1. Dolores Montero Division of Pharmacoepidemiology and Pharmacovigilance Department of Human Medicines Spanish Agency on Medicines and Medical Devices European Pharmacovigilance Legislation TAIEX Workshop 19 November, 2015

2. Pharmacovigilance as public health activity… … aimed at the identification, analysis and management of risk of medicines once marmete, with the purpose of maintaining favourable the relation between benefits and risks The European System working as a network with EMA coordination, should have a harmonised aproach for managing the risks of medicines

3. Directive 2010/84/UE of the European Parliament and Council, 15 December 2010 (into force from July 2012). Directive 2012/26/UE, 25 Octuber 2012Directive 2010/84/UE of the European Parliament and Council, 15 December 2010 (into force from July 2012). Directive 2012/26/UE, 25 Octuber 2012 Regulation No 1235/2010 of the European Parliament and Consejo, 15 December 2010 (into force from July 2012). Regulation No 1027/2012, 25 Octuber 2012Regulation No 1235/2010 of the European Parliament and Consejo, 15 December 2010 (into force from July 2012). Regulation No 1027/2012, 25 Octuber 2012 Reglamento de Ejecución (UE) 520/2012 de la Comisión de 19 de junio de 2012 sobre la realización de actividades de FV

4. Main objectives To improve efficiency (decrease burocracy, evaluation proportional to the risk)To improve efficiency (decrease burocracy, evaluation proportional to the risk) To improve risk communication and its basisTo improve risk communication and its basis To increase patient participationTo increase patient participation Legal basis for a more proactive approach of pharmacovigilanceLegal basis for a more proactive approach of pharmacovigilance To evaluate the impact of the regulatory measuresTo evaluate the impact of the regulatory measures Overall, to protect and promote public health reducing the probability of adverse drug reactions and optimising the use of medicines

5. 1.European coordination 2.Sharing the work among Member States 3.Common procedures for all medicines 4.Reporting of suspected adverse reactions 5.Posauthorisation studies 6.Transparency and communication 7.Guidance for implementation

6. Pharmacovigilance Risk Assessment Committee (PRAC) REGULATION (EU) No 1235/2010 The mandate includes…REGULATION (EU) No 1235/2010 The mandate includes… All aspects of risk management of the use of medicines, including the detection, evaluation, minimisation and communication of risks, taking into account the therapeutic effect of the medicine; design and evaluation of posauthorisation safety studies; pharmacovigilance inspections to pharmaceutical companies

7. 1 Pharmacovigilance Risk Assessment Committee (PRAC) Periodic safety updates Benefit-risk evaluation Risk Management Plan and Observational safety studies Report of suspected adverse reactions Signal detection, management, and priorisation Inspections and audits Medicines under additional monitorin additional monitorin Risk communication and Minimisation measures Urgent safety issues (referrals)

8. PRAC activities Risk identification Signal management Risk Evaluation Evaluation of risks and therapeutic effects Risk Comunication Risk minimisation and impact analysis of risk minimisation measures Inspections on pharmacovigilance Postauthorisation safety studies

9. 1 PRAC members Each Member State appoints… … 1 member and 1 alternate The European Commission appoints… 1 patient representative + 1 alternate 1 healthcare representative + 1 alternate 6 members

10. Evaluation of benefit-risk posautorisation PRACRecomendations about all safety issues of all medicines, taking into account therapeutic effects Assessment Reports Signal analysis (eudravigilance, Member States, other source Evaluation of periodic safety update reports Referrals triggered by safety issues Results from safety studies Rapporteur / lead MS + (co- Rapp/lead MS) + (co- Rapp/lead MS)

11. 2 Risk-benefit evaluation by active substance periodically:Risk-benefit evaluation by active substance periodically: Summary of all data on risks and benefits, including results from studiesSummary of all data on risks and benefits, including results from studies Critical appraisal of benefits and risks (based on all data, including studies performed in non-authorised indications)Critical appraisal of benefits and risks (based on all data, including studies performed in non-authorised indications) Drug utilisation dataDrug utilisation data Single evaluation by a Member State of periodic safety update reports (PSUR/PSUSA), with comments from others

12. 2 Risk-based approach: MAH do not need to present for generics, medicines of well established use, some homeopatics and herbals, unless a reasoned requestRisk-based approach: MAH do not need to present for generics, medicines of well established use, some homeopatics and herbals, unless a reasoned request Single evaluation by a Member State of Periodic Safety Updates, with comments from others

13. 2 Single evaluation by a Member State of Risk Management Plans, with comments from others Planing on how to address the uncertainties about risks, and how to minimise important identified risks Which info is unknown at the time of autorisation Important identified and potential risks Planned studies for addressing the above

14. 2 Single evaluation by a member state of Risk Management Plans, with comments from others Risk management plans are required for all medicines authorised after July 2012Risk management plans are required for all medicines authorised after July 2012 Content proportional to the risk (from routine pharmacovigilance to the request of studies, specific programms, specific materials for physicians…)Content proportional to the risk (from routine pharmacovigilance to the request of studies, specific programms, specific materials for physicians…) Can also be requested to medicines autorised previously, under justificationCan also be requested to medicines autorised previously, under justification Summary will be publicSummary will be public

15. Risk Minimisation Measures Routine ActivitiesRoutine Activities –Information: Summary of product characteristics, patient information leaflet –Legal status: prescription, hospital use, restricted use These conditions are country-specific: H, DH, ECM.These conditions are country-specific: H, DH, ECM. Additional activities (could be conditions for authorisation)Additional activities (could be conditions for authorisation) –Educational material, Dear Doctor Letters –Request of informed consent –Restricted access programmes –Patient registries…

16. 3 Referrals / Union Procedures Urgent benefit-risk assessment if a Member State is considering suspending a medicine, or not renewing the authorisation or major restrictionsUrgent benefit-risk assessment if a Member State is considering suspending a medicine, or not renewing the authorisation or major restrictions Also if the company request suspend marketing due to safety problemsAlso if the company request suspend marketing due to safety problems

17. 4 Spontaneous reporting of suspected adverse reactions New definition A response to a medicinal product which is noxious and unintended Definition therefore includes adverse reactions derived from… Definition therefore includes adverse reactions derived from… Use in authorised conditionsUse in authorised conditions Use in non-authorised conditionsUse in non-authorised conditions OverdoseOverdose Medication errorsMedication errors

18. 4 Spontaneous Reporting European Database with all suspected adverse reactions included (EudraVigilance)European Database with all suspected adverse reactions included (EudraVigilance) Signal identification responsibility of European network and MAHSignal identification responsibility of European network and MAH A statistical process for signal generation is established. Signals reviewed periodically by the responsible MS and the EMAA statistical process for signal generation is established. Signals reviewed periodically by the responsible MS and the EMA Patient reportingPatient reporting Medicines under additional monitoring (symbol)Medicines under additional monitoring (symbol)

19. 4 Spontaneous reporting Standard terminologiesStandard terminologies Standard format for electronic transmissionStandard format for electronic transmission Drug dictionary (under development)Drug dictionary (under development) EMA will review cases from some scientific literature and for some products for MAHEMA will review cases from some scientific literature and for some products for MAH

20. Ciitizens HealthcareProfessionals SEFV- FEDRA PharmaceuticalIndustry EMA-EudraV Serious and non-serious Re-routing Literature Review Notificación de sospechas de reacciones adversas

21. 4 Spontaneous reporting.- medication errors Collaboration with patient safety organisation in each member stateCollaboration with patient safety organisation in each member state Anonymised information in medication errors reportsAnonymised information in medication errors reports Only codified as errors if initial reporter has communicated so.Only codified as errors if initial reporter has communicated so.

22. 4 Spontaneous reporting Medicines under additional monitoring New active substancesNew active substances All biologicals (including biosimilars)All biologicals (including biosimilars) Authorisations under exceptional circumstancesAuthorisations under exceptional circumstances Study as a condition of authorisationStudy as a condition of authorisation Symbol (black triangle upside down) to be withdrawn at renewal or when conditions are fulfilledSymbol (black triangle upside down) to be withdrawn at renewal or when conditions are fulfilled Symbol in SmPC and PILSymbol in SmPC and PIL

23. 5 Posauthorisation Safety (PASS)/Efficacy (PAES) Studies Can be requested at the time of authorisation or at any time after authorisationCan be requested at the time of authorisation or at any time after authorisation Non-performance could motivate withdrawalNon-performance could motivate withdrawal European registry, with abstract publicationEuropean registry, with abstract publication Desirable common protocol for all companiesDesirable common protocol for all companies One evaluation at PRAC level (responsible Member State) of protocol and resultsOne evaluation at PRAC level (responsible Member State) of protocol and results

24. 6 Improvement on risk communication European web portal in connection with national web portals:European web portal in connection with national web portals: Summary of product characteristics, product information leaflet, summary of risk management plan, public assessment report, PRAC recommendations, decissionsSummary of product characteristics, product information leaflet, summary of risk management plan, public assessment report, PRAC recommendations, decissions Medicines under additional monitoringMedicines under additional monitoring Information on how to report ADRsInformation on how to report ADRs European coordination of safety messagesEuropean coordination of safety messages

25. 6 Citizens participation To enable patient reportingTo enable patient reporting Public access to EudravigilancePublic access to Eudravigilance Public audiences in the discussion of PRAC referralsPublic audiences in the discussion of PRAC referrals Access to referrals recommendations and assessment report, PRAC minutes and agendas, output of signals, PSUR/PSUSAAccess to referrals recommendations and assessment report, PRAC minutes and agendas, output of signals, PSUR/PSUSA

26. 7 Good Pharmacovigilance Practices Guidance on how to comply with legislationGuidance on how to comply with legislation Apply to companies, Member States, EMAApply to companies, Member States, EMA 16? Modules16? Modules Available at EMA websiteAvailable at EMA website

27. 7 Buenas practicas de farmacovigilancia (GVP) I. PhV and their Quality Systems II. PhV System Master File III. Audits IV. Inspections V. Risk Management Systems VI. Individual Case Safety Reports VII. Periodic Safety Update Reports VIII. Post-Authorisation Safety Studies IX. Signals X. Additional monitoring XI. Public participation XII. Continuous benefit-risk evaluation, communication planning and decision- making for regulatory action XIII. Incident management XIV. International collaboration XV. Safety communication XVI. Risk minimization measures

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