The Future of Pharmacovigilance: Hot Issues on the Horizon in the EU

The Future of Pharmacovigilance: Hot Issues on the Horizon in the EU Maurits Lugard, Partner November 8, 2007

What’s on the Horizon for the EU PV System a New EU Council Regulation? New EU PV Requirements (Volume 9A) New EU Penalties Regulation Overview Presentation

EU PV System Re-design • The Commission recently announced that it intends to re-design the EU PV system • Follows an open consultation from Spring 2006 • Commission’s primary goals: • Achieve a better implementation of the current PV system • Introduce changes to the legal framework to clarify and simplify standards and reporting requirements

EU PV System Re-design • 2004 Commission launches call for proposals for independent study of strengths and weaknesses of current system • 2005 Study conducted by Fraunhofer Institute & University of Tűbingen • 2006 Public consultation on outcome study • 2007 New strategy announced by Commissioner Verheugen & impact assessment • 2008 New legal proposal adopted by Commission

Some Key Weaknesses in EU PV Regime: • Legal framework is complex and difficult to rapidly understand • Implementation is not the same in all MS • Complex system with many players • Frequent duplication of work • Quality management is lacking • Resources vary considerably • 50 persons in Germany; a handful in some new Member States • Funding is problematic • Decision-making can be slow, especially at EU level

Better Implementation of Current EU PV System • Commission will: • Fund studies into both the safety of medicines and general methodologies used to conduct PV • Make efforts for the EU Member States to resolve implementation issues (reporting) • Ensure the EMEA has a stronger coordinating role in the overall process • Including better use of the Eudravigilance database

Anticipated Changes to the PV Legal Framework • Minimize duplications between Member States and the EMEA • Strengthen rules on transparency relating to PV data, assessment and decision-making • Involve stakeholders in the processes (patient groups) • Establish clear standards (Good Vigilance Practices) • Simplify reporting of ADRs • Establish a clear legal requirement to conduct post-authorization safety studies (PASS) • BIG OPEN QUESTION: Entirely new legal framework??

Council Regulation EU Directives EU Guidances National legislation International fora Instruments for Regulating PhV in the EU

Council Regulation • Adopted by the Council and the European Parliament based on a proposal from the European Commission • Directly applicable in EU Member States • Consistency of law throughout the EU territory is safeguarded - “no discrepancies” • Published in the Official Journal • Available in all official languages • Full legal certainty • Council Regulation 726/2004 (for central authorization – in force since 20 November 2005)

EU Directives • Adopted by the Council and the European Parliament based on a proposal from the European Commission • National implementation is required – “not directly applicable” • Discrepancies in national implementing laws • Published in the Official Journal • Available in all official languages • Legal certainty, but no EU uniform regime • Directive 2001/83/EC (for national authorization and mutual recognition – important amendments were to be implemented by EU Member States by 30 October 2005)

EU Guidances Commission guidances • Drafted by DG Enterprise in consultation with EMEA and other experts • No systematic input from other Commission services • No input from EU institutions, e.g. Council or European Parliament • Legally binding? • Sometimes ambiguous provisions • Available only on Internet (DG Enterprise website) and in English • Eudralex Volume 9A

EU Guidances EMEA guidance documents • Drafted by Pharmacovigilance Working Party • Not adopted through a legislative process • Legally binding? • EMEA/CHMP/313666/05 Note for Guidance on the Exposure to Medicinal Products during Pregnancy: Need for Post-Authorisation Data (Adopted November 2005) • EMEA/115735/2004 Note for Guidance on the Electronic Data Interchange (EDI) of Individual Case Safety Reports (ICSRS) and Medicinal Product Reports (MPRS) in Pharmacovigilance during the Pre-and Post-Authorisation Phase in the European Economic Area (EEA)(EudraVigilance TIG adopted September 2004)

National legislation • Country specific • Exists side-by-side with EU PhV legislation • Complex network of 27 national rules in national languages • Harmonization does not mean uniformity - rules are transposed differently and at different speeds in different Member States • Necessary to comply with different national obligations, including reporting requirements and timeframes • Duplication of national efforts ties up resources that could be better spent on drug safety

International Conference on Harmonization (‘ICH’) Council for International Organizations of Medicinal Sciences (‘CIOMS’) International Agreements

A PhV Council Regulation could address (certain) weaknesses in EU PV System • Detailed clear and concise provisions • Directly applicable in EU Member States • Eliminates national discrepancies • Prepared with input from all interested parties • Legally binding on all interested parties • Published in the Official Journal in all official languages

Volume 9A: Guidelines on Pharmacovigilance • Published January 25, 2007 • Took effect immediately • Applies to medicinal products for human use authorized in the EU • New content compared to Volume 9 • Revised guidelines on previously covered topics • New guidelines on new topics • Collection of other guidelines in one document

Part I, Section 1.2.1 – Role & Responsibilities Of The QPPV • Two types of responsibilities: • those that cannot be delegated and for which there is “direct responsibility” by the QPPV (2) those that can be delegated, but for which the QPPV must maintain “oversight responsibility”

Part I, Section 1.2.1 – Role & Responsibilities Of The QPPV • QPPV’s direct responsibilities are: • establish/maintain/manage MAH PV system 2. have overview of safety profiles and emerging safety concerns for all products for which the MAH holds authorization 3. be single contact point for Competent Authorities (24 hours!)

Part I, Section 1.2.1 – Role & Responsibilities Of The QPPV • QPPV’s oversight responsibilities are: • ensure collection of adverse reactions at one point in the EU • ensure preparation of ICSRs, PSURs, reports on PASSs • ensure continuous overall post-authorization PV evaluation • ensure that requests from CAs are answered fully & promptly • ensure that CAs are provided with any other relevant information re: risk-benefit, including information on PASS and data from sources related to reporting in special situations

Part I, Section 1.2.1 – Role & Responsibilities Of The QPPV • QPPV also has oversight responsibility to cover the functioning of the PV system in all relevant aspects including: • quality control and assurance procedures • SOPs • database operations • contractual arrangements • compliance data • audit reports • PV training of personnel

Part I, Section 1.2.2 – Role & Responsibilities Of The MAH v. QPPV • Pharmaceutical groups with more than 1 PV system can have more than 1 QPPV • “Each company (i.e. Applicant/MAH or group of MAHs using the same PV system) should appoint 1 QPPV responsible for overall PV for all medicinal products…”

Part I, Section 1.3 – Contractual Arrangements • New section • MAH may transfer any and all its PV tasks, including those of QPPV, to others (person/organization), but ultimate responsibility always remains with MAH • MAH must have “detailed and clear documented contractual arrangements” in place to meet PV obligations • MAH must provide authorities with “information on such arrangements”

Part I, Section 4 Requirements for Expedited Reporting of Individual Case Safety Reports • Clock for expedited reporting: starts (“day 0”) as soon as the minimum information has been brought to the attention of: • Any personnel of the MAH or • An organization having a contractual arrangement with the MAH, including medical representatives

Penalties Regulation • Commission Regulation (EC) No 658/2007 of 14 June 2007 concerning financial penalties for infringement of certain obligations in connection with marketing authorisations granted under Regulation (EC) No 726/2004 of the European Parliament and of the Council, OJ L 155, 15.6.2007, p. 10. • Effective from July 5, 2007 • Top line: • applies to centrally authorized products • lays down rules concerning the imposition of financial penalties to MAHs in respect of 17 infringements, including re: PV obligations • financial risk associated with non-compliance: up to 5% of total EU annual turnover

Infringements covered • 17 different types of infringement, which can be divided into four main categories: • completeness and accuracy of submissions to EMEA (article 1.1) • breach of the conditions and restrictions imposed in the marketing authorization re safe and effective use (articles 1.2 to 1.3) • breach of post-marketing obligations (articles 1.4 to 1.11) • infringement of PV rules, including: QPPV, AE reporting, communication (articles 1.12 to 1.17)

Enforcement procedures Two stages: • investigation stage by EMEA (to report within 18 months) • decision-making stage by the Commission

Enforcement procedures Investigation stage (I): ● By who? To be initiated by EMEA (article 5) either • at its own initiative; or • at the request of the European Commission; or • at the request of an EU Member State. ● When? In cases where the infringement concerned • may have significant public health implications in the Community, or • where it has a Community dimension by taking place or having its effects in more than one Member State, or • where interests of the Community are involved

Enforcement Procedures Investigation stage (II) • Third parties have no formal right to request an investigation by way of complaint • EU Member States and MAHs are required to cooperatewith EMEA in its request for information • failure to do so by MAH may result in fines up to 0.5% EU annual turnover, and periodic penalty payments per day of up to 0.5% of MAH’s daily EU turnover in case of continuous non-cooperation • MAH has right of access to the file • MAH has right to submit written observations prior to adoption of EMEA report

Enforcement Procedures • Decision-making stage: • Controlled by European Commission • Based on EMEA report, the Commission will decide whether to continue procedure • If so, it sends out Statement of Objections to MAH (with allegations and notice that fines may be imposed) • MAH has right to submit comments in writing • Right to request oral hearing, with legal representation

Forms of Penalties • Financial penalties can take two forms: • a fine of up to 5% of the MAH’s annual EU turnover; and • periodic penalty payments per day of up to 2.5% of average EU daily turnover in case of continuous infringement

Determination level of financial penalty • Which level of fine is appropriate? • European Commission has broad discretion • Principles of “effectiveness, proportionality and dissuasiveness” • taking into account a long list if circumstances • seriousness and effects of infringement; • presence or absence of good faith or evidence of willful deceit; • degree of diligence and cooperation or any obstruction by MAH; • need to adopt provisional measures as a matter of urgency; • repetition, frequency or duration of infringement; • prior sanctions imposed on MAH; • turnover of medicinal product concerned.

Questions? Thank you! Maurits J.F. Lugard Partner Sidley Austin LLP Square de Meeûs 35 B–1000 Brussels, Belgium Tel: + 32 2 504 64 17 E-mail: mlugard@sidley.com

The Future of Pharmacovigilance: Hot Issues on the Horizon in the EU