Pharmacovigilance and Drug Safety: Practical Problems and Challenges Issues surrounding enforcement and sanctions including penalties regulations

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1 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 1

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

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 3

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 4

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 5

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 6

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 7

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 8

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 9

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. 10

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 11

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

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) 13

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 14

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

16 France Applicable law: Art. L Art. R 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) 16

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 17

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) 18

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 19

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 Repetition: possibility to persecute 20

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 21

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 22

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 23

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 24

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 EMEA Decides to initiate IFP, conducts inquiry Can request NA to do manufacturing or PV inspections or test product Can request from MAH any information within 4 weeks National Authorities (NA) Can request EMEA to initiate IFP Conduct inspections and surveillance Cooperate in investigation Enforce obligations and collect fine 25

26 Evidence being able to respond Intentional or negligent infringement? Historic - s, 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 26

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 27

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. 28