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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 2008Carla Schoonderbeek

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Topics

• Introduction – context

• National versus EU mandates

• National examples (UK, DE, FR, NL)

• Penalties Regulation 658/2007

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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

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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

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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

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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

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Division of Drug Safety Mandates

• National versus EU– PhVig Decentralised Procedures– PhVig Centralised Procedures

• Within Member States– Reporting Systems– Competent Authority– Enforcement Agency / Inspectorate

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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

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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

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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.

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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

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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

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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)

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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

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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

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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)

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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

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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)

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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

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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

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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

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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

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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

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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”

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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 manufac- turing 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

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Evidence – being able to respond

• “Intentional or negligent infringement”?• Historic

- emails, internal memos, MA dossiers, AERs, internal R&Dand 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

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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

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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.