1. Horst Kastrup October 11, 2012 Implementation of the New EC Legislation on Pharmacovigilance A Challenge for Education and Co-operation Across Departments

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3. New Requirements for the EU Pharmacovigilance Systems New EU legislation increases the input of various functions into the pharmacovigilance processes and documentation  traditional key players: PV, DRA, scientific information, clinical research, …  background support: quality assurance, IT, human resources, …  new formalised requirements to contribute to the documentation of the PV system: supply chain, marketing, legal, business development, … Inclusion of world-wide activities into the EU PV processes and documentation 3 Stakeholders in the EU Pharmacovigilance system

4. Pharmaceutical Package (start of legislative activity in 2008) New European Pharmaceutical Legislation dealing with three items: Pharmacovigilance – increasing effectiveness Outcome: Regulation (EU) 1235/2010 of Dec. 15, 2010 Directive 2010/84/EU of Dec. 15, 2010 Implementing Regulation (EU) 520/2012 of June 19, 2012 Anti counterfeit measures Outcome: Directive 2011/62/EU of June 8, 2011 Information on prescription drugs to patients Draft Regulation and Directive under revision All amending Directive 2001/83/EC and Regulation (EU) 726/2004 4 EU Pharmaceutical Package

5. Press release of the Commission Brussels, December 10, 2008 Safe, innovative and accessible medicines: a renewed vision for the pharmaceutical sector The EU has been losing ground in pharmaceutical innovation. European patients still suffer from inequalities in the availability of information about medicines, whilst counterfeits are on the rise. To address these challenges, the Commission has tabled a package, consisting of four key parts: 1. A communication to launch reflections on ways to improve market access and to develop initiatives to boost EU pharmaceutical research. 2. A proposal to tackle the growing issues of counterfeiting and illegal distribution of medicines, 3. Proposals to enable citizens to have access to high-quality information on prescription-only medicines and 4. Proposals to improve patient protection by strengthening the EU system for the safety monitoring ('pharmacovigilance') of medicines. 5 EU Pharmaceutical Package

6. “Whereas” of Regulation 1235/2010 of December 15, 2010 In the light of the experience acquired and following an assessment by the Commission of the Union system of pharmacovigilance, it has become clear that it is necessary to take measures in order to improve the operation of Union law on the pharmacovigilance of medicinal products for human use. In order to allow all competent authorities to receive, access simultaneously and share pharmacovigilance information for medicinal products for human use authorised in the Union, the Eudravigilance database should be maintained and strengthened as the single point of receipt of such information. Member States should therefore not impose any additional reporting requirements on marketing authorisation holders. The database should be fully and permanently accessible to the Member States, the Agency and the Commission, and accessible to an appropriate extent to marketing authorisation holders and the public. 6 EU Pharmacovigilance Improvement

7. “Whereas” of Regulation 1235/2010 of December 15, 2010 In order to ensure the availability of the necessary expertise and resources for pharmacovigilance assessments at Union level, it is appropriate to create a new scientific committee within the Agency: the Pharmacovigilance Risk Assessment Committee (PRAC). As medicinal products for human use could be used outside the terms of the marketing authorisation, the marketing authorisation holder’s responsibilities should include providing all available information, including the results of clinical trials or other studies, as well as reporting any use of the medicinal product which is outside the terms of the marketing authorisation. 7 EU Pharmacovigilance Improvement

8. “Whereas” of Directive 2010/84 of December 15, 2010 The term ‘adverse reaction’ should be amended to ensure that it covers noxious and unintended effects resulting not only from the authorised use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorisation, including the misuse and abuse of the medicinal product. The marketing authorisation holder should establish a pharmaco- vigilance system to ensure the monitoring and supervision of one or more of its authorised medicinal products, recorded in a pharmacovigilance system master file which should be permanently available for inspection. Marketing authorisation holders should plan pharmacovigilance measures for each individual medicinal product in the context of a risk management system. 8 EU Pharmacovigilance Improvement

9. Regulation (EU) 1235/2010 of Dec. 15, 2010 Deals with PV issues and procedures related to centralised MAs Deals with decisions to be made by the EC Commission Deals with Institutions and Committees on the EC level (EMA/ CHMP/ CMD(h)/ PRAC) Directive 2010/84/EU of Dec. 15, 2010 Deals with PV issues and procedures related to national MAs including MRPs, DCPs Deals with decisions to be made by the national authorities 9 EU Pharmacovigilance Improvement

10. Pharmacovigilance package (Directive and Regulation)  Key Elements: ◦ EC Pharmacovigilance Risk Assessment Committee ◦ EC Pharmacovigilance Web Portal/ Database ◦ Implementation of authorisation to request:  Risk Management Plans  Post Authorisation Safety and Efficacy Studies  Non Interventional Safety Studies ◦ New rules for filing of PSURs (PBRERs) ◦ Modifications of the Referral Procedure ◦ Pharmacovigilance System Master File (PSMF) ◦ Minor amendments in standard labelling 10 EU Pharmacovigilance Improvement

11. Pharmacovigilance package (Directive and Regulation)  Key items ◦ Clear tasks and responsibilities for all parties ◦ Improved decision-making procedures and efficient use of resources ◦ Proactive and proportionate risk management avoiding unnecessary administrative burden and providing for stronger link between safety assessments and regulatory action ◦ Strengthened transparency, patient involvement 11 EU Pharmacovigilance Improvement

12. Pharmacovigilance package (Directive and Regulation)  Tasks and responsibilities ◦ EMA general coordinating role reinforced ◦ New supranational committee for PhV (PRAC) ◦ Increased cooperation and work-sharing among Member States (CHMP, CMD(h) and national agencies involved) ◦ MAH to operate a PhV system which must be documented in a PhV System Master File ◦ Strengthened obligations of MAH as regards continuous monitoring of safety information and update of MA ◦ Extended obligations re reporting of adverse events from countries outside the EC 12 EU Pharmacovigilance Improvement

13. Implementing Regulation (EU) 520/2012 of June 19, 2012 Deals with the details of  Pharmacovigilance system master file  Quality Systems for the performance of PV activities  Monitoring of data in the Eudravigilance Data Base  Use of terminology, formats, and standards  Transmission of reports of suspected adverse reactions  Risk management plans  Periodic safety update reports  Post-authorisation safety studies 13 Implementation of New EU Pharmacovigilance Legislation

14. 16 Good Vigilance Practice Modules (replacing EUDRALEX Volume IX) Guideline on good pharmacovigilance practices – adopted:  Module I – Pharmacovigilance systems and their quality systems  Module II – Pharmacovigilance system master file  Module V – Risk management systems  Module VI – Management and reporting of adverse reactions to medicinal products  Module VII – Periodic safety update report  Module VIII – Post-authorisation safety studies (with separate annex)  Module IX – Signal management  Annex I Definitions 14 Implementation of New EU Pharmacovigilance Legislation

15. Guideline on good pharmacovigilance practices – published for public consultation (closed):  Module III – Pharmacovigilance inspections  Module IV – Pharmacovigilance audits  Module X – Additional monitoring  Module XV – Safety communication – announced:  Module XI - Public participation in pharmacovigilance  Module XII – Continuous pharmacovigilance, ongoing benefit- risk evaluation, regulatory action and planning of public communication  Module XIII – Incident management (tbc)  Module XIV – International cooperation (tbc)  Module XVI – Risk-minimisation measures: selection of tools and effectiveness indicators 15 Implementation of New EU Pharmacovigilance Legislation

16. New or revised parts of the MAA dossier (Art. 8 Dir 2001/83/EC) (1)  (ia) A summary of the applicant’s pharmacovigilance system which shall include the following elements: — proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance, — the Member States in which the qualified person resides and carries out his/her tasks, — the contact details of the qualified person, — a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX, — a reference to the location where the pharmacovigilance system master file for the medicinal product is kept.  (n) is deleted (proof of availability of a QPPV – now covered by ia) 16 New Elements for Module I of the EEA MAA Dossier

17. New or revised parts of the MAA dossier (Art. 8 Dir 2001/83/EC) (1)  (iaa) The risk management plan describing the risk management system which the applicant will introduce for the medicinal product concerned, together with a summary thereof.’  Related information to be added after the second subparagraph: ‘The risk management system referred to in point (iaa) of the first subparagraph shall be proportionate to the identified risks and the potential risks of the medicinal product, and the need for post- authorisation safety data.´ 17 New Elements for Module I of the EEA MAA Dossier

18. New or revised parts of the MAA dossier (Art. 8 Dir 2001/83/EC) (2)  (l) Copies of the following: — any authorisation, obtained in another Member State or in a third country, to place the medicinal product on the market, a summary of the safety data including the data contained in the periodic safety update reports, where available, and suspected adverse reactions reports, together with a list of those Member States in which an application for authorisation submitted in accordance with this Directive is under examination; — the summary of the product characteristics proposed by the applicant in accordance with Article 11 or approved by the competent authorities of the Member State in accordance with Article 21 and the package leaflet proposed in accordance with Article 59 or approved by the competent authorities of the Member State in accordance with Article 61; — details of any decision to refuse authorisation, whether in the Union or in a third country, and the reasons for such a decision.’, 18 New Elements for Module I of the EEA MAA Dossier

19. Content of the pharmacovigilance system master file (Article 3 and 4 of REG 520/2012, GVP Module II) The pharmacovigilance system master file shall contain at least all of the following elements:  (1) Information relating to the qualified person responsible for pharmacovigilance  (2) A description of the organisational structure of the marketing authorisation holder, including the list of the site(s) where the pharmacovigilance activities are undertaken covering individual case safety report collection, evaluation, safety database case entry, periodic safety update report production, signal detection and analysis, risk management plan management, pre- and post- authorisation study management, and management of safety variations to product particulars.  (3) A description of the location of, functionality of and operational responsibility for computerised systems and databases used to receive, collate, record and report safety information and an assessment of their fitness for purpose. 19 Pharmacovigilance System Master File

20. Content of the pharmacovigilance system master file (Article 3 and 4 of REG 520/2012, GVP Module II) The pharmacovigilance system master file shall contain at least all of the following elements: (4) A description of data handling, recording and the process, concerning the following pharmacovigilance activities:  (a) A description of the continuous monitoring of the product risk- benefit profile(s), the result of that monitoring and the decision- making process for taking appropriate measures;  (b) a description of the risk management system(s) and of the monitoring of the outcome of risk minimisation measures;  (c) collection, assessment and reporting of individual case safety reports;  (d) drafting of periodic safety update report and submission;  (e) procedures for communicating safety concerns and safety variations to the summary of product characteristics and package leaflet to healthcare professionals and the general public. 20 Pharmacovigilance System Master File

21. Content of the pharmacovigilance system master file (Article 3 and 4 of REG 520/2012, GVP Module II) The pharmacovigilance system master file shall contain at least all of the following elements: (5) A description of the quality system for the performance of pharmacovigilance activities, including all of the following elements:  (a) a list of documented procedures and processes related to pharmaco- vigilance activities and interfaces with other functions, with details of how documentation can be accessed;  (b) a description of the management of human resources containing the following elements: the organisational chart indicating the number of persons involved in pharmacovigilance activities with a reference to the location of their qualification records; a list of the sites where the staff is located; a summary description of the training concept, including a reference to the location of training files; instructions on critical processes;  (c) documentation arrangements and the location of any records in relation to pharmacovigilance activities;  (d) a description of the system for monitoring the performance of the pharmacovigilance system and the compliance of the main outputs of the system. 21 Pharmacovigilance System Master File

22. Content of the pharmacovigilance system master file (Article 3 and 4 of REG 520/2012, GVP Module II) Article 4 Content of the annex to the pharmacovigilance system master file The pharmacovigilance system master file shall have an Annex containing the following documents: 1. A list of medicinal products covered by the pharmacovigilance system master file, including the name of the medicinal product, the international non-proprietary name (INN) of the active substances, and the Member States in which the authorisation is valid 2. A list of contractual agreements covering delegated activities including the medicinal products and territories concerned; 3. A list of the tasks that have been delegated by the qualified person for pharmacovigilance; … 22 Pharmacovigilance System Master File

23. Content of the pharmacovigilance system master file (Article 3 and 4 of REG 520/2012, GVP Module II) Article 4 Content of the annex to the pharmacovigilance system master file The pharmacovigilance system master file shall have an Annex containing the following documents: … 4. A list of all scheduled and completed audits; 5. Where applicable, a list of the performance indicators; 6. Where applicable, a list of other pharmacovigilance system master files held by the same marketing authorisation holder; 7. A logbook in accordance with Article 6(5). Note: Structure of content and annexes has been modified by GVP Module II 23 Pharmacovigilance System Master File

24. Challenges to maintain up-to-date information for pharmacovigilance purposes  Appendices to the PV-SMF - a list of medicinal products covered by the pharmacovigilance system master file (worldwide) incl. launch data and implementation of safety related changes - the list of subcontracts with third parties specifying the products and territories concerned - any deviations from the pharmacovigilance procedures, their impact and their management until resolved  xEVMPD (extended EUDRAVigilance Medicinal Products Dictionary) Database at EMA containing detailed information on all authorised medicinal products in the EC (centralised and national MAs) to be filled and maintained by marketing authorisation holders 24 Increased Transparency

25. PSURs (GVP Module VII) Changes in structure/ headlines (cave: current ICH E2C guideline revision) Cumulative risk information (instead of covering the last period only) Periodicity adjusted to risk potential including exemption of some generic low risk products from PSUR requirement – EEA lists of periodicity and harmonised due dates 25 Periodic Safety Update Reports

26. Standardisation of Information in the data elements of the xEVMPD database Dictionaries MedDRA coding of indications, adverse events HL7/ ISO Norms from 2015 Continuous update of safety related variations in the Pharmacovigilance System Master File (PV-SMF) including date of implementation of revised safety related labelling in the manufacture/ distribution 26 Labelling Challenges from the Pharmacovigilance Legislation

27. Critical Interfaces DRA – PV:  Detailed Description of the Pharmacovigilance System/ Master File (DDPS –> PSMF)  Risk Management Plans (RMPs)  Company Core Safety Information (CCSIs)  Periodic Safety Update Reports (PSURs) rsp. Periodic Benefit Risk Evaluation Report (PBRER) (ICH)  Urgent Safety Restrictions (USR)  Direct Healthcare Professional Communications (DHPCs) 27 Need for Enhanced Co-operation and Compliance

28. Other involved departments include e.g.  Upper management: resources, responsibility for support of PV by other involved departments  Quality assurance/ internal auditing: performance of PV activities/ obligations  IT (transmission standards (case reports, EVMPD messages), data bases for PSMF annexes etc.)  Labelling (safety related changes, CCDS/CCSI)  Marketing (marketing status, DHPCs)  Licensing (subcontracts)  Supply chain/ manufacturing (complaints, pharmaceutical risks, implementation of safety related changes in labelling incl. reporting of implementation dates by country to PV-SMF) 28 Need for Enhanced Co-operation and Compliance

29. Pharmacovigilance System Master File:  New centralised applications applied for from July 2, 2012  New national applications applied for July 21, 2012  For centralised applications applied for before July 2, 2012: -At the date of next MA renewal -At July 2, 2015 at the latest  For national applications applied for before July 21, 2012: -At the date of next MA renewal -At July 21, 2015 at the latest PASS - New rules applicable for studies commenced from July 2/ 21, 2012 EUDRAVIGLANCE Data Base - Rules applicable 6 months after full functionality of database 29 Time Schedules for Implementation

30. EVMPD:  All authorised products in the EU to be reported by July 2, 2012 Use of internationally agreed formats and standards - Adherence to Health Informatics Standards (ISO 27953-2, ISO 11615, ISO 11616, ISO 11238, ISO 11239, ISO 11240) from July 2016 New formats and content for PSUR/ PBRER, RMP, and PASS - Jan. 10, 2013 30 Time Schedules for Implementation

31. Successful implementation of new EC legislation on pharmacovigilance requires  Enhanced mutual understanding of roles and responsibilities of various departments contributing to an up-to-date information regarding the product status (incl. interaction with third parties), and to implementation of safety related measures  Implementation of multi-departmental SOPs and appropriate training of involved staff Open issue: Compliance of risk management/ case reporting in non-EC countries with EC standards 31 Conclusion

32. New Regulation and Directive updating the EU PV legislation agreed between Commission/ Parliament/ Council (to become effective in 2013) Topics include: “Products under special supervision” Notification of any market withdrawal (world wide) Authority safety procedures Labelling -> involvement of Supply Chain etc. 32 Note

33. EC Commission Website - Pharmacovigilance http://ec.europa.eu/health/human-use/pharmacovigilance/index_en.htm GVP-Guideline (Modules) http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_li sting/document_listing_000345.jsp&mid=WC0b01ac058058f32c Questions and answers on implementation of pharmacovigilance legislation http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/gen eral_content_000520.jsp&mid=WC0b01ac05804fa031 http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Pharmacovi gilance_Legislation/CMDh-257-2012-Rev2-2012_07.pdf PSUR periodicity/ synchronisation lists http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news /2012/09/news_detail_001616.jsp&mid=WC0b01ac058004d5c1 http://www.hma.eu/80.html 33 Web Links

34. 34 Consolidated Directive 2001/83/EU