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330 Cobert’s Manual of Drug Safety and Pharmacovigilance
concept and require a similar document. It is a wise
idea to prepare this document (customized for specific
regions that require it) and keep it current. By preparing
it, the company will deliver a detailed overview on the
status and quality of the company’s PV system for gov-
ernment inspectors and other interested parties such as
marketing or development partners. According to GVP
Module II, the PSMF is required as part of a quality
management system.
The EU Pharmacovigilance
System Master File (Guideline
on Good Pharmacovigilance
Practice Module II)
See EU GVP Module II for details
The key parts of the PSMF are as follows:
EU Qualified Person for Pharmacovigi-
lance (EU QPPV)
Responsibilities guaranteeing that the EU QPPV
has sufficient authority over the PV System;
CV with the key information on the role of the
EU QPPV (including qualifications and experi-
ence specific to PV and proof of EudraVigilance
registration);
Contact details including back-up arrangements
(24/7);
Same information for the deputy EU QPPV, if
applicable;
Copy of the EU QPPV registration dossier (and
deputy EU QPPV if applicable; and
List of delegated/outsourced tasks:
Note: Any delegation, backup, commitment, etc.,
must be in a signed document or contract.
Organizational structure of the MAH
Organizational structure of the MAH, showing
the position of the EU QPPV;
All sites in the world where the PV functions are
undertaken with their specific roles and respon-
sibilities; and
Delegated/outsourced activities with details on
partners references, roles and responsibilities
(of note, contracts may be requested by health
authorities during inspections or on an ad hoc
basis).
Sources of safety data
Description of the main units involved with
safety data collection, on a global basis, for solic-
ited and spontaneous case collection (products
authorized in the EU);
List describing the country, nature of the activ-
ity and the product(s) and providing a contact
point (address, telephone and e-mail) for the
site;
Detailed information about third parties, includ-
ing their specific roles and responsibilities; and
List of study sources, including any studies,
registries, surveillance or support programs
sponsored by the MAH through which ICSRs
could be reported. The list should describe,
on a worldwide basis, the status of each study/
program, the applicable country(ies), the pro-
duct(s) and the main objective.
Computerized systems and databases
List and description of the main PV systems
and databases;
Location, functionality and operational respon-
sibility for computerized systems and databases
used to:
Receive, collate, record and report safety
information;
Identify and manage safety signals;
Manage PSURs/PBRERs, RMPs (sched-
uling, production, review, validation and
submission);
Manage Corrective and Preventive Actions
(CAPAs), etc.;
Fit-for-purpose assessment of the IT system
(increasing dependance on The Cloud presents
challenges);
Validation status of key aspects of computer
system functionality: change control, nature of
testing, back-up procedures and electronic data
repositories vital to PV compliance; and
Pharmacovigilance System Master File 331
Description (and location) of the available
documentation.
Pharmacovigilance processes
“Continuous” monitoring of product risk–ben-
efit profile(s);
Results of evaluation and the decision-mak-
ing process for taking appropriate measures;
Signal generation, detection, evaluation,
and management;
Procedures and instructions concerning
Safety database outputs;
Interactions with clinical departments, etc.;
Risk management system(s) and monitoring of
the outcome of risk minimization measures;
ICSR collection, collation, follow-up, assess-
ment, and reporting (specifying local versus
global activities);
PSUR/PBRER scheduling, production and
submission;
Communication of safety concerns to consum-
ers, HCPs, and the competent authorities; and
Implementation of safety variations to the SmPC
and PIL, considering both internal and external
communications.
Pharmacovigilance system performance
Targets for the performance of the pharmacovig-
ilance system;
Correct reporting of ICSR assessment (with fig-
ures/graphs on timeliness for 15-day and 90-day
reporting over the past year — within Annexes);
Metrics used to monitor the quality of ICSR
reporting, PSURs/PBRERs or other submissions;
Overview of the timeliness of PSUR/PBRER
reporting to competent authorities in the EU;
Overview of the methods used to ensure timeli-
ness of safety variation submissions compared to
internal and competent authority deadlines; and
Overview of adherence to Risk Management
Plan (RMP) commitments, or other obligations
or conditions of the MAH that are relevant to PV.
Quality system
Document and Record Control: description of
archiving arrangements;
Procedural documents;
General description of the types of docu-
ments used in PV (standards, operating pro-
cedures, work instructions, etc.);
Applicability of these documents at
global, regional or local level within the
organization;
Controls that are applied to their accessibil-
ity, implementation and maintenance;
Information about the documentation sys-
tems applied to relevant procedures and
documents under the control of third par-
ties, e.g., licensing partners;
List of specific procedures and processes
related to the PV activities and interfaces
with other functions or partners (EU QPPV
& backup activities; contractual agree-
ments; collection, processing, data entry,
quality control, coding, classification, medi-
cal review, and reporting of ICSRs; aggregate
reports preparation, validation, delivery &
transmission, signal detection & manage-
ment processes; benefit–risk evaluation
processes; internal & external PV commu-
nication; interaction between safety issues
and product defects; responses to requests
for information from regulatory authorities;
handling of urgent safety restrictions and
safety variations; meeting commitments to
agencies, etc.).
Training
Description of the training systems and where
the training records, CVs, and job descriptions
are filed.
Auditing
Information about QA assurance auditing of
the PV System (audit plan approach, reporting
mechanisms and timelines, etc.);
List of scheduled and completed audits (five
year rolling period), including notes on any
changes to plan; and
Specific note for any major and/or critical find-
ing with a summary of CAPA(s).
332 Cobert’s Manual of Drug Safety and Pharmacovigilance
Annexes to the PSMF
Annex A
Tasks delegated by the EU QPPV;
CV of the EU QPPV;
EU QPPV contact details;
Annex B
List of contracts & agreements;
Annex C
Description of sources of safety data;
Annex D
Additional information on computerized
systems and databases;
Annex E
Lists of procedural documents;
Annex F
Lists of Key Performance Indicators (KPI)s;
Current results of performance assessment;
Annex G
Audit schedules (including changes);
List of audits conducted and completed;
Annex H
List(s) of products covered by the PV
system;
Any notes concerning the MAH per product;
Annex I
Logbook;
Documentation of history of changes for
Annex contents.
As you can see, this is an incredibly complete and
complex document that can run, with appendices, sev-
eral hundred pages in a large multi-national pharma
company. Keeping this complex document up to date
may be a full-time job in some companies.
Comment
Clearly the PSMF has been well thought out by the
EMA. It requests information that will show whether a
company has control (at least on paper) over each of the
key areas in drug safety. Pre-registration PV activities
and organizations are not, strictly speaking, within the
scope of the PSMF. However, the PSMF must be at the
ready when a marketing application is submitted, not
only after authorization.
This is a major document (and a legal requirement)
with multiple annexes/appendices and contains data
that must be obtained from many sources within the
company. Much of the data may not be handy or readily
available to the PV department. This document should
be prepared as a matter of routine, updated periodically,
and kept on file. It will be inspected!
Additional comments:
Companies should view the PSMF as a living docu-
ment, which should be kept up to date, with a strict
versioning process, posted on a secured repository,
under the direction and control of the EU QPPV.
Someone must “own” it and be responsible for it
within the organization. The EU QPPV is that per-
son, even though many of the associated tasks are
often delegated.
It should be considered as a tool to gain assurance
that the PV system is compliant and to document
information on deviations/deficiencies or risks in
the company’s PV system.
The PSMF must be provided to EU Authorities
upon request within 7-calendar days, but a request
may be made for an immediate response. In prac-
tice, this means that the PSMF must be up to date
and immediately available. For large companies, it
may be quite challenging to prepare this “on the
spot” for an audit or inspection.
It must be registered in the EMA EudraVigilance
System (Article 57 database).
A PSMF is to be available for any company:
Having at least one registered medicinal product
in one or more EEA country(ies).
Regardless of the registration procedure (cen-
tralized, national, mutual recognition or decen-
tralized).
When delegating any activities concerning the PV
system and its PSMF, the MAH retains ultimate
responsibility for the PV system, for submission of
information about the PSMF location, for mainte-
nance and for its provision to competent authorities
upon request.
Pharmacovigilance System Master File 333
The PSMF is a global document covering the com-
pany’s entire PV system. Activities outside the EEA
can and do impact the EU PV scope and system.
One single PSMF by company is simpler but
depending on the company’s history, organization,
products, etc., several PSMFs can be envisaged; but
any chosen option must be defensible in front of
inspectors. Reasons for more than one PSMF might
include split of independent business units within
an organization, e.g., one business unit for vaccines
and another for traditional chemical medicinal
products. Of course, as more jurisdictions outside
the EU require an equivalent document for their
region, these must be created and maintained.
The site/country where the PSMF is located in the
EU is important and much thought should be given
to where the company locates the EU QPPV and
PSMF. This is because the Member State where the
PSMF is held becomes the supervisory authority
handling all relations with the EMA as well as PV
inspections. Note that, as a practical matter, most
PSMFs are “located” in the “cloud” and the super-
visory regulatory authority usually defaults to the
country where the EU QPPV operates. If this is not
the case, the situation and reasons must be fully
explained in writing and be kept on file.
When preparing a PSMF, it is wise to include more
stable information in the main body of the docu-
ment, i.e., any information which does not change
frequently. Examples might be SOPs and com-
puter system information, etc. Other information
may change relatively quickly (e.g., contact infor-
mation) and this should be put into the annexes/
appendices. This makes updating the document
easier. Updating must, of course be done, formally
and under the aegis of the quality system in place.
The PSMF is an EU document but a local PSMF (at
the affiliate level in large companies) can be useful.
The purpose is not to duplicate information already
included in the EU PSMF but rather add specific
local organization, processes, etc. The document
is generally in English but “validated” translations
may be appropriate.
Even if the company does not operate in the EU, it
might be wise to keep on file a document like the
PSMF summarizing how the safety system works
in the company. This may be requested if market-
ing partners in the EU are or become involved. It
may be very difficult to prepare this document in a
hurry if a new marketing partner is enlisted with lit-
tle notice to the safety department and anyone else
preparing the PSMF.
Ownership of the PSMF must be clear. It is usu-
ally the EU QPPV. However, he/she may not do the
actual collection and preparation of all the multi-
ple parts of the document but he/she will be held
responsible for it.
In summary, the EU PSMF is a complex, obligatory
document that must be carefully and accurately done. It
is used as the basic information source for inspections.
It should also reflect reality. It is not a theoretical docu-
ment. The processes and systems described in the PSMF
must really exist and be visible to the inspectors when
they inspect the company, talk to PV personnel, etc. It
must be kept up to date. Likewise, for other jurisdic-
tions that may require similar documents (and they all
must be in synch).
CHAPTER
335
30
The Qualified
(Individual) Person(s)
Responsible for
Pharmacovigilance
T
his chapter addresses responsi-
bility for a MAH’s pharmacovigi-
lance system.
Single Point of
Responsibility for
Post-Marketing
Pharmacovigilance
For companies with products registered in the European
Union (as well as in certain other territories), Direc-
tive 2010/84/EU requires that there be an EU “Quali-
fied Person for Pharmacovigilance” (QPPV). This is
a critical role and function within the company. The
concept of a QPPV or a “an individual person respon-
sible for pharmacovigilance who is permanently and
continuously available to the MAH” is most interest-
ing: a named individual (and backup) takes corporate
and personal responsibility for the functioning of drug
safety and the pharmacovigilance (PV) system for each
company that has a Marketing Authorization (MA) in
the respective jurisdiction. In many cases, the respon-
sible person must reside in the covered territory for
enforcement purposes For example, the EU QPPV must
reside in the EU. In most jurisdictions, if a company
does not yet have an MA or a submission and is only
doing clinical trials, there is ordinarily no requirement
for a responsible person. However, a candidate respon-
sible person must be identified and named at the time of
MA submission. In addition, a pharmacovigilance (PV)
system that addresses requirements in the post-market-
ing phase must be in place even if the system is not yet
being used. More than 70 jurisdictions, some within the
EU, have adopted the role of a qualified or responsible
person for pharmacovigilance.
The EU QPPV functions at the EU level. Others
operate at the country level. In the EU, all local QPPVs
must report to the EU QPPV. The EU QPPV position
and requirements are defined in Directive 2010/84/EU
and GVP Module I.
336 Cobert’s Manual of Drug Safety and Pharmacovigilance
The concept of the QPPV originated in the EU.
However, this role has since been legislated elsewhere
over the years. Examples are: Australia, Belgium, Bul-
garia, Croatia, Cyprus, Czech Republic, Denmark,
France, Germany (called the Stufenplanbeauftragter),
Greece, Hungary, India, Latvia, Lithuania, Luxembourg,
Netherlands, Poland, Romania, Russia, Slovakia, Spain,
Uganda, United Kingdom, and others. Note that having
a requirement on the record does not ensure compli-
ance, particularly when enforcement is not consistent
and penalties for non-compliance are variable. Check
detailed requirements locally.
The US has yet to require a
single qualified person for
pharmacovigilance, which
can contribute to a lesser
degree of understanding
of requirements when US-
only organizations expand
outside the USA
Since there is no direct counterpart for the EU QPPV
in the US and Canada the responsibility for a phar-
macovigilance system lies at the corporate level. Note
that the EU QPPV is not responsible for manufacturing
issues; there is a separate QP for manufacturing.
Directive 2010/84/EU and GVP Module I note the
following:
Each company must submit a summary of the appli-
cant’s pharmacovigilance system master file (PSMF)
which shall include the following elements:
Proof that the applicant has at his disposal a
Qualified Person Responsible for PharmacoVig-
ilance (QPPV);
The Member State(s) in which the qualified per-
son resides and carries out his/her tasks; and
The contact details of the QPPV.
The MAH should have permanently and continu-
ously at his disposal a QPPV residing and operating
in the EU or EEA with 24/7 availability.
One QPPV per PV system in a company is required,
but one single QPPV may have oversight of several
PV systems. There could be a qualified deputy also
residing in the EEA. The name and contact informa-
tion must be provided to EMA/Member States.
Some Member States require a named person/
national QPPV, too. This person may or may not be
the same as the EU QPPV.
The QPPV should be appropriately qualified, with
documented experience in all aspects of pharma-
covigilance. If the QPPV is not medically qualified
(i.e., an MD), access to a medically qualified person
should be available 24/7.
The EU QPPV has multiple responsibilities:
Establishing and maintaining/managing the
MAH’s pharmacovigilance system;
Ensuring that a PSMF is in place and up to date
(some jurisdictions also have local requirements
for the equivalent of a local or regional PSMF,
which must be consistent with the EU PSMF);
Ensuring that all ARs (including literature
searches) are collected, collated, and accessible
at least at one point within the EU;
Ensuring preparation, validation and submis-
sion of ICSRs and synthesis reports (PSURs/
PBRERs, RMPs, benefit–risk assessment, etc.)
and company-sponsored post-authorization
safety/efficacy studies (PASS & PAES);
Evaluating continuously the overall pharma-
covigilance system, including in particular,
during the post-authorization period;
Having oversight of signal detection and risk
management, including PASS/PAES and risk
minimization measures (routine and non-
routine measures); being involved in the
review and sign-off of protocols of PASS con-
ducted in the EU or included in the RMP
approved in the EU;
Being aware of any new information about ben-
efit–risk assessments for all registered drugs;
Ensuring that any request from the health
agency is answered fully and promptly;
Being the contact person for EMA PV inspec-
tions as well as inspections by other non-EU
agencies and third parties.
Note: GVP Module I specifies that “The QPPV
may delegate specific tasks, under supervision, to
The Qualified (Individual) Person(s) Responsible for Pharmacovigilance 337
appropriately qualified and trained individuals, for
example, acting as safety experts for certain products,
provided that the QPPV maintains system oversight
and overview of the safety profiles of all products. Such
delegation should be documented.” Accountability may
not be delegated,
The QPPV should have oversight of the PV system,
including and, therefore, “sufficient authority to influ-
ence the performance of the quality system and the
pharmacovigilance activities and to promote, maintain
and improve compliance,” i.e., authority over:
The organization of the Drug Safety department,
processes, tools, and performance/compliance;
The needed measures for signal detection and
risk management activities, including benefit–risk
assessments;
The decision to take for variations, urgent safety
restrictions, and communication to patients and
healthcare professionals;
Partnerships.
The MAH, as well, has responsibilities to the
following:
Support the QPPV and ensure appropriate pro-
cesses, resources, communication mechanisms, and
access to all sources of relevant information in place
for the QPPV.
Ensure full documentation of all procedures and
activities of the QPPV.
Implement mechanisms for the QPPV to be kept
informed of emerging safety and risk–benefit issues
including clinical trials and contractual agreements.
Ensure the QPPV has the authority to implement
changes to the MAH’s PV system to maintain
compliance.
Ensure the QPPV has input into Risk Management
Plans and the preparation of regulatory action in
response to emerging safety concerns.
Ensure the presence of back-up procedures (e.g., in
case of non-availability of personnel, AE database
failure, failure of other hardware or software with
impact on electronic reporting and data analysis).
Note: The MAH may transfer/outsource PV activi-
ties to another person or organization. A detailed and
clear written contract must be in place documenting
such transfers and outsourcing. The contracted person
or organization should implement QA/QC and allow
auditing by the MAH. It is possible to outsource the EU
QPPV function but the ultimate responsibility for all PV
obligations always resides with the MAH.
Practicalities
The QPPV is a responsible and very challenging posi-
tion. The person must be involved and have real influ-
ence in the safety system of the company. He or she
must be knowledgeable and able to discuss, at least at
a high level, particularly during a governmental inspec-
tion, the PV system in place globally, including standard
operating procedures (SOPs); working documents;
quality assessment/quality control (QA/QC); databases
in use for drug safety, privacy, and security issues; all
products marketed in the EEA and where they are
sold outside of Europe; global licensing; distribution;
co-marketing; agency commitments; compliance status
and key performance indicators (metrics); signal iden-
tification; analysis and workup mechanisms in place;
specific signals and safety issues pending globally; the
risk management system and business continuity/crisis
management plans in place; post-marketing trials under
way, and new indication trials for marketed drugs; safety
training; and issues with health authorities (HAs).
He or she must review and sign Periodic Safety
Update Report (PSURs/PBRERs) and other PV docu-
ments submitted to HAs. To succeed in this position,
communication across the organization is critical!
There must be mechanisms in place for the QPPV
to send and receive information and data he or she
needs on a timely basis to do the job. Good commu-
nication skills are also needed to link the QPPV with
management, drug safety, the rest of the organization,
the European Medicines Agency (EMA) and member
state HAs, deputy and national QPPVs, and so forth.
There must be a formal job description, and many
companies also have a formal, written contract with
the QPPV. The person, often a medical doctor (MD),
should have senior management’s ear.
Many companies, particularly small companies and
generic houses, will outsource the QPPV to a Clinical
Research Organization (CRO) or consultant. Although
338 Cobert’s Manual of Drug Safety and Pharmacovigilance
this is legal and feasible, the company and the QPPV
must take the job seriously, e.g., who covers during
holidays and vacations?. Some QPPVs at CROs may be
performing this function for 15 or more clients! Whether
this is practical and wise is debatable. All delegation,
both within the company and outsourced, must be rig-
idly and carefully documented. The specific delegated
functions must be written down and all parties must
sign off. Note that all companies with MAs must have
a QPPV. This includes generics, over-the-counter prod-
ucts, and so forth. No exceptions. Large companies with
many products or marketing partnerships may need to
have staff supporting the QPPV in the company, espe-
cially if information is needed from other continents or
non-EU countries. Sometimes convincing personnel in
company divisions abroad who do not normally inter-
act with headquarters may not fully appreciate that they
must supply information to support sales in the EU.
This can be a challenge, especially if there is frequent
turnover in far-away places.
The EU QPPV is not required to be part of the PV
team. He/she can have a non-PV position with oversight
of the PV organization and performance. In such cir-
cumstances, it is best to have the EU QPPV at least at
the same hierarchy level of the head global PV.
Note: The CMO or the Head of Global PV can
also be the EU QPPV as long as they are appropriately
qualified.
Frequent QPPV Inspection
Findings by the EMA
No QPPV or interim measures (change of QPPV, no
backup procedures for absence, etc.);
More than one QPPV per PV System or unclear
organization; lack of Local Person for PV (LPPVs)
in coutries where the products is licensed but not
marketed;
Not resident or operating in the EEA;
No job description;
Failure to notify Competent Authorities of QPPV
details;
Lack of 24/7 coverage;
Inadequate oversight of the pharmacovigilance sys-
tem (ICSRs, PSURs/PBRERs, RMPs, PASS, PAES,
safety profile of products, audits and inspections,
QA & QC, database(s));
Lack of training or experience (or lack of documen-
tation of same);
No or inadequate training of drug safety staff;
Roles and responsibilities not formally defined
(especially important if parts of role are delegated);
and
Inadequate access to medically qualified personnel.
Penalties can be severe and can include fines of up
to 5% of the MAH’s EU sales, with further penalties if the
problems are not promptly corrected. Civil and criminal
penalties for the MAH and the QPPV are possible.
Frequently Asked Questions
Q: Why would anyone want to do this job?
A: Good question, and we may not have a good answer.
Perhaps a combination of responsibility, power, the
desire to have a meaningful job that makes an impact,
a good salary (though some say they could never be
paid enough to do this job), visibility, and the like. For
people who like and accept being empowered (and who
really are empowered), and who like playing a fascinat-
ing role with interactions in all areas and in all levels of
the company and with health authorities, this can be
a marvelous job. Until something bad happens. Then
the stress level rises and it truly becomes a 24/7 job,
particularly in the age of the Internet, with instant com-
munications and media knowledge of problems (often
incomplete or poorly understood). Word of problems
and misbehavior travels quickly.
Q: Why would anyone not want to do this job?
A: Good question also! As specified before, such respon-
sibilities could become a 24/7 job with real and stress-
ful roles and responsibilities, particularly if the QPPV
does not have the full support of the company. As icing
on the cake, two legal consequences must be empha-
sized: First, even after the EU QPPV transitions to new
responsibilities or a different organization, he or she
The Qualified (Individual) Person(s) Responsible for Pharmacovigilance 339
will still be responsible for a safety issue that occurred
during his or her tenure as EU QPPV. In addition, any
decision/measure, taken (or not taken) during the EU
QPPV tenure can be challenged at any time and that
individual will be committed “forever”. In other words,
one can be prosecuted ten, twenty or more years after
leaving the EU QPPV post. Second, as an EU QPPV and
in case of a major safety issue, you can face criminal
charges. In such a situation, it would be too late if you
did not, before the issue arises or at the start of your
QPPV tenure, secure a commitment of well-financed
legal support from the MAH. Many EU QPPVs have
tried to include such a protective statement in their
contract, but most often, the company is reluctant to
accept ... Have fun!
Q: What do I do if I am QPPV but not empow-
ered and cannot get management to act on
the appropriate needs, resources, and safety
issues?
A: Quit. First, do your utmost to convince management
that this is serious business and certain things must
be done. You may need to get allies to make the case
(e.g., the regulatory and legal colleagues in the com-
pany or an outside auditor). Point out the key sections
from the EU Regulations. Document fully in writing
everything you have done and everyone notified (and
when), all items, actions, resources, and so forth, that
you have requested, plus the responses. Always do and
say the right thing and document it. Give it a reasonable
attempt and length of time to get actions and correc-
tions. It helps to have a forceful type-A personality. If all
fails, update your CV and get a new job. You’ll sleep bet-
ter and your gastric acid and blood pressure will return
to normal.