Transcript Pharmacovigilance and Drug Safety

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
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Topics
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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 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
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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
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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.
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