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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