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

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 -gt PhVigWP -gt CHMP -gt EC
• NCA -gt PhVigWP -gt CHMP -gt 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 Inspectors 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 6Art. 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 RD 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 MAHs 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.