The impact on information flow, safety and labelling documents, document granularity, naming of documents and metadata, the preparation and submissions of XEVMPD dossiers

1. New EU Pharmacovigilance Legislation The impact on information flow, safety and labelling documents, document granularity, naming of documents and metadata, the preparation and submissions of XEVMPD dossiers Hans van Bruggen - eCTDconsultancy

2. Aims of the New Legislation Clarify roles and responsibilities NCA, EMA and MAHs Establish a clear legal framework for post-authorization monitoring Minimize duplication of effort across EU Free up resources by rationalizing and simplifying adverse drug reaction (ADR) Reporting of periodic safety update report (PSUR) Scope All medicinal products and Advanced Therapeutic Medical Devices Across EEA (EU + Iceland, Lichtenstein and Norway) Copyright eCTDconsultancy B.V. Pharmacovigilance Legislation 2

3. Time lines Dec 2010: Directive and Regulation released Apr/June 2011: Information to stakeholders Sep 2011: Publication of technical specifications Oct/Nov/Dec 2011: EMA offers end user training on their eSubmission tool (for SMEs) Nov 2011: testing environment available at EMA Requires registration in EudraVigilance Jan 2012: EMA can accept electronic submissions Jul 2012: EVMPD data submitted and maintain as such Jan 2015: Adjust technical specs to ISO IMPD standards Jan 2016: ISO IMPD data submitted and maintain Pharmacovigilance Legislation 3 Copyright eCTDconsultancy B.V.

4. Impacts Safety evaluation Scope Product information Submission format Electronic specifications Portals Routing Roles and responsibilities Translations of product information in all EU languages !? Infrastructure Portals Terminology (elements and values) Pharmacovigilance Legislation 4 Copyright eCTDconsultancy B.V.

5. Safety evaluation Improvement of signal detection Inclusion of literature case reports AE submission from studies via DSUR Change of content of PSUR Electronic PSUR submission only via EudraVigilance Worksharing of PSURs by NCAs and EMA New scientific committee “Pharmacovigilance Risk Assessment Committee” (PRAC) to be hosted by EMA Pharmacovigilance Legislation 5 Copyright eCTDconsultancy B.V.

7. Incorrect interpretation of seriousness and applicability to labelled useCopyright eCTDconsultancy B.V.

8. Product information and PSURs SmPC and Package leaflet Safety sections will have to be adjusted (occurrences will increase) PSUR Comparison labelled vs. unlabelled will shift Comparison expected vs. unexpected will shift Pharmacovigilance Legislation 7 Copyright eCTDconsultancy B.V.

9. Electronic specifications XEVPRM Based on a XML Schema Definition (=XSD) Mandatory elements Non-mandatory elements “If you like” (very little) or “If applicable” (mostly) Product information to be provided as single PDF files Likely in accordance with QRD template CP: in English per MAA or per procedure #? DCP/NP/MRP: in all EEA languages (concatenated/language) Substance information in addition to SSI in attached PDF To be submitted as a ZIP file (<60 MB per submission!!!) No tools available yet Validation criteria under development Pharmacovigilance Legislation 8 Copyright eCTDconsultancy B.V.

10. Potential sources for data eCTD Envelope Cover letter Application form, in accordance with Trade registries, GMP certificates, QP for batch release, Declaration QPPV, Etc. Product information RMP DDPS 32S1, 32P1, 32S21, 32P31, 32P21 on excipients, 32P51 Change control databases Registration tracking databases EV codes (IDs) by EMA for MAH and manufacturers Pharmacovigilance Legislation 9 Copyright eCTDconsultancy B.V.

11. Portals EMA Web portal, provide data in XSD format as per technical specification EMA interface “Webtrader” for single case entry Third party software packages, software currently in use to capture individual safety case reports Adjust PV system interface with EMA systems Most likely, MAH responsible for maintaining accounts Disable accounts when people leave the company! Pharmacovigilance Legislation 10 Copyright eCTDconsultancy B.V.

12. Roles and responsibilities Reporting of product information with PV relevance Permanently keep PI up to date in all EEA languages (<15 days after approval ! Under review) Generate a PV System Master File and keep it up to date And also still in eCTD EU M1 !! RMP for all medicinal product of the company List products under surveillance by EMA and NCAs Surveillance statement to be included in PI Include phone no. in SmPC and PIL for ADR contacts, medical information requests, or product complaints Pharmacovigilance Legislation 11 Copyright eCTDconsultancy B.V.

13. Infrastructure Central office (CO) To have LOs Providing data Reviewing the submission Local offices (LO) To provide national information to CO To inform CO when products are approved To share national product information with CO To inform CO about changes in the MAH details Pharmacovigilance Legislation 12 Copyright eCTDconsultancy B.V.

14. Terminology (elements and values) Details on the medicinal product Name of the medicinal product Therapeutic indication (MEDRA), therapeutic area(s) (ATC code!) Substance preferred name (controlled vocabulary version 1.0) Detailed description of active substance, adjuvants and excipients (structured substance information version 1.0) Details on the marketing authorization holder Name, address and contact details of the MAH Code number of QPPV as in Eudravigilance database Information (incl. location) of the PV master file Designation of additional monitoring, obligatory for biological products; for others only if applicable Details on the MA and its status Pharmacovigilance Legislation 13 Copyright eCTDconsultancy B.V.

15. Terminology (elements and values) Strength of the active substance Pharmaceutical dosage form Route(s) of administration Description of packaging information Electronic copies of SmPC, PIL, Label Information on MAH for batch release, conditions of approval (=specs that might be different across the EEA!) Product information in all EU languages! Granularity? Naming convention of documents? Pharmacovigilance Legislation 14 Copyright eCTDconsultancy B.V.

16. ISO Identification Medicinal Product (IDMP) Must be used by Jan 2015 Medicinal Product ID Pharmaceutical Product ID Substance ID Controlled vocabularies for: Dosage form Route of administration Packaging components Units of presentations Units of measurement Description of manufacturing process to be submitted too Pharmacovigilance Legislation 15 Copyright eCTDconsultancy B.V.

17. Challenges in process Obtaining the relevant information What is the authoritative source Central vs. local offices Regulatory Affairs vs. Pharmacovigilance vs. other disciplines Who is responsible for maintaining the source information Can this information be reused across eCTDs, NEES and submission and tracking tools? Who is responsible for the XEVMPD submissions? What values to be used How can vendors develop tools if cannot get an account? Impact on class labelling and reimbursement/pricing due to clustering based on MEDRA indications Pharmacovigilance Legislation 16 Copyright eCTDconsultancy B.V.

18. Operational challenges Coping with inconsistencies in guidelines; e.g.: Country code: ISO 3166-1 vs. eCTD M1 specs Dosage form: controlled vocabulary vs. ones selected for eCTD Single value vs. multiple values Uncertainty for language of values for non-CP products Are all substances and excipients listed in the SSI? E.g. Magnesium stearate is not in Non-compendial excipients and proprietary excipients/adjuvants? Biosimilars? 128.000 products to be updated in EVMPD 400.000 products to managed from scratch Redundancy in AS information submitted by >1 MAH Pharmacovigilance Legislation 17 Copyright eCTDconsultancy B.V.

19. Conclusions The new legislation must be adhered to before July 2012 It is work in progress, so (slowly) moving target Needs dialogue between industry-agency-vendor Needs dialogue between company’s disciplines Central Office and Local Office EVMPD team and suppliers Labelling Registration Managers CMC-RA IT and Business Support Pharmacovigilance, Drug Safety and Epidemiology Pharmacovigilance Legislation 18 Copyright eCTDconsultancy B.V.

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