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PSMF in Practice –
Your Questions Answered! GPvP Symposium, 14 March 2014
Jonathan Rowell, Senior GPvP Inspector
Content
• Answer industry questions related to the PSMF
• MHRA inspector’s preparation: How we use the PSMF
• Questions and areas for further discussion
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Disclaimer
• This material represents the view of the MHRA.
• I’m not going to answer detailed questions about individual
MAH scenarios during Q&A.
• EMA have published Q&As – Update November 2012:
http://www.ema.europa.eu/docs/en_GB/document_library/R
egulatory_and_procedural_guideline/2012/05/WC5001276
58.pdf
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Your Questions Answered!
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Location and Registration (1)
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Where should the PSMF be located if the QPPV is a one person
contractor in the UK and all PV activities are conducted outside
EEA? Should the PSMF reside with the QPPV in his/her home?
• GVP Module II, the PSMF “shall be located within the EU, either
at the site where the main pharmacovigilance activities are
performed or at the site where the qualified person responsible
for pharmacovigilance operates”.
• If no other site qualifies, this may include a private residence.
Location and Registration (2)
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Does a new PSMF location require a new MFL number in XEVMPD?
• EMA guidance document on XEVPRM: the extended
EudraVigilance medicinal product report message (version 3.2):
• Published 31 Jan 2014 and effective 16 June 2014.
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/docume
nt_listing/document_listing_000336.jsp&mid=WC0b01ac058079126c
• “Variations to the information on PSMF location may trigger the
generation of new EV Codes.”
Location and Registration (3)
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If the PSMF is located in another EU country (outside the UK) does
that mean that we are less likely to be inspected by the MHRA?
• According to GVP Module III, scheduling routine inspections
should be according to a risk-based methodology.
• MHRA does not account for PSMF location when scheduling
national inspections. They can be scheduled at anytime.
• The scope of MHRA inspections may be tailored to account for
inspections conducted by other NCAs including by the
Supervisory Authority (if applicable).
Inspection Planning (1)
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How do MHRA Inspectors use the PSMF?
• The section on organisational structure and annex B (contracts)
can help to determine the scope and length of the inspection.
• The section on pharmacovigilance processes describes how
pharmacovigilance activities are performed, and aids preparation
of the inspection plan.
• The PSMF can be used to establish what studies, registries or
other programmes are on-going. A list may be provided in annex
C or may have to be requested.
Inspection Planning (2)
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How do MHRA Inspectors use the PSMF?
• The section on Pharmacovigilance System Performance is key.
Are regulatory reporting obligations being met?
• The section on Quality System may contain notes associated
with audits where significant findings are raised. MHRA
inspectors routinely check whether corrective and preventative
actions are within proposed resolution dates.
EEA QPPV
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Do changes in QPPV contact details require a variation?
• Once it becomes fully functional, changes in QPPV contact
details (telephone, address and email) may be updated through
the Article 57 database (without a variation).
• Currently, changes require a type IAIN variation.
What should be included in the summary CV in the body text?
• Abbreviated details (name, contact information and qualification)
• The full CV should be included in Annex A.
Organisational Structure and
Annex B: Contracts
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Which sub-contracted/ delegated activities should be included in the
list? Can it be limited to agreements at corporate level?
• GVP guidance includes:
– distributors, licensing partners, co-marketing partners
– medical information, auditors, PSP and data management
– other technical providers (e.g. hosting of computer systems).
• Not just limited to corporate level agreements.
• Worldwide agreements which are applicable to EU authorised
product, including agreements entered by affiliates must also be
described.
Sources of Safety Data (1)
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What is the expectation for the description of “main units” collecting
safety data?
• The body text description may be brief. It should highlight the
main units (or types of unit) where safety data may originate on
a global basis.
• This may include affiliates, medical information centres, studies,
registries or surveillance programmes.
• The Annex C lists should be comprehensive and describe the
country, nature of the activity, products and site contact details.
Sources of Safety Data (2)
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Does the MHRA expect to see lists of studies, registries,
surveillance or support programmes in Annex C?
• GVP Module II: Lists of studies and support programmes “may
be located in an Annex or provided separately”.
• Findings would not be raised if these lists were not included.
• The guidance indicates that the MAH must be able to provide
such lists for inspection purposes.
• They will routinely be requested by MHRA Inspectors. It is
preferable (not mandatory) that they are included in the PSMF.
Computerised Systems (1)
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Besides the safety database, which other systems or databases
need to be described?
• Any MAH system used to “receive, collate, record and report
safety information”.
• This might include:
– medical information systems
– product quality databases
– clinical trial systems
– any system important for the collection of safety data.
• An element of judgment is involved.
Computerised Systems (2)
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What should be included in Annex D of the PSMF – Computerised
Systems?
• There is limited guidance in GVP.
• The body text should provide descriptive information about the
location, functionality (including validation status) and
operational responsibility for computerised systems .
• Annex D can be used to provide tabular information about those
systems.
Pharmacovigilance Processes
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Is it acceptable to simply list the documented procedures of the
MAH or is something further required?
• A description of the following processes should be included:
– Continuous monitoring of risk-benefit profile(s)
– Risk management system(s)
– ICSR collection, collation, follow-up and reporting
– PSUR scheduling, production and submission
– Communication of safety concerns
– Implementation of safety variations
Pharmacovigilance System
Performance (1)
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Case processing is delegated to a vendor. The vendor maintains
KPIs to monitor the quality of ICSRs. Should this be provided to the
MAH for inclusion in the PSMF?
• The MAH and QPPV should monitor the quality of ICSRs. A
description of quality monitoring must be included in the PSMF.
• If the MAH monitors quality using metrics then these should be
supplied in the PSMF.
• The MAH may delegate aspects of quality to the vendor (but
retains responsibility). If the MAH uses the vendor quality
metrics for its own purpose then these should be in the PSMF.
Pharmacovigilance System
Performance (2)
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What are the expectations regarding the performance indicator
targets for ICSR and PSUR submission compliance?
• There is no defined acceptable level of non-compliance.
• Targets can only reasonably be defined depending upon the
volume of submissions within your organisation.
• As a general rule, ICSR expedited reporting compliance which
drops below 95% may raise questions during inspection.
• PSUR submission targets are harder to define. In a small
organisation, one missed PSUR may represent 100% failure.
Quality System: Audits (1)
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• Questions about the inclusion of audit findings and deviations in
the PSMF was the most popular topic from delegates.
• Article 104(2) of the Directive: “The marketing authorisation
holder shall perform a regular audit of his pharmacovigilance
system. He shall place a note concerning the main findings of
the audit on his pharmacovigilance system master file”.
• The legal requirement only relates to audits conducted or
commissioned by the MAH on its own system.
Quality System: Audits (2)
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If the MAH conducts an external audit of a partner or contractor, do
the major and critical findings need to be recorded in the MAH
PSMF?
• Yes. This audit is conducted or commissioned by the MAH.
• This is an example of an audit of the MAH’s PV system, as the
partner/ contractor is performing activities on behalf of the MAH
(this may only include case collection in a single territory).
• The MAH is not the CAPA owner but CAPA implementation
should still be confirmed or verified by the MAH.
Quality System: Audits (3)
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Do major and critical findings identified during an audit of the MAH
by a partner company need to be recorded in the MAH PSMF?
• No. The audit is not conducted or commissioned by the MAH. It
is not mandatory to include the findings identified by partners in
the MAH PSMF.
• However, the MAH is encouraged to include significant findings
(to the extent that they are relevant to the MAH’s PV system).
• The result of partner audits could be an input to the MAH’s own
risk-based audit planning. As a result the MAH may trigger its
own internal audit.
Quality System: Audits (4)
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A vendor identifies critical or major findings through its own internal
audit. Do these findings need to be recorded in the MAH PSMF?
• No. The legal requirement for PSMF inclusion relates to audits
conducted or commissioned by the MAH.
• The MAH should be notified of relevant non-compliance
identified by the vendor and this should be stipulated in the
contract with the vendor.
• The findings should be inputs into the MAH’s own risk-based
audit planning.
• As a result the MAH may trigger its own vendor audit.
Quality System: Audits (5)
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Do open CAPA from Competent Authority Inspections need to be
included in the PSMF?
• GVP guidance is only applicable to audit findings and
deviations.
• NCAs routinely have access to inspection findings from other
Member States through information sharing processes.
• It can be helpful [but is not mandatory] to include open CAPA
from NCA inspection in the PSMF.
Quality System: Audits (6)
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Can audit findings be included in the PSMF annex rather than the
body text? It is easier the manage the addition and removal of
annex information.
• The EU legal interpretation is that the note should be in the
PSMF body text.
• The addition, amendment or removal of audit notes must be
recorded in the logbook.
• Only body-text sections are subject to logbook control.
• Recording removal in the logbook verifies that sufficient
improvement has been demonstrated or independently verified.
Quality System: Deviations
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Do all deviations or only those equivalent to major and critical need
to be described in the PSMF?
• The PSMF shall document deviations from pharmacovigilance
procedures (including impact) until they are resolved. There is
no additional guidance in GVP.
• MHRA would not expect to see every single SOP deviation
recorded in the PSMF (although repeat deviations to the same
process may indicate an underlying issue).
• Both planned and unplanned deviations should be considered.
• An element of judgment is involved.
Annex G: Audit Schedule
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Should the Annex G audit schedule also include the internal audit
plans of partner companies?
• No. The intention is to give an overview of audits planned and
conducted by the MAH (including those conducted by an
external auditor on behalf of the MAH).
Annex H: Product List (1)
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Annex H requires information about products and their “presence on
the market”. What exactly is required? A product which was last
shipped to a country may still be on the market with a long shelf-life.
• Annex H should include a list of products covered by the
pharmacovigilance system master file.
• A product is considered to be “on the market” whilst it remains
available to patients i.e. during its shelf-life.
• Pharmacovigilance requirements continue as long as a product
is on the market.
• GVP Module VI includes requirements and recommendations for
products which have been suspended (or withdrawn).
Annex H: Product List (2)
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MAH 1 places its products on the market but uses the system of
MAH 2 to fulfil its pharmacovigilance obligations. Which PSMF
should cover the relevant products?
• The product should be included in the PSMF of MAH 2 (i.e. the
pharmacovigilance system in which it resides).
• MAH 1 should make reference to the additional PSMF in the
annex of its own PSMF.
• Thus the entire MAH product portfolio can be related to the set
of pharmacovigilance system master files.
Logbook
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To what extent should changes be recorded in the logbook?
• The Commission Implementing Regulation states that the MAH
shall record “any alteration of the content of the [PSMF] made
within the last five years, with the exception of the information
referred to in point 1(b) to (e) of Article 2 and in Article 3.”
• It is not considered necessary log-book minor formatting
changes such as typos and grammatical errors.
Version Control (1)
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Does a change to the annex require an immediate change in PSMF
version number?
• Annex information may change rapidly and can be managed
outside of the PSMF.
• Change history for the annex information should be available ‘on
demand’.
• PSMF content and annex information may be independently
versioned.
Version Control (2)
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Can changes to annex information be introduced periodically rather
than immediately after each change?
• The PSMF is a living document and may constantly change.
• If requested by a NCA, the PSMF must be submitted within 7
days and it should be up-to-date at the time of submission.
• It is understood that some companies have implemented a
quarterly revision cycle. This may be acceptable as long as an
up-to-date version can be provided on request (i.e. in 7 days).
Your Questions Answered
(hopefully)……..
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