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50 Cobert’s Manual of Drug Safety and Pharmacovigilance
Risk Management
The EU has developed a comprehensive risk manage-
ment strategy for all products in the EEA. This is a
strategy that covers the entire life cycle of a product,
and a risk analysis is required for every product upon
approval (or during its marketing). A specific commit-
tee (PRAC), replacing the former PV Working Party,
was set up in 2012 (see below). The goal is to have a
set of pharmacovigilance activities and potential non-
routine interventions designed to identify, characterize,
prevent, and minimize risks relating to medicinal prod-
ucts, including the assessment of the effectiveness of
these interventions.
EudraVigilance — The EU Safety
Database
In 2001, an EU-wide central database, called the Eudra-
Vigilance System, was created. This database serves
as a repository and “clearinghouse” to ensure that all
appropriate cases are available to the appropriate Mem-
ber States. It is used to capture SAEs electronically as
Individual Case Safety Reports (ICSRs) both pre- and
post-authorization as well as spontaneous non-serious
AEs. It has been designed to manage and analyze infor-
mation on suspected adverse reactions to medicines
which have been authorized or are being studied in
clinical trials in the European Economic Area (EEA).
The EMA operates the system. This allows for a sin-
gle European Pharmacovigilance database accessible to
the Member States’ HAs. Individual cases (ICSRs) must
now be reported electronically from both public and
private PV organizations (using the gateway or a web
reporting application).
The pharmaceutical industry can only access
detailed, proprietary data for medicines for which they
hold a marketing authorization. This restriction is in
place to remain in compliance with EU personal data
protection and privacy legislation. They can, of course,
access the high level summary information available
to the general public on all medications in EudraVig-
ilance (http://www.adrreports.eu/en/index.html). Sim-
ple queries can deliver online summary tables or figures
depending on the selected criteria.
The European pharmacovigilance issues track-
ing tool (EPITT) is a database developed by EMA for
the communication of pharmacovigilance and risk-
management issues between the Agency and Member
States. It provides access to documents related to the
safety of products/substances authorized in the EEA.
The EPITT provides the functionalities for national reg-
ulatory authorities in the EEA and EMA to track signals
at EU level. It is not available to the public or the phar-
maceutical industry.
Other computerized systems have been developed
by the EMA:
EudraVigilance Medicinal Products Dictionary
(XEVMPD), also known as the Article 57 database.
This is the EU drug dictionary.
SIAMED II is the Agency’s product information
and application tracking system which will be soon
migrated into the PMS (Product Management Ser-
vice) hub.
The European Clinical Trials Database (EudraCT)
is the EU’s electronic database of clinical trials. It
contains information submitted by sponsors and
informs users about ongoing clinical trials in all
EEA countries, enabling an overview of multi-state
trials.
The European Network of Centres for Pharmaco-
epidemiology and Pharmacovigilance (ENCePP —
https://www.encepp.eu/structure/index.shtml)
databases contain independent (from pharma com-
panies) post-authorization studies focusing on
safety and on benefit–risk, using available expertise
and research experience across Europe.
Studies database is the E-Register of Studies (EU
Post-authorization Studies (PAS) register) aims to
provide a publicly accessible resource for the reg-
istration of pharmacoepidemiological and pharma-
covigilance studies; they are hosted in the ENCePP
system.
PSUR/PBRER repository is a single, central plat-
form for PSURs/PBRERs and related documents
to be used by all regulatory authorities and phar-
maceutical companies in the EU. The use of the
PSUR Repository is mandatory for all PSUR/PBRER
submissions as of June 2016 (via the e-submission
Gateway).
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The European Medicines Agency 51
In addition to the EMA, each European coun-
try has its own national Health Authority (HA) or
authorities that handle drug safety. They are often
called “competent authorities (CA)” in EU regula-
tory jargon. The EU is still evolving and the Lisbon
Treaty (2005) and other subsequent treaties have
altered some of the basic structures and functions
of the EU governing bodies. The EU remains still a
work in progress. The interplay between the central
authority (primarily in Brussels but with various
agencies scattered throughout the EU, such as the
EMA in Amsterdam and the European Central Bank
in Frankfurt, Germany) and the individual countries
is dynamic and often changing. Note also that the
EMA does not have jurisdiction over food. The Euro-
pean Food Safety Authority in Parma, Italy handles
those matters.
As noted, for drug safety, some functions are pri-
marily centralized in the EMA and some remain in
each member state. Some national authorities are very
large and powerful and exert strong influence over
smaller member states. This division and, in many
cases, duplication of labor, as well as the multitude
of languages involved in the EU, produce a challenge
for safety reporting both for the pharmaceutical indus-
try and for the member states themselves. Most of the
work in drug safety is done at the international level in
English, but, obviously, at the local level the national
languages are still used. The comparison with other
countries, particularly the US, where the drug safety
function is clearly centralized, is striking. The closest
analogy would be if each of the 50 states in the US
had its own mini-FDA and used languages other than
English. With the UK leaving the EU, there remain
only two countries that have English as a native,
national language: Malta and Eire (Ireland). There has
been some talk of now using more French and Ger-
man. “A voir”. “Bleibt abzuwarten”. We shall see.
In terms of pharmacovigilance, the EMA has largely
harmonized along the lines of ICH. They have codified
the pre-marketing requirements in a document known
as Regulation (EU) No. 536/2014 of the European
Parliament and of the Council of 16 April 2014 and
the post-marketing requirements in Regulation (EU)
Nos. 1235/2010 and 1027/2012. Each is discussed in
detail below. Nonetheless, there are still differences,
particularly for clinical trial pharmacovigilance, from
country to country.
With the regulation updated in 2010, a major effort
has been made for an accurate communication and
transparency. Numerous tools and publications have
been set up to comply with this commitment includ-
ing the EMA web portal, the publishing of committee
meetings’ agendas and minutes, ad hoc newsletters such
as “What’s new in Pharmacovigilance QPPV Updates”,
public hearings, etc.).
For more information on the EMA, see the follow-
ing websites (Current as of late 2024):
EMA website (http://www.ema.europa.eu/ema/);
EMA PV System Manual (http://www.ema.europa.
eu/docs/en_GB/document_library/Other/2014/07/
WC500170226.pdf);
Eudravigilance (https://www.ema.europa.eu/en/
human-regulatory/research-development/pharma
covigilance/eudravigilance/eudravigilance-system-
overview);
PV Q&A web page (http://www.ema.europa.eu/ema/
index.jsp?curl=pages/regulation/q_and_a/q_and_
a_detail_000135.jsp&mid=WC0b01ac058066e97
a%20-).
What Is Not in the Scope
of EMA?
EMA does not perform the following:
Evaluate the initial marketing authorization appli-
cation of all medicines in the EU (as many drugs
have been approved in each EU country before the
creation of the EMA in 1995, the vast majority of
medicines registered in the EU are authorized at a
national level). However, the centralized process
must be used for new products, e.g., biosimilars,
gene products, etc.
Evaluate applications for the authorization of clini-
cal trials. The authorization of clinical trials occurs
at Member State level, although the Agency plays
a key role in ensuring that the standards of good
52 Cobert’s Manual of Drug Safety and Pharmacovigilance
clinical practice are applied. The EMA also manages
the database of clinical trials carried out in the EU.
Evaluate food supplements and cosmetics. These
are evaluated at national level, except for products
having a pharmacological activity.
Carry out research or develop medicines.
Make decisions on the price or availability of medi-
cines. This is done at the national level.
Control medicines advertising. Also done at the
national level.
Control or have information on pharmaceutical
patents.
Develop treatment guidelines.
Provide medical advice to any stakeholder group.
Develop laws concerning medicines. The European
Commission develops EU legislation concerning
medicines and the European Parliament together
with the Council of the European Union adopt the
legislation. The European Commission also devel-
ops EU policies in the field of human or veterinary
medicines and public health.
Issue marketing authorizations. The legal decision
to grant, suspend or revoke a marketing authoriza-
tion for any medicine falls under the remit of the
European Commission for centrally authorized
products, and the national competent authorities
of the EU Member States for nationally authorized
products.
Note 1: The EMA is, since 2021, now responsible for
some Medical Devices (see https://www.ema.europa.eu/
en/human-regulatory/overview/medical-devices)
The Pharmacovigilance Risk
Assessment Committee
The Pharmacovigilance Risk Assessment Committee
(PRAC) has experts from each member state; it pro-
vides its advice and recommendations to the EU net-
work, and for many procedures these recommendations
are considered by the CHMP before they become legally
binding. They meet for 3–4 days each month.
The PRAC was formally established in July 2012,
replacing the former PV Working Party (PhVWP); it is
responsible for assessing all aspects of risk management
of human medicines, including the following:
The detection, assessment, minimization and com-
munication of the risk of adverse reactions, while
taking the therapeutic effect of the medicine into
account to evaluate the benefit/risk balance;
The design and evaluation of post-authorization
safety studies (PASS);
Pharmacovigilance audits/inspections.
The PRAC also advises the EMA on the development
of guidelines, standards, and provides advice on opera-
tional aspects of the EU pharmacovigilance system.
The PRAC provides recommendations on questions
involving pharmacovigilance and risk management sys-
tems, including the monitoring of their effectiveness, to
the following:
CHMP for centrally authorized medicines and refer-
ral procedures;
CMDh for mutual recognition and decentralized
procedures;
The EMA secretariat, Management Board, and Euro-
pean Commission, as applicable.
The PRAC’s primary duties include evaluation of
potential signals arising from spontaneous reports and
or PSURs/PBRERs, advising on risk and risk manage-
ment (including regulatory options) and monitor-
ing regulatory actions. Their domain is largely in the
post-approval area, but they do have authority for drugs
under study.
The PRAC’s member contact information and dec-
larations of interest are published on the EMA website.
The PRAC includes independent experts from all EU
member states in pharmacoepidemiology, clinical phar-
macology, biologics, signal detection, risk communi-
cation, and vaccine vigilance. The Detailed Rules for
PRAC procedures have been published (see the EMA
Website).
A yearly PRAC work plan is published during the
first quarter of the year. They issue work programs in
advance of their monthly meetings and publish meeting
highlights and meeting minutes which usually involve
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The European Medicines Agency 53
safety issues on specific drugs. The meeting highlights
are posted on the EMA website the day after the meet-
ing and the minutes are published after PRAC’s about
a month later. You can find the meeting minutes by
accessing the EMAs website, by going to “Committees”
and then to “PRAC”.
An analysis of the first 18 months of PRAC activities
has been published and concluded positively: “Early
signs, … based on process indicators such as those
reported here for RMPs, ADRs, signals, PSURs and EU
Pharmacovigilance Referrals, point to more systematic
and proportionate risk management planning, the pro-
motion of reporting (including from patients), greater
coordination of real-time signal management, faster
assessment and decision-making, and thus strengthen-
ing of the link between pharmacovigilance assessments
and regulatory actions such as labelling changes to opti-
mize safe and effective drug use.”
1
Post-marketing PV EU
Regulation
Four different kinds of documents exist at the EU level
as follows:
Regulations: These are mandatory requirements
and are applicable in all EU countries as written.
They are translated exactly into national languages
but cannot be altered. They are usually high-level
documents.
Directives: These, too, are mandatory require-
ments as well, but can vary in each EU country
depending on the local translation/adaptation. Often
the member states have up to three years to put
these directives into effect as national legislation.
Guidances/Practices/Decisions: These are
also mandatory requirements. They are more focused
on a specific topic or theme. Note that in the US, the
term guidance or guideline represents FDA’s current
1
Peter Arlett et al., Proactively managing the risk of marketed
drugs: experience with the EMA Pharmacovigilance Risk Assess-
ment Committee, Nat Rev Drug Discov 2014; 13: 395–397.
thinking on a topic but, unlike the EU, they are not
mandatory.
Recommendation/Opinion: These are not
mandatory and are usually more general documents
(e.g., healthcare policy, providing priorities).
The previous legally-binding document covering
post-authorization PV was called EudraLex Volume
9A. It covered all EU PV Regulations. It was amended
in 2010 and since then thousands of pages of docu-
ments have been issued to update the EU PV Regula-
tion. This new legislation aims to rationalize, simplify
and improve workflow, to stop useless tasks, to be more
consistent, to focus on risks, to improve transparency to
all stakeholders, to help ensure that commitments made
are actually done and to involve patients and the public.
It is impossible to provide here an exhaustive list
of these numerous documents, below are listed the key
ones to consider:
Regulations (EU) Nos. 1235/2010 and 1027/2012
Directives 2010/84/EU and 2012/26/EU
Good Vigilance Practices (GVP)
Note 1: Modules XI, XII, XIII and XIV have been
cancelled. Their content has been incorporated
into other documents.
2: These are living documents. They are peri-
odically updated, submitted to PV stakehold-
ers (including the pharmaceutical industry)
for comments/proposals, validated, and then
published.
These documents require the EMA, the member
states, and others to set up systems to handle the collec-
tion, verification, exchange, and presentation of adverse
reaction reports within the European Union but also to
identify safety signals and manage risks.
The roles and responsibilities of the MAH are spelled
out and require that an appropriate system of PV is put
in place by the MAH. All information regarding the ben-
efit–risk profile must be promptly and fully sent to the
competent authorities. And most critically, it describes
the role of the EU Qualified Person for Pharmacovig-
ilance (EU QPPV), to be appointed by the MAH and
to be continuously (24/7) available for safety matters.
54 Cobert’s Manual of Drug Safety and Pharmacovigilance
Table 1.
EU Good Pharmacovigilance Practice (GVP) Modules and Annexes.
GVP Module GVP Title Details
GVP Introductory
Cover Note
— This module introduces all GVPs and annexes and details the following:
Background to GVP;
History of the GVP development process and latest updates;
Objectives of pharmacovigilance;
Pharmacovigilance in the EU: roles of different actors;
Legal basis, scope and process for GVP;
Maintenance and further development of GVP;
Structure of GVP;
Referencing of legal requirements in GVP;
Practical advice for the public consultation.
GVP Module I Pharmacovigilance
Systems and Their
Quality Systems
This module contains guidance for the establishment and maintenance of quality
assured PV systems for MAH, competent authorities of Member States and the
Agency (EMA). How the systems of these organizations interact while undertaking
specific PV processes is described in each respective Module of GVP.
The PV system is a system used by the MAH and by Member States to monitor the
safety of authorized medicinal products and detect any change to their risk-benefit
balance. The Agency likewise maintains a PV system to fulfil its pharmacovigilance
activities.
GVP Module II Pharmacovigilance
System Master File
A pharmacovigilance system master file (PSMF) is a detailed description of the
PV system used by the MAH with respect to one or more authorized medicinal
products.
This module provides detailed guidance regarding the requirements for the PSMF,
including its maintenance, content and associated submissions to competent
authorities.
GVP Module III Pharmacovigilance
Inspections
This module contains guidance on the planning, conduct, reporting and follow-up
of PV inspections in the EU and outlines the role of the different involved parties.
GVP Module IV Pharmacovigilance
Audits
This module provides guidance on planning and conducting the legally required
audits, and in respect of the operation of the EU regulatory network, the role,
context and management of PV audit activity. This module is intended to facilitate
the performance of PV audits, especially to promote harmonization, and encourage
consistency and simplification of the audit process. The principles in this Module
are aligned with internationally accepted auditing standards, issued by relevant
international auditing standardization organizations and support a risk-based
approach to PV audits.
GVP Module V Risk Management
Systems
The aim of a risk management plan (RMP) is to document the risk management
system considered necessary to identify, characterize and minimize a medicinal
product’s important risks. To this end, the RMP contains:
1. The identification or characterization of the safety profile of the medicinal
product, with emphasis on important identified and important potential risks
and missing information, and also on which safety concerns need to be managed
proactively or further studied (the “safety specification”).
2. The planning of PV activities to characterize and quantify clinically relevant risks,
and to identify new adverse reactions (the “pharmacovigilance plan”).
3. The planning and implementation of risk minimization measures, including the
evaluation of the effectiveness of these activities (the “risk minimization plan”).
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The European Medicines Agency 55
GVP Module GVP Title Details
This Module includes the principles of risk minimization and should be read in
conjunction with GVP Module XVI and GVP Module XVI Addendum I on educational
materials.
A RMP template has been developed by the EMA (see EMA Website): it is not
considered as part of the GVPs.
GVP Module VI Collection,
Management and
Submission of Reports
of Suspected Adverse
Reactions to Medicinal
Products
This module of GVP addresses the legal requirements which are applicable to
competent authorities in Member States, MAHs and the Agency (EMA) as regards
the collection, data management and submission of individual reports of suspected
adverse reactions (serious and non-serious) associated with medicinal products for
human use authorized in the European Union (EU).
GVP Module VI —
Addendum I
Duplicate Management
of Suspected Adverse
Reaction Reports
The guidance in this document proposes methods for detecting, confirming and
managing duplicate cases suitable for organizations receiving PV data in various
different formats and describes methods for stakeholders to collaborate with
the Agency (EMA) in the detection and management of duplicate cases; it is also
provided for situations where individual cases might be reported by different
senders.
GVP Module VII Periodic Safety Update
Report
(PSUR/PBRER)
This guidance specifies scope, objectives, format and content of the PSUR/ PBRER.
Further details and guidance for the submission of PSURs/PBRERs in the EU,
including the list of Union references dates and frequency of submission, are
provided.
The process to follow for a single assessment of PSURs/PBRERs in the EU for different
medicinal products containing the same active substance or the same combination
of active substances authorized in more than one Member State for which a Union
reference date and frequency of submission of PSURs has been established, is also
detailed.
GVP Module VIII Post-authorization
Safety Studies
(PASS)
This module concerns both interventional and non-interventional PASS, with a main
focus on non-interventional ones. It does not concern pre-clinical safety studies.
Non-interventional PASS concerned by this guidance are those initiated, managed
or financed by a MAH voluntarily or pursuant to an obligation imposed by an EU
competent authority.
The purposes of this module are to:
provide general guidance for the transparency, scientific standards and quality
standards of non-interventional PASS conducted voluntarily or pursuant to an
obligation imposed by an EU competent authority;
describe procedures whereby an EU competent authority may impose on a MAH
an obligation to conduct a PASS;
describe procedures that apply to non-interventional PASS pursuant to an
obligation imposed by an EU competent authority for the protocol oversight and
reporting of results and for subsequent changes to the marketing authorization.
GVP Module VIII —
Addendum I
Requirements and
Recommendations
for the Submission of
Information on Non-
interventional Post-
authorization Safety
Studies
This addendum provides additional information on legal requirements and
recommendations for the submission of study protocols, progress reports and final
study reports of non-interventional PASS to national competent authorities and the
Agency (EMA).
It also provides additional information as regards the registration of non-
interventional PASS in the EU PAS Register. It does not provide recommendations
for the transmission of information to ethics committees, national review boards or
other bodies in place according to national legislation.
Table 1. (Continued )
(Continued )
56 Cobert’s Manual of Drug Safety and Pharmacovigilance
GVP Module GVP Title Details
GVP Module IX Signal Management The objectives of this module are to:
provide general guidance and requirements on scientific and quality aspects of
signal management;
describe roles, responsibilities and procedural aspects in the setting of the EU
signal management process overseen by the PV Risk Assessment Committee
(PRAC).
This module applies to all organizations involved in signal management, i.e., MAHs,
national competent authorities and the European Medicines Agency.
GVP Module IX —
Addendum I
Methodological
Aspects of Signal
Detection from
Spontaneous Reports
of Suspected Adverse
Reactions
This addendum lists some of the methodological aspects that should be considered
in detecting potential signals.
The proposed approach complements the classical disproportion -ality analysis with
additional data summaries, based on both statistical and clinical considerations.
GVP Module X Additional Monitoring This module is divided in two sections:
X.B. provides general principles for assigning additional monitoring status to
medicinal products and on communication and transparency aspects;
X.C. describes the operation of the EU network regarding the supervision of
additional monitoring status, the communication strategy and the impact on PV
activities.
GVP Module XI Cancelled — Included
in other GVPs
Not applicable
GVP Module XII Cancelled — Included
in Other GVPs
Not applicable
GVP Module XIII Cancelled — Included
in Other GVPs
Not applicable
GVP Module XIV Cancelled — Included
in Other GVPs
Not applicable
GVP Module XV Safety Communication This module provides guidance to MAHs, competent authorities in Member
States and the EMA on how to communicate and coordinate safety information
concerning medicinal products authorized in the EU.
Section XV.B of this module describes principles and means of safety
communication. Section XV.C provides guidance on the coordination and
dissemination of safety communication within the EU network. Both sections give
particular consideration to direct healthcare professional communications and
provide specific guidance for preparing them.
GVP Module XVI Risk Minimization
Measures: Selection of
Tools and Effectiveness
Indicators
The guidance provided in this Module should be considered in the context of the
wider GVP guidance, in particular in conjunction with GVP Module V.
This Module provides guidance on the principles for:
The development and implementation of additional risk minimization measures,
including examples of risk minimization tools;
The evaluation of the effectiveness of risk minimization measures.
Table 1. (Continued )
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The European Medicines Agency 57
GVP Module GVP Title Details
Section XVI.B describes the development, implementation and coordination of
risk minimization measures and the general principles of the evaluation of their
effectiveness. Section XVI.C considers the application of those measures and
principles in the setting of the EU regulatory network.
GVP Module XVI —
Addendum I
Educational Materials This addendum to GVP Module XVI provides further guidance for MAHs on the
submission of draft educational material(s) to the competent authorities of Member
States, as well as, guidance for these authorities to support the assessment of such
materials, in particular with regard to format and content.
Because of the specificities of the national healthcare systems and of how particular
risk(s) are managed within these systems, individual Member States may have
additional requirements. In this case, the guidance in this addendum to GVP Module
XVI should be followed together with national guidelines.
Draft GVP Module XVI
Addendum III
Pregnancy prevention
programme and other
pregnancy-specific risk
minimisation measures
Pregnancy prevention program; when such program is needed; risk-minimisation
measures to be considered
Anticipated date for coming into effect after finalization: 2023
Product- or Population-
Specific Considerations
I
Vaccines for Prophylaxis
Against Infectious
Diseases
The objective of this GVP Considerations Chapter is to strengthen the conduct of PV
for vaccines. It should be noted that the overall objectives and processes of PV are
similar for vaccines and other types of medicinal products and this guidance does
not replace the information provided in the process-focused modules of the Good
Pharmacovigilance Practices (GVP). This document focusses on vaccine-specific
aspects and unique challenges that should be borne in mind when designing and
implementing PV activities for vaccines.
Product- or Population-
Specific Considerations
II
Biological Medicinal
Products
This document applies to all biological medicinal products regardless of the
regulatory pathway of approval or market exclusivity status, i.e., it applies to
reference biological medicinal products, to biosimilars and to products which
contain the same or closely related active substance but not authorized as
biosimilars (e.g., different versions of interferon beta-1a, factor VIII or normal human
immunoglobulin).
The legal requirements for PV and the good PV practices (GVP) apply to biologicals
just as they do for other medicines. The guidance of this Module does not replace
any of these. However, biologicals are associated with several specific challenges in
PV.
This module is intended to be read and followed alongside the process-related
GVP Modules when developing and implementing PV for biologicals to ensure that
these challenges are addressed. Section P.II.A describes some of the specific issues
and challenges; section P.II.B provides guidance on addressing these in the context
of the main PV processes described in the GVP and Section P.II.C provides guidance
related to operation of the EU network.
Product- or Population-
Specific Considerations
III
Pregnant and
breastfeeding women
This document aims to provide guidance to MAA/MAH, competent authorities of
Member States and the Agency for facilitating appropriate pharmacovigilance for
medicinal products that may be used in pregnant or breastfeeding women
Anticipated date for coming into effect after finalization: 2023
Table 1. (Continued )
(Continued )
58 Cobert’s Manual of Drug Safety and Pharmacovigilance
GVP Module GVP Title Details
Product- or Population-
Specific Considerations
IV
Paediatric Population This guidance provides details on paediatric PV activities, including ICSRs
management, signal detection and risk management.
The guidance contained in this Chapter is addressed to MAHs, the competent
authorities in Member States and the Agency (EMA). It covers all paediatric
age groups. The paediatric use of vaccines and safety surveillance of paediatric
outcomes after exposure to medicines in utero are outside the scope.
GVP Annex I Definitions This document details all commonly used PV terms, from “Abuse of a medicinal
product” to “Validated signal”
GVP Annex II —
Templates
Templates: Cover Page
of Periodic Safety
Update Report (PSUR)
Template providing the detailed information which is to be displayed on the cover
page of each PSUR/ PBRER.
GVP Annex II —
Templates
Direct Healthcare
Professional
Communication (DHPC)
This template should be used for the preparation of a core EU Direct Healthcare
Professional Communication (DHPC).
GVP Annex II —
Templates
Communication
Plan for Direct
Healthcare Professional
Communication (CP
DHPC)
This template lists the stakeholders to be involved/informed in case of DHPC.
GVP Annex III — Other
Pharmacovigilance
Guidances
Guideline on the
Exposure to Medicinal
Products During
Pregnancy: Need for
Post-authorization Data
This guideline provides criteria to select medicinal products for which active
surveillance for collecting post-authorization data in pregnancy is necessary. It
provides guidance on how to monitor accidental or intended exposure to medicinal
products during pregnancy and specific requirements for reporting data and
adverse outcomes of pregnancy exposure.
GVP Annex III — Other
Pharmacovigilance
Guidances
EudraVigilance Access
Policy
The guideline also includes detailed recommendations regarding presentation of
data collected on exposure in pregnant women. The guideline relates in particular
to new products, for which a summary of the potential risks of exposure in
pregnancy and of the potential need for the product during pregnancy should be
included in the RMP (Safety Specifications). The aim of these specifications is that
the MAH proposes a PV Plan in order to evaluate the potential risk of a product and/
or to provide missing information on the safety of the product in pregnancy.
The Agency (EMA) is granting medicines regulatory authorities in the EEA
unrestricted access to all ICSRs held in EudraVigilance. Since May 2012, healthcare
professionals, the public, MAHs and academia have certain levels of access to
spontaneous reports focusing on centrally authorized medicinal products. This
access is provided through the adrreports.eu portal of the Agency and was
extended in September 2014 to all active substances contained in medicinal
products authorized in the EEA.
This Access Policy defines the overall principles for providing access to ICSR data
held in EudraVigilance in line with the EU legal framework and taking into account
that the interest in and the use of the data may vary between stakeholders.
GVP Annex V Abbreviations This document lists all acronyms used in the EU regulation from “A-CASI: Audio
computer-assisted self-interviewing” to “XEVPRM: eXtended EudraVigilance Product
Report Message”
Table 1. (Continued )
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The European Medicines Agency 59
In brief, the QPPV establishes and maintains the PV
system, has an overview of all the products and safety
issues pending, and makes sure all safety functions are
handled properly. The QPPV’s roles are discussed in
detail elsewhere in this manual. The QPPV must ensure
that all suspected ADRs are collected, collated, reported,
and accessible within the EU. The MAH must prepare,
update, and have available a “Pharmacovigilance Sys-
tem Master File” (PSMF). Requirements for risk man-
agement systems, expedited reporting, PSURs/PBRERs,
special situations, databases, documentation, company
post-marketing safety studies, quality assurance/control
and regulatory matters are also addressed (Regulations
and Directives). These topics are covered in detail in
this manual in the individual chapters.
Specific obligations for member states’ national
health agencies are similar to what is required for phar-
maceutical industry; how PV is to be done, handling
of ICSRs, PSURs/PBRERs, signal detection, medica-
tion errors, benefit–risk analyses, communication, data
exchange, crisis management plans relating to safety
matters, inspections, rapid-alert and non-urgent infor-
mation communication system, how referrals to the
EMA are to be done.
The Practices Annexes to the Modules include
a glossary, abbreviations, terminology, references to
guidelines and templates for the EU Risk Manage-
ment Plan, the PSUR/PBRER sections, and distribution
requirements for reporting to competent authorities.
In summary, this is a complete and well-prepared set
of documents that shapes a consistent PV System at the
EU level. The documents are rich in explanations and
background and anyone in the field of PV, whether in the
EU or elsewhere, should read and be familiar with these
documents. Many of the principles and procedures are
used throughout the rest of the world as they are based
on the common seminal antecedent documents of PV,
namely, the Council for International Organizations of
Medical Sciences (CIOMS) and ICH documents.
Volume 10 Clinical Trial PV
As with the post-marketing requirements, the regula-
tion of drug safety surveillance during clinical devel-
opment has been updated over the last several years.
The changes are not as dramatic as those put in place
for post-marketing surveillance but are significant.
EudraLex Volume 10 has been amended and new Reg-
ulations have been put in place (2019) (see w: Regula-
tion (EU) No. 536/2014. Contrary to Post-marketing
Regulation for which specific PV documents (Direc-
tives, Practices, Q&A, etc.) are issued, the drug safety
surveillance rules during clinical studies are part of
the clinical study regulation.
Regarding clinical trial PV, the main changes repre-
sent a simplification of the rules on safety reporting as
follows:
The protocol may provide that not all adverse
events (AE) and suspected serious adverse events
are recorded and reported as part of the safety
assessment if they are used as efficacy endpoints,
for example.
For a clinical trial involving more than one investi-
gational medicinal product (IMP) it is now possible
to submit a single safety report on all the IMPs used
in the trial to the EudraVigilance database.
Suspected unexpected serious adverse reactions
(SUSARs) are reported to the Clinical Trial Eudrav-
igilance database:
Note 1: For multinational trials, all SUSARs,
whether occurring within the EU or in a third
country, are reported to the Agency.
Note 2: Fatal or life-threatening SUSARs
are within 7 calendar days. Non-fatal or
non-life-threatening SUSARs within 15 calen-
dar Days.
The regulation requires Member States to collab-
orate in assessing the annual Development Safety
Update Reports (DSURs) and SUSARs:
Note: Unexpected events which affect the
benefit–risk balance of the clinical trial must be
reported within15 calendar days.
The sponsor’s responsibilities are described in terms
of collecting, recording, handling, and communicating.
Additional requirements are explained regarding eth-
ics committees, interactions with investigators, issues
unique to trials (e.g., unblinding), expedited reporting,
annual reporting, inspections’ outcomes disclosure, and
other details.