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Pharmaceutical regulatory and compliance congress and best practices forum Paris 29 May 2008 Carla Schoonderbeek

Pharmacovigilance and Drug Safety: Practical Problems and Challenges Issues surrounding enforcement and sanctions including penalties regulations. Pharmaceutical regulatory and compliance congress and best practices forum Paris 29 May 2008 Carla Schoonderbeek. Topics .

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Pharmaceutical regulatory and compliance congress and best practices forum Paris 29 May 2008 Carla Schoonderbeek

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  1. Pharmacovigilance and Drug Safety: Practical Problems and ChallengesIssues surrounding enforcement and sanctions including penalties regulations Pharmaceutical regulatory and compliance congress and best practices forum Paris 29 May 2008 Carla Schoonderbeek

  2. Topics • Introduction – context • National versus EU mandates • National examples (UK, DE, FR, NL) • Penalties Regulation 658/2007

  3. Introduction • Why health damage through drug use? • Sub-standard drugs: • Adulteration, piracy, inadequate production • Misuse and abuse of drugs • ‘Off-label use’ for pleasure or addiction • Compensation for life style • Human error • Prescription errors/Unknown interactions and contra-indications • Inappr.off-label use/Patient non-compliance • Inherent safety issues of drugs

  4. Introduction (2) • Instruments to enhance Drug Safety should look at: • Pirates, Patients, Physicians and Pharmacists • Pharmaceutical Industry • Unsafety of medicinal products • Caused by many factors, but only to a limited extent to: • Authorised manufacturers marketing authorised medicinal products

  5. Introduction (3) • With respect to efficacy, effectiveness and added value, governments and industry have big differences of opinion • Not so with respect to Adverse Drug Reactions and Pharmacovigilance • Industry has no interest in losing their marketing authorisation • Industry has no interest in (product) liability • Industry has interest in improving public image

  6. Introduction (4) • Even though regulatory requirements with respect to pharmacovigilance (PhVig) are steep and expensive: • Compliance is natural • Safety issues are discussed openly and transparently • (almost) no serious pharmaceutical company would use Drug Safety spending as an element of cost-cutting • Enforcement/Sanctions - on average - not a big issue

  7. Division of Drug Safety Mandates • National versus EU • PhVig Decentralised Procedures • PhVig Centralised Procedures • Within Member States • Reporting Systems • Competent Authority • Enforcement Agency / Inspectorate

  8. Division of Drug Safety Mandates (2) • Pharmacovigilance: • Spontaneous reporting systems • national responsibility • Risk Management system • Enforcement NCA • Regulatory decisions • Rapporteur -> PhVigWP -> CHMP -> EC • NCA -> PhVigWP -> CHMP -> NCA

  9. European Mandate • CP: EC decision on Urgent Safety Restriction, Variation, Suspension or Revocation on the basis of CHMP opinion • DCP/MRP: National decisions, possibly Arbitration

  10. Enforcement PhVig obligations • Responsibility of National Inspection Services • Collaboration through Inspector’s WP and with PhVigWP • Legal basis: national legislation with respect to mandate of inspectors, sanctions, etc.

  11. Directive 2001/83/EC • Art. 111 • Obligation for Member States to conduct repeated inspections of compliance • Requirement for Member States to apply dissuasive, proportionate and effective measures in relation to compliance

  12. The UK • Competent Authority: MHRA • Enforcement Agency: MHRA • Powers of inspection and investigation (Medicines Act 1968, sections 111-115): • entry onto premises; • provision of (copies) of materials and documents; • obligation to give assistance and information

  13. The UK (2) • Offences in legislation: • Non-compliance with pharmacovigilance requirements by MA-holder (SI 3144 of 1994 The Medicines (Marketing Authorisations etc) Regulations 1994 as amended) • Fine £5000 on summary conviction (magistrates) • Fine and/or imprisonment (max 2yrs) on conviction on indictment (Crown Court)

  14. Germany • Applicable law: • Arzneimittelgesetz, • Arzneimittel- und Wirkstoffherstellungsverordnung • Ordnungswidrigkeitengesetz • Competent authority for enforcement • Local (regional) supervising authorities • Federal agencies (BfArM, PEI, BVL) • Liability: • QPPV • MAH for QPPV breaches • Officers of the MAH company

  15. Germany (2) • Penalties • Administrative offence not criminal • Fine max 25000 Euro (QPPV). • No imprisonment of QPPV provided for • Defences: • Breach by QPPV must be wilful or intentional

  16. France • Applicable law: • Art. L 5421-6 6°Art. R 5121-150 etsq French Public Health Code • French Pharmacovigilance Good practices • Guidelines published on the AFSSAPS’ website • Competent authority for enforcement • AFSSAPS (French Drug Agency) • Public Prosecutor (Ministère public) ; Competent Court • Professional Board (Board of pharmacists)

  17. France (2) • Liability • MAH and/or “Exploitant” (company commercializing the product) if not the same entity • Officers of the MAH and/or “Exploitant” • “Responsible Pharmacist” • QPPV • Available defences are limited: MA Holder and/or “Exploitant” is liable even if breach unintentional

  18. France (3) • Penalties • Administrative sanctions (withdrawal of marketing authorisation and/or establishment authorization) • Offence: fine 3,750 Euro • Repeated offence: fine 7,500 Euro and 3 months imprisonment • Company fines: x5 that of natural persons (competent court may also order the closing down of the pharmaceutical establishment)

  19. The Netherlands • Competent Authority: Medicines Evaluation Board (CBG) • Enforcement Agency: Health Care Inspectorate (IGZ) • Powers of inspection and investigation (Medicines Act, Article 115 and the General Administration Law): • enter onto premises, • provision of (copies) of materials and documents; • obligation to give assistance and information

  20. The Netherlands (2) • Offences in legislation: • Non-compliance with pharmacovigilance requirements by MA-holder (Article 76 and 77 juncto 101 Medicines Act). • Administrative penalty € 4.500 • Repetition: possibility to persecute

  21. Penalties Regulation • Reg. 726/2004, Art 84(3) mandates European Commission to: • Impose financial penalties to the holders of a marketing authorisation (centralised) • Lay down maximum penalties as well as conditions of and procedure for imposing penalties in a regulation

  22. Penalties Regulation (2) • Reason for this new provision: no proportional sanction in legislation for “regulatory irregularities” • Before Review 2001: • Suspension of MA (not in the interest of patients) • “shaming and blaming” (not in the interest of regulators

  23. Penalties Regulation 658/2007 • Seventeen offences for MAH, four different categories: • inaccurate submissions to EMEA (art. 1(1)), • breach of conditions and obligations contained in marketing authorisation (art.1(2) and 1(3)) • breach of post-marketing obligations • make variations technical/scientific progress (Art. 1(4)) • placing on the market in accordance with SmPC (Art. 1(8)) • notification of: date of actual marketing, date product ceases to be on market, volumes of sales/prescriptions (art. 1(11)).  • infringements of PhVig rules (art. 1(12) to 1(17)) • e.g. recording suspected/serious adverse reactions

  24. Procedure • Although art. 1 phrased as strict liability, penalties only for companies that negligently or intentionally break rules (art.16(1)) • Two stage procedure: • investigating stage conducted by EMEA • decision/penalty stage under control Commission. • EMEA has to take account of any infringement procedure based on same legal issue and facts (art. 2) – “double jeopardy”

  25. Procedure (2) European Commission (EC) • Can require MAH to provide info or documents within 4 weeks, subject to fine• Can request EMEA to initiate IFP, EMEA not obliged to act• Decides to continue IFP• Fixes and imposes financial penalties National Authorities (NA)• Can request EMEA to initiate IFP• Conduct inspections and surveillance• Cooperate in investigation• Enforce obligations and collect fine EMEA • Decides to initiate IFP, conducts inquiry • Can request NA to do manufac- turing or PV inspections or test product • Can request from MAH any information within 4 weeks

  26. Evidence – being able to respond • “Intentional or negligent infringement”? • Historic - emails, internal memos, MA dossiers, AERs, internal R&D and marketing documents, independent scientific research • New/response - creation of new documents for written or oral representations; interviews • Managing evidence- document retention notices to all staff - e-data: restoration of back-up tapes/live snapshot - instructions not to destroy documents - relevance to issue

  27. Financial Penalties • Reg. 658/2007: • art. 16: maximum penalties: • Fine not exceeding 5 % of the MAH’s Community turnover in the preceding year • Continuous infringement: daily fine not exceeding 2.5 % of daily Community turnover • art. 19: non-cooperation • 0.5 % of Community annual turnover • Daily fine of 0.5 % of daily Community turnover in case of continuous non-cooperation

  28. Penalties Regulation • Expectations: Useful instrument? Doubtful: • Not for important problems (because suspension would be appropriate) • Only if national authorities can not resolve the issues • Safety and PhVig as important for MAHs as they are for regulators.

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