Proposals For New EU

Pharmacovigilance
Regulations

Barry Arnold
EU Qualified Person for Pharmacovigilance
AstraZeneca

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Disclaimer

I attend this conference as an individual expert and not

as an EFPIA representative. The views expressed here
may not be quoted as being made on behalf of EFPIA
and shall in no way be binding for EFPIA.

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 Strengthening
Pharmacovigilance to Reduce
Adverse Effects of Medicines
Proposed EU legislation
December 2008

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Rationale for new legislation

In light of experience and following an assessment

made of the EU pharmacovigilance system……made by
the Commission, it has become clear that new
measures are necessary to improve how the EU rules
operate on the pharmacovigilance of medicinal
products.
Today’s proposals seek to change the existing EU
legislation on pharmacovigilance (…). They aim at
strengthening and rationalizing the EU
pharmacovigilance system, with the overall objectives of
better protecting public health, ensuring proper
functioning of the internal market and simplifying the
current procedures.

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Current Status

• Initial proposals reviewed by three European Parliament

committees → amendments considered → agreement
on final draft text
• European Parliament adopted the proposed legislation
on 22nd September 2010
• New legislation to take effect 18 months from date of
publication in Official Journal of the European Union
(expected 1Q11)
• Requires ‘Implementation Instruction’ and/or Good
Pharmacovigilance Practice Guideline?

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Implementation Instruction - Scope

• Content and maintenance of the PV system master file

• Minimum requirements of the PV ‘quality system’
• Use of internationally agreed terminologies, formats and
standards for the conduct of pharmacovigilance
• Content and format of electronic transmission of
suspected ADRs
• Content and format of electronic PSURs and RMPs
• Format of protocols, abstracts and final study reports for
PASS’s

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Issues resolved

• The following issues previously identified by European

industry have been resolved:
• Imposition of national ADR reporting requirements – will not be
allowed (unless justifiable for pharmacovigilance reasons)
• New definition of suspected ADR - no longer proposed
• Will encompass adverse events associated with off-label use
(including misuse and abuse) & medication errors
• Community procedure – EMA to develop guidelines on modus
operandi with stakeholder input
• Summary of Essential Information - no longer proposed;
Commission to assess how SmPC & PIL can be improved to
meet needs of HCPs & patients; to be completed within 24
months of publication of legislation

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Pharmacovigilance Risk Assessment Committee

• To replace Pharmacovigilance Working Party

• To comprise:
• Members appointed by Member States
• Competent in safety of medicines (including detection,
assessment, minimisation and communication of risk),
design of post-authorisation safety studies and
pharmacovigilance audit
• Independent scientific experts & representatives of healthcare
professionals and patients
• To be appointed by the European Commission
• CHMP & CMDh to “rely upon” recommendations from PRAC
but retain responsibility for benefit-risk assessments

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EudraVigilance

• EudraVigilance to be maintained and strengthened as

the single point of receipt for ADR reports, once fully
functional (i.e. to the satisfaction of Member States)
• Member States, EMA & Commission to have full
access; MAHs and public to have ‘appropriate’ access

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European Medicines Web-portal

• European medicines web-portal to be created and

maintained by the EMA → increase transparency of
pharmacovigilance issues
• To include public access to:
• PRAC meeting agendas & minutes
• List of products subject to ‘additional monitoring’
• List of locations of MAH ‘master files’ & contact
information for pharmacovigilance enquiries
• PSUR assessment reports (conclusions)
• PASS protocols & abstracts of results
• Summaries of RMPs
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Adverse reaction reporting

• All suspected ADRs to be submitted electronically to

EudraVigilance only
• Serious ADRs within 15 days
• Non-serious ADRs (EU only) within 90 days
• May include non-serious ADRs from PASS
• To include overdose & medication error reports that result
in ADRs
• Competent authorities to facilitate ‘consumer reporting’,
including web-based structured forms
• MAHs to access ‘regulatory authority’ ADRs via
EudraVigilance
• Will necessitate active screening of EudraVigilance for
ADR reports by companies
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Expedited notification of new safety information

• MAH to inform the relevant competent authorities

‘forthwith’ about:
• Any prohibition or restriction imposed by the authorities of
any country in which the medicinal product is marketed
• Any other new information which might influence the
benefit-risk evaluation of the medicinal product
• To include positive and negative results of clinical trials
or other studies in all indications and populations,
whether or not included in the marketing authorisation,
as well as post-marketing data on ‘off-label’ use

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Periodic Safety Update Reports

• Routine PSURs will not be required for products of ‘low

risk’ or where reporting would be duplicative (e.g.
generic products)
• PSURs should provide greater emphasis on analysis of
benefit-risk profile, rather than “detailed presentation of
individual case reports”
• To include scientific evaluation of the benefit-risk profile,
including summaries of relevant scientific/clinical data and
available sales/prescription data
• PSURs to be submitted electronically, with a risk-based
frequency
• PSUR Assessment Report conclusions to be publicly
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available via EMA safety web-portal
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Post-authorisation studies

• MAHs may be required to conduct post-authorisation studies

on safety and efficacy
• To be part of the marketing authorisation; can be required
at the time of granting marketing authorisation or later
• Post-authorisation efficacy studies may be required when
understanding of the disease or clinical methodology
indicate that previous efficacy evaluations could be
significantly changed
• Aimed at collecting data to enable the assessment of
safety or efficacy of medicinal products in everyday
medical practice
• May be accompanied by requirement for enhanced ADR
reporting requirements for specific products
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Post-authorisation safety studies

• Harmonised guiding principles and regulatory

supervision of non-interventional post-authorisation
safety studies to be introduced
• To cover PASS requested by competent authorities
and/or those initiated, managed or financed by MAHs, and
that involve the collection of data from patients or
healthcare professionals in the EU
• PRAC to be responsible for supervision of PASS
• May be delegated to a Member State if study conducted
in a single country

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Post-authorisation safety studies cont’d

• For studies required by competent authorities:

• MAH will be required to submit the study protocol to the
PRAC (or relevant competent authority if conducted in
only one country) and allow 60 days for comment
• PRAC/competent authority will have right to object to
initiation of the study (if deemed promotional or of poor study
design): letter of approval will be required before the study
can commence
• Final study report to be submitted to PRAC/competent
authority within 12 months of end of data collection
• Copies of PASS protocols and study results (abstracts) to
be made publicly available via EMA web-portal
• Assessment of study results by PRAC to be made public
via EMA safety web-portal
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Additional monitoring

• Products to be subject to ‘additional monitoring’ activities:

• All medicinal products with a new active substance and biological
medicinal products, including ‘biosimilars’
• May also apply to specific products that require post-authorisation
safety studies or have conditions or restrictions with regard to safe
and effective use (as specified in the risk management plan)
• For example: products for paediatric use, those necessitating
significant change in marketing authorisation (e.g. new
manufacturing process for a ‘biotech’ product)
• Affected products to be identified by a black symbol &
standard explanatory sentence in the SPC & PIL, usually for
5 years from authorisation
• EMA to maintain a publicly available list of specified
products; to include a link to the SPC/PIL & a summary of
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the RMP
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Off-label use

• New provisions recognise that medicinal products could

be used outside the terms of their marketing
authorisations i.e. ‘off-label’
• MAHs to provide all information on ‘off-label’ use,
including results of clinical trials or other studies
• ‘Off-label’ use will be taken into account as and when
marketing authorisations are being renewed

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Supervisory authority

• The ‘supervisory authority’ for pharmacovigilance will be

the competent authority of the Member State in which
the MAH pharmacovigilance system master file is sited
• Where is this ‘site’ for an electronic master file?
• Will the location of the QPPV be relevant?
• Responsible for verifying on behalf of the Community
that the MAH meets pharmacovigilance requirements
i.e. through PV inspections
• May conduct pre-authorisation pharmacovigilance
inspections to verify the accuracy of the PV system
described in the application
• AZ: likely to be the MHRA (UK)
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Internal audit findings

• Amended text:
• The marketing authorisation holder shall be required to perform
a regular audit of his pharmacovigilance system. He shall place
a note concerning the main findings of the audit on the
pharmacovigilance system master file and, based on the audit
findings, ensure that an appropriate corrective action plan is
prepared and followed. Once the corrective actions have been
fully implemented, the note may be removed.

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Local contact person – reporting to the QPPV

• National competent authorities may request the

nomination of a (local) contact person for
pharmacovigilance at a national level reporting to the
EU QPPV
• It is not clear how this will work in practice

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Conclusion

• Overall, the legislation should be viewed as

positive, from an industry as well as public health
perspective
• Some provisions could have an unintended impact on
the viability of R&D investments due to increasing costs
and generating regulatory paperwork
• Requests for new post authorisation efficacy studies by
PRAC, if not reserved to specific/exceptional situations
• Needs to be implemented carefully, with clear guidelines
• Increase in regulators' burden could lead to an increase in
fees for industry

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 Backup slides

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Marketing Authorisation Application

• Summary of the Pharmacovigilance System (accompanies

MAA) to include the following information:
• Site where the Pharmacovigilance ‘Master File’ is maintained
• Statement signed to confirm that the applicant has the
necessary means to fulfill its pharmacovigilance responsibilities
• Proof that the applicant has the services of a QPPV
• Member State where the QPPV resides
• Contact details for the QPPV
• Master File to be provided within 7 days of request from a
competent authority

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Post-Authorisation Safety Studies

• Amended definition: Any study with an authorised

medicinal product conducted with the aim of identifying,
characterising or quantifying a safety hazard, confirming
the safety profile of the medicinal product, or of
measuring the effectiveness of risk management
measures
• Competent authorities may require PASS as condition
of marketing authorisation
• Competent authority to specify rationale, objectives and
timeframe for submission/conduct
• ‘Harmonised guiding principles’ to be introduced to
ensure PASS are non-promotional
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Transparency

• EMA and/or Member States to maintain ‘safety web-portals’; to

include publicly available copies of:
• List of locations where MAH Master Files are sited
• MAH contact information for pharmacovigilance enquiries
• PSUR Assessment Reports (conclusions)
• PASS protocols & study results (abstracts)
• Summaries of RMPs
• Healthcare professionals and patients to be given ‘appropriate’
access to EudraVigilance
• Data to be available in aggregate format, with explanation
• Individual ADR reports may be requested, subject to data privacy

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Environmental considerations

• Pollution of waters and soils with certain pharmaceutical

residues is an emerging problem
• Member States to consider measures to monitor and
evaluate the risk of environmental effects, including
those which may have an impact on public health
• European Commission to review the scale of the
problem, and assess if amendments to EU legislation
are required

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