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300 Cobert’s Manual of Drug Safety and Pharmacovigilance
large degree, on the ICH E2E guideline. Most of the
E2E concepts have since been incorporated into GVP
Module V. GVP Module V on risk management intro-
duces the principles of risk minimization and, thus, it
should be considered in the context of GVP Module
XVI (risk minimization measures: selection of tools and
effectiveness indicators) and GVP Module XVI Adden-
dum I (educational materials). Note that all medicinal
products must have routine risk minimization measures
and only a subset of products has a safety concern(s)
that requires additional, non-routine risk minimization
measures. Further, due to a variety of reasons, safety
concerns that require non-routine measures are not
necessarily the same in all parts of the world and nei-
ther are the available tools.
All companies must have a PV system (per Arti-
cle 1 of Directive 2001/83/EC and described in GVP
Module I). The PV system that a company maintains is
different from the risk management system described
in GVP Module V. Per GVP Annex I (Rev. 4), a risk
management system is defined as, “A set of pharma-
covigilance activities and interventions designed to
identify, characterize, prevent or minimize risks relat-
ing to a medicinal product, including the assessment
of the effectiveness of those activities and interven-
tions [DIR 2001/83/EC Art 1(28b)].” As noted above,
for most drugs, the usual “routine” pharmacovigilance
activities (spontaneous reporting, PBRER/PSURs, etc.)
will suffice. For others, however, certain non-routine
conditions or restrictions on supply or use of the prod-
uct may be appropriate and required (for both centrally
and nationally authorized products). The concept is
that a product’s benefits should outweigh its risks in
the target population.
Per GVP Annex I (Rev. 4), an RMP is “A detailed
description of the risk management system [DIR
2001/83/EC Art 1(28c)]. The risk management plan
established by the marketing authorisation holder shall
contain the following elements: (a) an identification
or characterisation of the safety profile of the medici-
nal product(s) concerned; (b) an indication of how to
characterise further the safety profile of the medicinal
product(s) concerned; (c) a documentation of mea-
sures to prevent or minimize the risks associated with
the medicinal product, including an assessment of the
effectiveness of those interventions; (d) a documenta-
tion of post-authorisation obligations that have been
imposed as a condition of the marketing authorisation
[IR 520/2012 Art 30(1)].”
Bottom line: All drugs need a risk management
system, which addresses risk minimization. Routine
risk minimization is performed on all products. This
is detailed in Parts III & V of the RMP and covers the
usual and routine PV activities a company performs.
If the applicant and health authorities feel that more
actions are needed to control risk for a particular prod-
uct, then Part III (PV Plan) and/or Part V (Risk Minimi-
zation Plan) must be expanded with additional PV and/
or minimization measures.
Note 1: A “Safety Concern” in the EU is an import-
ant identified risk, an important potential risk or miss-
ing information. Early descriptions referred to “import-
ant missing information”, but reflection resulted in
deletion of “important” because if the missing informa-
tion was so important the product should not have been
approved without it.
Note 2: From 20 October 2023, EMA is publishing
RMPs (main body and annexes 4 and 6) for all cen-
trally authorized products. This is applicable for initial
evaluations (CTD submissions) and for RMP updates
as well. From the same date, EMA no longer publishes
RMP summaries. The aim is to increase transparency
of the safety review process for all centrally authorized
products.
When is an RMP Needed?
At any point in a drug’s life cycle, an RMP may be
needed. The health authority and/or the applicant may
determine an RMP is needed:
At the time of application for a new MA or a new
active substance;
For “a similar biological medicinal product”;
For certain generic/hybrid products;
For an application for pediatric use;
For a significant change in marketing: new dosage
form, new route of administration, new manufacturing
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 301
process of a biotech product, significant new indica-
tion, new pediatric indication;
For certain other situations, including fixed combi-
nation products;
In the case of a new (or newly understood) import-
ant safety concern for a product without a current
RMP (i.e., product was authorized before RMPs
were required).
EU RMP Content
The EMA delivered a template (retrievable on the Agency
website: EMA/PRAC/613102/2015 Rev.2 accompany-
ing GVP Module V Rev. 2), which is applicable for all
medicinal products in the EU. This template provides
a detailed table of contents, as for PSURs/PBRERs. For
new products, all sections must be completed; for older
products, only the applicable sections are required.
Part I: Product(s) Overview
(GVP V. B.4)
Part I should provide administrative information on the
RMP and an overview of the product(s); the following
summary is per GVP V.B.4 (Rev. 2). The information
presented in Part I should be “current and accurate in
relation to the ongoing application as it is anticipated
to appear in the marketing authorization”. This should
be organized according to the RMP template and the
following information must be provided:
Active substance(s) (INN or common name);
Pharmacotherapeutic group(s) (ATC Code);
Name of applicant or marketing authorization
holder (expected or actual);
Invented name(s) in the European economic area
(EEA);
Marketing authorization procedure;
Brief description of the product and other particulars;
Hyperlink to the product information;
Approved and/or proposed Indication(s) in the
EEA;
Dosage (posology) in the EEA;
Pharmaceutical form(s) and strengths;
Whether or not the product is expected to be sub-
ject to additional monitoring in the EU (at initial
marketing authorization application conclusion or
with RMP updates).
Part II: Safety Specification
(GVP V.B.5)
The purpose of this section of the RMP is to provide the
safety profile of the product and discuss the areas that
may need non-routine risk minimization activities. Part
II includes a summary of the important identified risks,
important potential risks, and missing information.
Early versions referred to “important” missing informa-
tion, but, as thinking evolved, if the missing informa-
tion was really so important, the product should not
be approved without it. There is guidance on how this
information should be presented.
Part II also addresses at-risk populations, i.e., the
populations where the product is likely to be used
(including anticipated off-label use) and any outstand-
ing safety questions that need additional data to refine
the benefit–risk assessment.
The safety specification consists of eight RMP mod-
ules, which correspond to the safety specification head-
ings in the ICH E2E guideline. However, there are addi-
tional elements required by the EU (see GVP V.B.5.7,
RMP Module SVI, “Additional EU requirements for the
safety specification”). This part should also address the
potential for misuse for illegal purposes, and, where
appropriate, any proposed risk minimization measures,
e.g., limited pack size, controlled access program, spe-
cial medical prescription, etc. (Directive Art 71(2) and
GVP V.B.8).
In addition, the following should be addressed in
Part II if they could lead to risks related to product use:
Potential harm from overdose (intentional or
accidental);
Potential for risks resulting from medication errors;
Potential for transmission of infectious agents;
Potential for off-label use;
Evidence that refutes any class-related safety
concerns;
302 Cobert’s Manual of Drug Safety and Pharmacovigilance
Important risks related to identified and potential
pharmacokinetic and pharmacodynamic interac-
tions with other products anticipated for use in the
target population;
Potential risks in pregnancy or lactation, e.g., tera-
togenic risk (exposure of mother or partner) and
effects on fertility;
Environmental impact, i.e., risks associated with
the disposal of the used product;
Potential risks related to the administration of the
product(s);
Safety concerns specific to special populations, e.g.,
pediatric or elderly populations;
For advanced therapy medicinal products, also con-
sider possible specific risks related to such products.
RMP part II should also address risks considered
important for inclusion in the list of safety concerns,
but also addresses risks not considered important
enough for inclusion in the list of safety concerns. This
discussion should include a summary of risk serious-
ness and frequency and their impact on the benefit–risk
assessment (by indication).
General considerations for generic
products and advanced therapy
medicinal products (GVP V.B.5.1)
For generics, the expectation is that the safety speci-
fication is the same as that of the reference product
or of other generic products for which an RMP is in
place. Because of the unique nature of advanced ther-
apy medicinal Products (ATMPs), risks may occur that
are not normally a concern with other types of medic-
inal products. These might include, for example, risks
to living donors, risks of germ line transformation, or
transmission of vectors. Such risks need to be consid-
ered for ATMPs.
Epidemiology of the indication(s) and
target population(s) (GVP V.B.5.2 RMP
part II Module SI)
This module should include incidence, prevalence,
outcome of the (untreated) target disease (i.e., indications),
and relevant comorbidities. If appropriate, consider-
ation should be given to demographic stratification
(e.g., age, gender, etc.) Disease risk factors and the
current standard of care should also be described.
The emphasis should be on the situation relevant to
the EU. Differences in the epidemiology in different
regions should be discussed (where epidemiology var-
ies across regions). This section should also describe
the relevant adverse events that would be anticipated
in the (untreated) target population in the EU, their
frequency, and characteristics. The text should help
anticipate potential signals (and possibly facilitate
interpretation of them) as well as possibilities for risk
minimization. This section should be concise and, as
with all parts of the RMP, should be non-promotional.
Note that non-EEA data are accepted when considered
relevant to the EEA situation.
What else should be included in the epidemiology
section? Supplement the above, as appropriate, with the
following:
The natural history of the indicated condition in
the untreated population, including mortality and
morbidity;
A discussion on possible stages of disease progres-
sion to be treated and applied to the natural history
of the indication in the (untreated) population;
The primary available treatment options with
their expected safety profiles (and outcome in the
absence of treatment with the medicinal product).
The Non-clinical part of the safety
specification (GVP V.B.5.3 RMP part II,
Module SII)
This section should include a discussion of findings
not adequately addressed by clinical data, such as the
following:
toxicity, including repeat-dose, reproductive and
developmental toxicity, nephrotoxicity, hepatotox-
icity, genotoxicity, carcinogenicity;
general pharmacology, including cardiovascular,
QT prolongation, nervous system;
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 303
drug interactions;
discussion of the relevance to drug use in humans.
Clinical trial exposure (GVP V.B.5.4 RMP
part II, Module SIII)
This section should start with “limitations”. That is,
limitations:
Of the size of the safety database and the patients
not studied due to inclusion/exclusion criteria in
the clinical trials;
With regard to patients expected to be exposed to
the drug after marketing;
Regarding the ability to detect infrequent ADRs;
In regard to finding long-term risks (e.g., cancer);
and
Regarding populations not studied in the pre-
marketing period (e.g., pediatric, pregnancy, comor-
bid conditions, more severe, sub-populations).
Relevant information should be provided in an
appropriate format (e.g., tables/graphs) and updated
when there is important new information (e.g., new
exposure data from line extension studies in a new indi-
cation). The content of this section should be assessed
for relevance over time and, in the absence of new clin-
ical trial exposure data, does not need to be updated.
Tabulated information must be included specifying
duration of exposure, age groups, and gender, dose, eth-
nic origin (overall and per indication for each).
Populations not studied in clinical trials
(GVP V.B.5.5 RMP part II, Module SIV)
This section should discuss the populations which have
not been studied or have only been studied to a limited
degree in the pre-approval phase. This would include
populations considered under missing information (e.g.,
often might include pregnant women, breast-feeding
women, patients with renal impairment, hepatic impair-
ment or cardiac impairment, populations with relevant
genetic polymorphisms, immuno-compromised patients,
and populations of different ethnic origins). The implica-
tions of this with respect to predicting the safety of the
medicinal product in the marketplace should be explic-
itly discussed.
Post-authorization experience (GVP
V.B.5.6 RMP part II, Module SV)
This section covers clinical post-marketing experience
from outside the EU (if any) that is helpful for risk
management planning purposes. It should be a con-
cise overview, not a duplication of the PSUR/PBRER.
It should discuss exposure data (amount sold, use in
special populations, such as children, market research
information, etc.), as well as the actual way the drug is
prescribed and used (including off-label use) compared
with the approved labeling. This section should discuss
any new safety concerns and whether any regulatory
actions were taken in any jurisdiction for safety matters.
Risks that require further evaluation should be
identified and discussed, in particular more frequent
or more serious/severe suspected ADRs. The possible
mechanism, risk factors, risk groups, reversibility, and
estimated frequency should be discussed.
Risk data, where available, should then be pre-
sented. This assessment should be based on study or
epidemiologic data, which allows for quantitative risk
estimation, including excess risk (versus placebo and
available comparators), risk by various populations
studied, time-to-event data (e.g., survival data), stratifi-
cation by drug, placebo, age, gender, dose, and so forth.
If pharmacokinetic or pharmacodynamic interac-
tions are suspected, any possible further studies should
be detailed.
The impact of the key actual and potential risks
should be addressed using strength of evidence, bio-
logical plausibility, nature of evidence, potential pub-
lic health burden, morbidity, and mortality. Special
attention should be paid to at-risk, susceptible patient
groups. A structured format and classification by expo-
sure, indication, gender, age group, region, dose, time,
and risk factors should be used.
Data from indications not authorized in the EU, if
any, should also be summarized and implications for
the EU should be discussed.
304 Cobert’s Manual of Drug Safety and Pharmacovigilance
Additional EU requirements for the
safety specification (GVP V.B.5.7 RMP
part II, Module SVI)
This section must detail the potential for misuse for
illegal purposes, if applicable. When appropriate, a pro-
active discussion of proposed non-routine risk mini-
mization measures (e.g., limited pack size, controlled
access program, special medical prescription, etc.)
should be included.
Identified and potential risks (GVP
V.B.5.8 RMP part II, Module SVII)
This module should focus on “safety concerns” for the
product. This would include details on “important”
identified and potential risks, as well as missing infor-
mation. Non-important risks are also to be listed, even
if proposed in the draft EU SmPC (Summaries of Prod-
uct Characteristics). The reason for not including an
identified or potential risk in the list of safety concerns
in the RMP should also be justified.
Each important risk (identified or potential) should
be detailed; information on nature, severity, outcome,
frequency and benefit–risk balance must be provided.
For each risk, the following information is to be
addressed:
Evidence source(s) and strength of evidence.
Characterization of the risk.
Risk factors and risk groups.
Preventability.
Impact on the risk–benefit balance of the product.
Public health impact.
The impact and measures scheduled in the PV plan
and/or risk minimization sections of the RMP are to
be detailed in this section. Similar information is to be
included for missing information, focusing on risks or
populations in need of further characterization or on
the anticipated risks or possible consequence(s) of the
missing information.
Since RMPs are to be updated according to sched-
uled milestones, identified important risks, potential
important risks, and missing information should be
reassessed, according to new information received since
the previous version of the RMP. Clear and robust ratio-
nales must be provided if the identified or potential
risks or missing information sections are modified.
The RMP should also discuss other risks, where
appropriate, such as the following:
Known or suspected class effects;
Potential for overdose, especially if there is a narrow
therapeutic window;
Potential for transmission of infectious agents;
Potential for off-label use, particularly use in special
populations (e.g., children or the elderly).
Summary of the safety concerns (GVP
V.B.5.9 RMP part II, Module SVIII)
A tabulated summary of the safety concerns identified
in previous section should be provided per identified
risk, potential risk, and missing information. This sim-
plified categorization scheme for safety concerns should
be used for the following:
Important identified risks;
Important potential risks;
Missing information.
Part III: PV Plan, Including Post-
authorization Safety Studies (GVP
V.B.6 RMP part III)
This part of the RMP is intended to present a structured
plan for further characterization of safety concerns
in the safety specification. It does not include actions
intended to reduce, prevent or mitigate risks, which are
considered in RMP part V.
Routine PV activities (GVP V.B.6.1 RMP
part III)
Routine PV is the primary set of activities required to
fulfill the minimum legal requirements for PV in Direc-
tive 2001/83/EC and Regulation (EC) No. 726/2004.
The purpose in the RMP is not to repeat what is already
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 305
included in the pharmacovigilance system master file
(PSMF) describing these activities.
“Routine” PV activities, not specified in the PSMF,
can be as follows, for instance:
Specific adverse reaction follow-up questionnaires
for a safety concerns; purpose and description of
the materials used to obtain structured information
on reported suspected adverse reactions of special
interest; and
Enhanced passive surveillance high level descrip-
tion, observed versus expected analyses, cumula-
tive reviews of adverse events of interest.
Note that the descriptions of these activities in the
PV system master file (PSMF) are not required to be
repeated here in the RMP.
Additional PV activities (GVP V.B.6.2
RMP part III)
In this section, the applicant (or marketing authori-
zation holder) should describe additional PV activ-
ities such as non-clinical, clinical, or epidemiological
(non-interventional or interventional) studies, and
explain why they are needed.
For each proposed Post-Authorization Safety Study
(PASS), whether committed or imposed, the following
should be detailed:
Study short name and title;
Rationale and study objectives;
Study design;
Study population;
Milestones.
Studies in the PV plan should be designed and con-
ducted according to legislation and recommendations
in GVP Module VIII.
Summary table of additional PV
activities (GVP V.B.6.3 RMP part III)
This section should be a complete overview of all on-
going and planned safety studies included in the PV
Plan, regardless of whether they were designed to assess
the safety of the medicinal product, or the effectiveness
of the risk minimization measures.
Studies required in jurisdictions outside the EU
would not ordinarily be included in the EU RMP, unless
they would also be expected to impact an EU safety
concern. Of course, safety concerns arising from any
such studies should be reported as per the applicable
requirements.
Note that for generic products, the PV plan should
reflect the outstanding PV needs at the time of their
authorization for marketing (not necessarily the full
initial plan for the innovator).
Part IV: Plans for Post-authorization
Efficacy Studies (GVP V.B.7 RMP
part IV)
This section includes a list of the planned and on-going
imposed PAES (Post Authorization Efficacy Studies),
i.e., studies imposed by an EU competent authority as a
condition of marketing authorization, or which are spe-
cific obligations in the context of conditional marketing
authorization, or marketing authorization under excep-
tional circumstances. If no such studies are required,
RMP Part IV may be left empty.
Part V: Risk Minimization Measures
(Including Evaluation of the
Effectiveness of Risk Minimization
Activities) (GVP V.B.8 RMP part V)
This part should provide details of the risk minimiza-
tion measures designed to reduce risks associated with
the indicated safety concerns. It is applicable for all
initial marketing authorization applications, except for
generic, hybrid medicinal products, and fixed combina-
tion products with no new active substance, where the
originator product does not have additional (non-rou-
tine) risk minimization activities.
A table listing the routine and additional risk mini-
mization activities, stratified by safety concern, should
be provided in this section (i.e., the SmPC section
306 Cobert’s Manual of Drug Safety and Pharmacovigilance
number where the risk appears in the SmPC, the list of
educational materials, etc.) A further summary of PV
activities should be included, as described in the EMA
guidance on format of the RMP in the EU.
Routine risk minimization activities
This section should provide a description of routine risk
minimization measures, stratified by safety concern.
Routine risk minimization activities are those which
apply to every medicinal product:
The summary of product characteristics (SmPC);
Labeling on the inner and outer carton;
The package leaflet (PL);
The pack size(s);
The legal status of the product.
The formulation itself should be described if it is
expected to play an important role in minimizing the
risk(s) of the product.
SmPC and PL
The SmPC and PL are important tools for risk minimi-
zation as they are standardized formats for informing
stakeholders about the product. The guideline on the
SmPC provides guidance on how information should
be organized and presented. Both materials provide
routine risk minimization recommendations; however,
there are two basic types of messages the SmPC and PL
can provide:
(a) Routine risk communication messages (usually
found in section 4.8 of the SmPC or Section 4 of
the PL).
These communicate undesirable effects to help
inform treatment decisions.
(b) Routine risk minimization activities that recom-
mend specific clinical measures to address the
risk (usually found in Sections 4.2 and 4.4 of
the SmPC, but can also be found in Sections 4.1,
4.3, 4.5, 4.6, 4.7, and 4.9 and Sections 2 and 3 of
the PL).
These include specific activities to address the
risk(s) of the product. Examples of such activi-
ties might be one or more of the following:
A test before the start of treatment;
Laboratory monitoring during treatment;
Clinical monitoring for specific signs and symptoms;
Dose modification (including discontinuing the
medication) related to adverse events laboratory
parameters;
A “wash-out” procedure after treatment interruption;
Recommendations for contraception;
Contraindications for use with other medicines;
Treating or preventing the product’s risk factors or
harms;
Recommendations for long-term follow-up.
There are certain other impactful measures that can
be considered to minimize potential harms:
Pack size: Since every product has an autho-
rized pack size, planning the number of “dosage
units” within each pack and the range of pack
sizes available can be considered as a form of
routine risk management. Careful planning of
pack size could reinforce the need for patients
to see a healthcare provider on a regular basis,
which could increase the opportunity for test-
ing or another follow-up. A smaller pack size
may help address risks of overdose or diversion.
Legal status: In addition to prescription sta-
tus, government controls may include details
of any conditions placed on the supply or use
of the product. Approval may restrict by whom
the product may be prescribed (e.g., by a spe-
cially trained prescriber) or where the product
can be used (e.g., in a hospital or in settings
with special resuscitation provisions).
Restricted medical prescription: For this
option, several factors should be considered
(EU Directive Art 71(3)):
Pharmaceutical characteristics or novelty of the
product that should be reserved for a controlled
environment;
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 307
Diagnostic procedures require special facilities
(follow-up may be carried out elsewhere);
Very serious adverse reactions (or the possibil-
ity of abuse, etc.) can be anticipated that may
require special supervision throughout the
course of therapy.
Member state customization: It is possible
that member states may impose local require-
ments to adapt to their national situation. The
definitions and, therefore, also implementation,
may vary in those member states where cer-
tain subcategories of risk minimization or their
modification are contemplated or are in place.
Additional risk minimization activi-
ties: Additional non-routine activities should
only be suggested when they would be essen-
tial for the safe and effective use of the product.
A clear rationale should be provided and these
activities should be described in detail. The
need for continuing with such measures should
also be reviewed on a periodic basis. Where rel-
evant, key messages of any additional activities
should be provided in RMP Annex 6 (details of
proposed additional risk minimization activi-
ties). See GVP Module VIII.
Following are examples of additional measures that
might be considered:
Healthcare professional and patient/carer guide;
Healthcare professional training material;
Prescriber checklist;
Patient diary;
Patient alert card;
Pregnancy prevention programs.
For each proposed non-routine risk minimization
measure, the following information should be provided:
Objectives;
Rationale for the additional risk minimization activity;
Target audience and planned distribution path;
Plans to evaluate the effectiveness of the interven-
tions and the criteria for success.
Evaluation of the effectiveness of non-
routine risk minimization activities
When the RMP is updated, the risk minimization plan
should include the results of any formal assessment(s)
of non-routine risk minimization activities when avail-
able. Adjustments should be made if a particular strat-
egy proves ineffective or causes an undue burden on
patients or the healthcare system.
Summary of risk minimization measures
This section should include all risk minimization mea-
sures and PV activities stratified by safety concern.
Part VI: Summary of the RMP (GVP
V.B.9 RMP part VI)
This summary must address the following:
The medicine and what it is used for;
The risks associated with the medicine and activi-
ties to minimize or further characterize the risks:
list of important risks and missing information;
summary of important risks;
Post-authorization development plan:
Studies which are conditions of the marketing
authorization;
Other studies in post-authorization develop-
ment plan.
General Remarks on the EU RMP
The EU RMP can be summarized as follows:
EU RMP Part Details
Part I:
Product(s)
overview
Active substance, MAH, MA procedure, product
description, indication, dosage, pharmaceutical
form(s), and strengths
Part II:
Safety
specifications
Epidemiology of the indication(s) and target
population(s)
Non-clinical safety
Clinical trial exposure
Populations not studied
Post-authorization experience
Potential for misuse for illegal purposes
(Continued )
308 Cobert’s Manual of Drug Safety and Pharmacovigilance
EU RMP Part Details
Summary of important Identified risks, potential
risks, and missing information
Part III:
PV plan
PV activities to characterize and quantify
clinically relevant risks and to identify new
adverse reactions
Routine and additional PV activities
(including PASS)
Part IV:
Plans for
PAES
Planned and on-going PAES that are conditions
of the marketing authorization or that are
specific obligations
Part V:
Risk
minimization
measures
Actions which will be taken to prevent and/
or minimize risk(s) and results assessment
(effectiveness)
Routine and additional minimization
activities
Part VI:
Summary of
the RMP
Product information summary
Important risks and missing information
Activities to minimize or further characterize risks
post-authorization development plan
The RMP should propose non-routine risk minimi-
zation actions to take, in addition to usual safety report-
ing and signal detection:
If no special concerns are seen, routine PV is
sufficient;
If additional concerns, further activities should be
done that can include (note that these are addi-
tional surveillance activities and are different from
minimization actions (similar to US ETASUs)).
Safety studies;
Active surveillance (e.g., formal follow-up of
patients filling a prescription for drug X with a sur-
vey and telephone contact later on);
Sentinel sites of selected prescribers interviewed
and medical record review;
Intensive monitoring schemes where case data are
collected from prescribers or hospitals on a specific
drug or problem;
Prescription event monitoring (especially the
United Kingdom). Identify patients electronically
and send follow-up questionnaires periodically to
find course and outcome;
Registries by drug, disease/outcome with follow-up
questionnaires;
Epidemiologic studies:
Comparative observational studies to validate
signals — prospective or retrospective;
Cross-sectional studies or surveys to collect data
on patients at a single point in time or over an
interval regardless of exposure or disease status;
Cohort studies of a population on drug X at risk
for a specific adverse event to be followed over
time (prospectively or retrospectively) for the
occurrence of that event, allowing the calcula-
tion of an incidence rate;
Case-control studies where patients with a spe-
cific AE already seen are selected and a control
group without the AE also chosen. Exposure to
the drug is then searched for;
Occurrence of disease studies of the specific AE
to better characterize the patients at risk, the
clinical course, and so forth;
Novel designs to be worked out with the health
authorities.
Clinical trials particularly with the subgroups at
risk: children, elderly, and so forth;
LSSS (randomized trial but minimal data collection
and follow-up);
Drug utilization studies of the marketing, prescrib-
ing, and use in a population and how this influences
outcomes;
Medication errors should be discussed if there is
risk of such a problem.
Next, risk minimization activities (similar to the
US REMS ETASUs) should be detailed, and they may
include one or more of the following:
Providing information (SmPC, Patient Leaflet,
other);
Additional educational material for patients, practi-
tioners, and others that could include special train-
ing, use of checklists, or guides;
Restrictions on availability (“legal status change”)
with use only in hospitals or prescribing only by a
specialist;
Controls at the pharmacy level, e.g., Control of pre-
scription size or time the prescription is valid;
Informed consent;
Restricted access;
Patient registries;
(Continued )
Risk Assessment, Evaluation, Management, Mitigation, & Strategy 309
Special risk communication using other media for
key messages.
Direct, periodic measurement of the effectiveness of
the activities should be done by looking at metrics, such
as the incidence of a particular SAE or outcome such as
pregnancy while using the drug in question or a survey
of whether leaflets are actually read (and understood).
The PV plan must be a written document covering
the safety concerns, objectives and rationale of the pro-
posed actions, monitoring of the plan, and milestones
for evaluation. After the HA(s) accept the RMP, periodic
updates to the EMA or HAs (Health Authorities) should
be done, usually at the same time of the PSURs delivery
(if PSUR (Periodic Safety Update Report)/PBRER con-
clusions raise a need for RMP update) or at pre-defined
milestones scheduled in the RMP.
The instructions for the risk management system
and plan are found in GVP Module V, as revised. There
is a very specific and useful template (revised) that
should be followed when preparing the document. The
template is referenced in GVP Module V.
Practicalities, Co-ordination,
and Other Comments
Risk management strategies in the United States, the
European Union, and elsewhere have been in use in
their current form for only a relatively short time. US
REMS really began in earnest in April 2008 and the
18-month effectiveness assessments are now under
way. The instruction documents on risk management
are guidance, not regulations, though they are function-
ing, de facto, as obligatory regulations. After periodic
review of their effectiveness, modification, i.e., changes
in content and requirements have been made for nearly
all approved REMS. In the EU, a formal RMP using the
EMEA (European Medicines Evaluation Agency) tem-
plate was first required in 2005; both, requirements and
RMP content, evolved over the last 10 years. The role
of REMS, RMPs, and post-marketing commitments and
requirements is somewhat ill-defined, but will likely be
clarified over time.
There are significant differences between risk
requirements in the United States and the European
Union:
In the United States, only some products will have
a REMS. In the European Union, all new products
and old products upon re-approval need some level
of a RMP.
Formats and some content are different in the United
States and European Union. The legal requirements
are different and are governed by local legislation.
Attention should be paid to local risks. That is, coun-
try- or region-specific risks should be addressed in
the European Union and United States.
In the European Union, the qualified person is
clearly identified and has ownership of PV in a com-
pany. Ownership is less clear in the United States.
Although there is a large degree of overlap in the
goals and content for risk plans in various jurisdictions
(the United States, European Union, and Japan in par-
ticular), the format, timing, and implementation can be
quite different. That is, there is not much harmoniza-
tion. Companies and agencies are still debating how to
use risk plans both strategically and tactically, and, to a
degree, companies are debating how much to offer up
voluntarily and how long to wait for a mandate from the
HA. Evaluation groups are studying risk handling in the
agencies in the United States, the European Union, and
elsewhere. It is expected that updates and changes will
be made in the United States and the European Union
requirements. The reader should pay attention to new
guidances and regulations from the FDA and European
Union and member states, in particular to updates to
GVP Module V. The European Union is expected to
make changes in the next few years. Subscribing to the
FDA’s, European Union’s, and other agencies’ RSS feeds
or e-mail alerts is free and a worthwhile adjunct to
your other means of keeping current with the changing
requirements. Another good RSS feed to subscribe to
is that of the European Federation of Pharmaceutical
Industries and Associations (EFPIA) at: https://www.
efpia.eu/
It is also hoped, perhaps less optimistically, that
there will be international coordination and harmo-
nization at some point to avoid duplication of efforts