

47. GVPsavailable

48. GVPsunderdevelopment

49. ‘Special’ GVPs 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 •……

50. Post Authorisation Safety Studies (PASS) Implementing Regulation GVPModule VIII