Implementation of the New Pharmacovigilance Legislation HMPWG meeting Warsaw, 7-8 December 2011 Presented by: Tomasz Jabłoński Legal Administrator, Legal Service - Directorate

In this presentation New pharmacovigilance legislation: Why? New pharmacovigilance legislation: How? New pharmacovigilance legislation: What? New pharmacovigilance legislation: What to deliver? Conclusions Implementation of the New Pharmacovigilance Legislation

Why: to further strengthen pharmacovigilance (1/2) EC impact assessment: 5% of all hospital admissions are for ADRs, 5% of all hospital patients suffer an ADR, 5th most common cause of hospital death Estimated 197,000 deaths per year in EU from ADRs Societal cost of Euro 79 Billion Cost savings to society from the legislation in range Euro 237 Million – 2.4 Billion Health savings between 591 and 5910 lives saved per year Implementation of the New Pharmacovigilance Legislation

Why: to further strengthen pharmacovigilance (2/2) Annual industry spending on PhV Euro 833 Million Annual industry savings from the proposals Euro 145 Million (17.4%) Cost to EMA: Euro 3.9 million set up cost Euro 10.1 million annual running costs (covered by new fees) Significant changes to the EMA tasks during the co-decision procedure. Implementation of the New Pharmacovigilance Legislation

Why: high level objectives The new regulation and directive on pharmacovigilance constitute the biggest change in legal framework for the EMA since its establishment in 1995. The provisions impact far beyond a narrow definition of pharmacovigilance and risk management. Implementation of the New Pharmacovigilance Legislation

Why: high level objectives (1/2) Promote and protect public health by reducing burden of ADRs and optimising the use of medicines: Clear roles and responsibilities Risk based/proportionate Increased proactivity/planning Reduced duplication/redundancy Integrate benefit and risk Implementation of the New Pharmacovigilance Legislation

Why: high level objectives (2/2) Promote and protect public health by reducing burden of ADRs and optimising the use of medicines (cont’d): Ensure robust and rapid EU decision-making Strengthen the EU Network Engage patients and healthcare professionals Increase transparency and accountability Provide better information on medicines Implementation of the New Pharmacovigilance Legislation

How: making of new legislation by the European Commission (1/3) 2003: EC decision to undertake an assessment of the Community system of pharmacovigilance 2005: Independent study completed to map the strengths and weaknesses of the EU system 2006-2008: Research, consultation, policy development December 2008: “Pharma package” (PhV, information to patients and falsified medicines) adopted by the European Commission and transmitted to Council and European Parliament for co decision procedure to start Implementation of the New Pharmacovigilance Legislation

How: making of new legislation by the European Commission (2/3) Co-decision work starts on revisions to Directive 2001/83/EC and revisions to Regulation (EC)2004/726 23 June 2010: Agreement on final text (first reading agreement) 22 September 2010: Final favourable vote in the European Parliament Implementation of the New Pharmacovigilance Legislation

How: making of new legislation by the European Commission (3/3) Publication in OJ L 348 Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products (applicable from 2 July 2012) Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use (applicable from 21 July 2012) Implementation of the New Pharmacovigilance Legislation

How: further amendments envisaged ‘(…) in view of recent pharmacovigilance events in the EU, the Commission has detected certain areas where the legislation could be further strengthened’ Amended EC proposal for a Regulation amending Regulation (EC) 726/2004 as regards information to the general public on medicinal products subject to medical prescription and as regards pharmacovigilance Amended EC proposal for a Directive amending Directive 2001/83/EC, as regards information to the general public on medicinal products subject to medical prescription and as regards pharmacovigilance Implementation of the New Pharmacovigilance Legislation

Impact on homeopathic medicinal products Article 16(3) Dir. 2001/83/EC: ‘Title IX [Pharmacovigilance] shall apply to homeopatic medicinal products, with the exception of those referred to in Article 14(1)’ References to HMP registered according to the simplified procedure (Article 14 Dir. 2001/83/EC) in the amended Regulation (EC) 726/2004 Implementation of the New Pharmacovigilance Legislation

What: key changes for ADRs (1/2) Better ADR Reporting New ADR definition: ‘A response to a medicinal product which is noxious and unintended’ So far: ‘A response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoriation, correction or modification of physiological function 13 Implementation of the New Pharmacovigilance Legislation

What: key changes for ADRs (2/2) Medication errors that result in an ADR are reported Patient reporting – the debate on ‘if’ is over! Now debate ‘how’! After transitional period: All ADRs from companies and from Member States are sent to Eudravigilance only (MSs only get their national reports and industry accesses reports via EudraVigilance) with major increases in data volumes - from 40,000 now to 100,000 case reports per month anticipated, Member States are ‘auto-forwarded’ their national data Companies access reports in Eudravigilance Implementation of the New Pharmacovigilance Legislation

What: PRAC and decision-making (1/5) New Pharmacovigilance Risk Assessment Committee Mandate: all aspects of the risk management of the use of medicinal products including the detection, assessment, minimisation and communication relating to the risk of adverse reactions, having due regard to the therapeutic effect of the medicinal product, the design and evaluation of post-authorisation safety studies and pharmacovigilance audit Implementation of the New Pharmacovigilance Legislation

What: PRAC and decision-making (2/5) Composition: Members/alternates appointed by each MS 6 members appointed by Commission 1 member/alternate representing health care professionals 1 member/alternate representing patients associations with a view to ensuring that the relevant expertise is available within the Committee, including clinical pharmacology and pharmacoepidemiology, on the basis of a public call for expressions of interest Possible delegation from only one MS to another (max 1) Collaboration with CHMP rapporteur or the reference MS Implementation of the New Pharmacovigilance Legislation

What: PRAC and decision-making (3/5) - Role: Interaction with CHMP/coordination group recommendations forwarded to CHMP for opinion Coordination group for agreement Justification if not in accordance with recommendations PRAC recommendations publicly available with opinion/agreement Agreement and monitoring RMPs Implementation of the New Pharmacovigilance Legislation

What: PRAC and decision-making (4/5) Single AR prepared by the Member State appointed by the CMD “No CAP concerned” PRAC to adopt the AR If any regulatory action results from the AR, CMD to reach a position: maintenance, variation, suspension or revocation + according timetable for implementation MS = CMD ≠ PRAC MS ≠ Decision sent the MAHs and MSs concerned Detailed explanations to be annexed. CMD has the legal power Position of the majority of MSs to be sent to the Commission which will adopt a decision Implementation of the New Pharmacovigilance Legislation

What: PRAC and decision-making (5/5) Single AR prepared by the Rapporteur appointed by the PRAC “At least 1 CAP concerned” PRAC to adopt the AR If any regulatory action results from the AR, CHMP to adopt an opinion: maintenance, variation, suspension or revocation + according timetable for implementation Commission to adopt a decision concerning the regulatory action(s) Implementation of the New Pharmacovigilance Legislation

What: referrals (1/2) New ‘urgent Union procedure’ replaces current Article 107 and can include CAPs Article 36 deleted 2 procedures for pharmacovigilance data, depending on urgency: Article 107i urgent procedure Article 31 all other cases All pharmacovigilance referrals go to PRAC – PRAC to issue recommendation Implementation of the New Pharmacovigilance Legislation

What: referrals (2/2) EMA can enlarge scope of referrals ‘May’ clause re. public hearing (with EMA guidance on when and how), Member States retain discretion of when to refer (the original Commission concept of automatic referrals is lost) To be applied to all products (including centralised) New role for the Coordination Group on the decision making process Article 20 for pharmacovigilance data also goes to PRAC Implementation of the New Pharmacovigilance Legislation

What: Risk Management planning (1/2) New definition of a ‘risk management system’ : ‘a set of pharmacovigilance activities and interventions, such as studies and reports, designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those activities and interventions’ New definition of a ‘Risk management plan’: ‘ a detailed description of the risk management system’ Requirement for all new products but risk proportionate Implementation of the New Pharmacovigilance Legislation

What: Risk Management planning (2/2) Legal basis to require a risk management system/ plan for an authorised product. (‘if there are concerns about the risks affecting the risk-benefit balance’) Safety and efficacy studies included (move towards integrated B/R) Systematic role for the new Committee (PRAC) Implementation of the New Pharmacovigilance Legislation

What: Periodic safety update reports (PSURs) (1/3) Content: Summaries of data relevant to the BR of the medicinal product, incl. results of all studies with a consideration of their potential impact on the marketing authorisation A scientific evaluation of the R-B balance of the medicinal product All data relating to the volume of sales of the medicinal product and any data in possession of the MAH relating to the volume of prescriptions, incl. an estimate of the population exposed to the medicinal product Implementation of the New Pharmacovigilance Legislation

What: Periodic safety update reports (PSURs) (2/3) Submitted electronically to EMA (where Member States access) Some products categories (e.g. generics, homeopathic medicinal products registered according to the simplified procedure, traditional herbal medicinal products) exempted from ‘regular’ submissions. PSURs required only: - where such obligation has been laid down as a condition in the MA - when requested by a competent authority on the basis of concerns relating to PhV data or due to the lack of PSURs relating to an active substance after MA has been granted Implementation of the New Pharmacovigilance Legislation

What: Periodic safety update reports (PSURs) (3/3) For established substances, single EU assessment for all products Assessment leads to automatic regulatory action: variations, suspension, revocation Periodicity will be established by EMA (binding list on website) Likely to replace many referrals Implementation of the New Pharmacovigilance Legislation

What: PASS/PAES (1/2) Strengthened legal basis to require post-authorisation studies: post-authorisation safety study (PASS) post-authorisation efficacy study (PAES) Regulators can require study by industry at first authorisation Regulators can require study by industry post-authorisation Implementation of the New Pharmacovigilance Legislation

What: PASS/PAES (2/2) Study is a condition of the authorisation and is legally binding In the event that the same safety concern applies to more than one medicinal product, the EMA / national competent authority shall …… encourage the marketing authorisation holders concerned to conduct a joint post-authorisation safety study Implementation of the New Pharmacovigilance Legislation

What: medicinal products subject to additional monitoring New active substances New MA biological products (including biosimilars) Any other upon request (+PRAC) for products specific requirements in the RMP Symbol and statement and standardised explanatory sentence in SmPC and leaflet Deletion from the list after 5 years or conditions met Implementation of the New Pharmacovigilance Legislation

What: signal detection (1/2) For first time the concept is recognised Clear roles and responsibilities for EMA and Member States; EMA will lead the signal detection for CAPs and support and coordinate signal detection by the MSs for NAPs Minimum standards for signal detection will be the subject of a legally binding Commission regulation and of independent audit ‘Monitor the data in the EudraVigilance database to determine whether there are new risks or whether risks have changed and whether those risks impact on the risk benefit balance’ PRAC performs initial analysis and prioritisation of signals of new risks or risks that are changing or changes to the R-B balance Implementation of the New Pharmacovigilance Legislation

What: signal detection (2/2) Increased ADR volumes need to be analysed Signal detection linked to patient reporting will be required Signal detection linked to PSURs will be required For NAPs there is a need to develop new procedures and analyses Implementation of the New Pharmacovigilance Legislation

What: EU medicinal product dictionary ‘The Agency shall establish a list of all medicinal products authorised in the Community. To this effect the following measures shall be taken: (a) the Agency shall…..make public a format for the electronic submission of medicinal product information (b) MAHs shall, by (18 months after the entry into force of regulation), electronically submit to the Agency information for all medicinal products authorised or registered in the Community, using the format referred to in point (a); (c) from the date set out in point (b), MAHs shall inform the Agency of any new or varied authorisations (…) Implementation of the New Pharmacovigilance Legislation

What: transparency and communication EU and national medicines web-portals linked together MSs to add their product information to their national web-portals Dramatic increase in transparency (all assessment conclusions public) EMA to coordinate MSs safety announcements on NAPs (as well as CAPs) Public hearings Overall the communication/networking/transparency provisions will require significant IT (for web-portal) and staff resources Implementation of the New Pharmacovigilance Legislation

What: key changes keeping product info up to date MAH shall inform of any prohibitions or restrictions or any new information which may influence the evaluation of benefits and risks….’include both positive and negative results of clinical trials or other studies in all indications and populations, whether or not included in the marketing authorisation, as well as data on use of the medicinal product where such use is outside the terms of the marketing authorisation’. MAH shall keep their product information up to date with current scientific knowledge, including the conclusions of the assessments and recommendations on the EU medicines web-portals Regulators may at any time ask the MAH to forward data demonstrating that the BR balance remains favourable. MAH shall answer fully and promptly any such request. 34 Implementation of the New Pharmacovigilance Legislation

Funding pharmacovigilance activities EMA to collect fees for pharmacovigilance activities for services provided by the EMA or Coordination Group Rapporteurs to be paid by the EMA Fees for pharmacovigilance, literature monitoring, information technology tools, provision of information to the public Payment rapporteurs providing assessment for Union pharmacovigilance procedures, PSURs, PASSs protocols and risk management systems Implementation of the New Pharmacovigilance Legislation

Further changes – EC proposals Article 23 Reg. (list of medicinal products subject to additional monitoring Article 20 Reg. (clarification of respective scopes of this provision) Article 107i Dir. (automatic procedure at EU level in the cases of specific serious safety issues with NAPs) Article 13 and Article 14b Reg. / Article 23a and 123 Dir. (in order to avoid that voluntary withdrawal of a MA could lead to safety issues not being addressed in the EU) Implementation of the New Pharmacovigilance Legislation

Implementing measures (1/2) Reg. (EC) 726/2004 Art. 87a Dir Implementing measures (1/2) Reg. (EC) 726/2004 Art. 87a Dir. 2001/83/EC Art. 108 After public consultations (deadline: 7 November 2011) The content and maintenance of the pharmacovigilance system master file kept by the MAH The minimum requirements for the quality system for the performance of pharmacovigilance activities by the Agency (the NCAs and MAH) The use of internationally agreed terminology, formats and standards for the performance of pharmacovigilance activities Implementation of the New Pharmacovigilance Legislation

Implementing measures (2/2) Reg. (EC) 726/2004 Art. 87a Dir Implementing measures (2/2) Reg. (EC) 726/2004 Art. 87a Dir. 2001/83/EC Art. 108 The minimum requirements for the monitoring of data included in the EV database to determine whether there are new risks or whether risks have changed The format and content of electronic transmission of suspected adverse reactions by MSs and MAHs The format and content of electronic PSURs and RMPs The format of protocols, abstracts and final study reports of the PASS Implementation of the New Pharmacovigilance Legislation

Clarification of roles (1/3) EMA Scientific and coordinating role reinforced New scientific committee Pharmacovigilance Risk Assessment Advisory Committee (PRAC) with important role ‘For the fulfilment of its pharmacovigilance tasks including agreement and monitoring of risk management systems, it (CHMP) shall rely on scientific assessment and recommendations of the PRAC’ Key role for EMA and PRAC in signal detection and follow up Remuneration by EMA contract with rapporteurs for PSURs, Union procedures Implementation of the New Pharmacovigilance Legislation

Clarification of roles (2/3) Member States Conducting pharmacovigilance for products on their market, signal detection and follow up Operation of the pharmacovigilance system Increased cooperation and worksharing Improvement coordination group (alternates, EMA support, remuneration, decision making process) Penalties for non-compliance + other obligations (Article 102 Dir. 2010/84/EU) Implementation of the New Pharmacovigilance Legislation

Clarification of roles (3/3) MAHs Operation pharmacovigilance system Summary to authorities Detailed updated pharmacovigilance system master file on site (inspection) Risk management system (proportionate to risks) in all MA Continuous monitoring of safety information and update MA Implementation of the New Pharmacovigilance Legislation

What to deliver: governance structure for EMA tasks (1/6) Need to cope with the Complexity of the network Number of (scientific) fora directly affected by the new legislation and providing input into the preparation for the implementation Need for Consensus – building within the network Interaction with stakeholders Implementation of the New Pharmacovigilance Legislation

What to deliver: governance structure for EMA tasks (2/2) Project Oversight Committee (ERMS-FG) Project Coordination Group 6 EMA/MSs Project Teams EMA/MSs Project Team 1 - Audit/ Inspections EMA/MSs Project Team 2 PSURs EMA/MSs Project Team 3 ADR reporting /Additional Monitoring/ -Signals EMA/MSs Project Team 4 -RMP/ PASS/PAES -Effectiveness of risk Minimisation EMA/MSs Project Team 5 -Committees/ Referrals EMA/MSs Project Team 6 -Communica- tion/ Transparency 12 EMA Subproject Teams EMA Task- Force PSUR Product Info. Committees Fees Lit. monit/ Signal detect. RMS 43 Implementation of the New Pharmacovigilance Legislation Implementation of the New Pharmacovigilance Legislation PASS/PAES EV/ADR rep. Referrals Com./Transp Insp./PhV sy. PhV audits

What to deliver: working methodology Project Oversight ERMS FG Status Report Concept Paper Impl. Meas. Adopted Project Coordination Group Status Report Concept Paper Impl. Meas. Adopted Drafted/ Agreed Project Teams Actions Table Issue Log Tracking Table Status Report Concept Paper Impl. Meas. Subproject Teams Actions Table Issue Log Tracking Table Concept Paper Impl. Meas. Drafted 44 Implementation of the New Pharmacovigilance Legislation

What to deliver: reporting timelines Friday 2 weeks before CHMP Subproject Teams submit Status Report Friday Week before CHMP Project Coord. Group submits Status Report to ERMS FG Project Teams submit Status Report Wednesday Week after CHMP Project Coord. Group meets to review Status Reports Wednesday CHMP week 45 Implementation of the New Pharmacovigilance Legislation

What to deliver: implementation phasing plan Q1 – Q2 2011 Phase I Q3 2011 – Q3 2012 Phase II First round of Business Process Mapping -IT requirements Technical contribution to EC draft implementing measures Format of product Information (Reg. Art.57) -Key papers Good Vigilance Practice and other guidelines Second and third rounds of Business Process Modelling Standard Operating Procedures, Working Instructions, Templates RoP, Mandate ICT tools development July 2012 -Documentation update -ICT tools maintenance Implementation of the New Pharmacovigilance Legislation

What to deliver: prioritisation EMA/MSs technical contribution to EC Implementing measures (priority) Business process mapping IT requirements supported by business process mapping Concept papers (for policy issues) Good Vigilance Practice guidelines SOPs/WINs/Templates 47 Implementation of the New Pharmacovigilance Legislation Implementation of the New Pharmacovigilance Legislation

What to deliver: Hierarchy of rules Deliverables EMA/MSs Technical contribution Guidelines SOP/WIN/Templates IT tools Concept Papers Process Mapping IT requirements Implementation of the New Pharmacovigilance Legislation

What to deliver: interaction with stakeholders Stakeholders meetings involving EMA, Member States, EC, industry, patients and healthcare professionals representatives Positive feedback from 3 stakeholders meeting held at EMA’s permisses Scheduling of additional Stakeholders forum will be based on content development Implementation of the New Pharmacovigilance Legislation

Overall implementation plan: key activities 50 Implementation of the New Pharmacovigilance Legislation

Conclusions: EMA is the hub of the European network New legislation: opportunity to strengthen and rationalise public health Major work to ensure full and effective implementation Resources are needed Collaboration will be key 51 Implementation of the New Pharmacovigilance Legislation

THANK YOU. Any questions THANK YOU! Any questions? The views expressed in this presentation are those of the author and do not necessarily reflect and cannot be quoted as the views of the European Medicines Agency Implementation of the New Pharmacovigilance Legislation