Risk Management

1
125 February 2016

2EMA/PRAC/613102/2015 Rev.2 accompanying GVP Module V Rev.2
3Human Medicines Evaluation
4Guidance on format of the risk management plan (RMP)

5in the EU in integrated format
6
Comments should be provided using this template. The completed comments form should be sent to
RMPtemplate@ema.europa.eu
7
8This guidance should be read in conjunction with the GVP module V.
9According to the GVP module V, the primary aim and focus of the RMP is
10to obtain appropriate risk management planning throughout a medicinal
11products lifecycle. Therefore, to achieve this, the RMP must contain
12the following:
13 Characterisation of the safety profile of the medicinal product
14 including what is known and not known and, importantly, which risks
15 need to be further characterised or managed proactively (the safety
16 specification);
17 Planning of pharmacovigilance activities to characterise and
18 quantify important identified or potential risks of adverse drug
19 reactions, and to identify new adverse drug reactions (the
20 pharmacovigilance plan);
21 Planning and implementation of risk minimisation measures, including
22 the evaluation of the effectiveness of these activities (the risk
23 minimisation activities).
24Throughout this document, please be as concise as possible. Consider
25which information will add value to the readers understanding of the
26products safety profile and how best to interpret and manage the
27important identified and potential risks as well as the uncertainties
28surrounding the information available. Please focus the document
29accordingly. Tabulation of any data is acceptable if it aids the
30presentation.
31The Applicant/Marketing Authorisation Holder (MAH) should provide
32hyperlinks to the relevant part of the eCTD dossier of the supporting
33documents or PSURs when applicable. Specific requirements for other
30 Churchill Place Canary Wharf London E14 5EU United Kingdom

Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555
Send a question via our website www.ema.europa.eu/contact An agency of the European Union
European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.
3
34types of initial marketing authorisation are described within each

35section of the template.
4
EU Risk Management Plan for <Invented name> (INN or common name)
EMA/PRAC/613102/2015 Rev.2 accompanying GVP Module V Rev.2 Page 2/45
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6
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36EU Risk Management Plan for <Invented name> (INN or

37common name)
38
Active substance(s) (INN or common name):
Pharmaco-therapeutic group
(ATC Code):
Name of Marketing Authorisation Holder or

Applicant:
Names of medicinal products to which this RMP

refers:
Product(s) concerned (brand name(s)):
39Details of the currently approved RMP:

40There can only ever be ONE currently approved RMP for a product or
41products.
42Version number: <NA for initial MAA submission> <enter a version number>
43Approved with procedure: <enter a procedure number>
44QPPV name
45QPPV signature
46A signed cover page should be provided at least with the RMP submitted
47in the last eCTD sequence of the procedure (usually the closing
48sequence).
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9
10
11
49RMP version to be assessed as part of this application:

50RMP Version number: <Insert number>
51A new RMP version number should be assigned each time any of its
52parts/modules are updated. RMPs submitted within a procedure should be
53version controlled (e.g. 1.1, 1.2, 1.3, etc. or 0.1, 0.2, 0.3. etc.)
54and dated. The version number of the RMP version agreed at the time of
55the CHMP opinion should be the same as the one provided with the last
56eCTD submission in the procedure (most often closing sequence) and is
57advisable to use a major version number (e.g. version 1.0., 2.0, 3.0,
58etc.).
59Data lock point for this RMP: <Enter a date>
60Date of final sign off: <Enter a date>
61Procedure number: <indicate procedure number>
62Rationale for submitting an updated RMP

63<Summary text>
64
65Table Modules.1 Overview of the RMP Parts and Modules in the current RMP
Part Module/annex Module version and Module
procedure number version for
where the module the proposed
was last approved update
e.g. Enter only

for
v3.0
updated
EMEA/H/C/00999/ modules
II/14
e.g. v3.1
Part II SI <version no> <version no>

Safety Epidemiology of the indication and
<procedure number>
Specification target population(s)
SII <version no> <version no>

Non-clinical part of the safety
<procedure number>
specification
SIII <version no> <version no>

Clinical trial exposure
<procedure number>
SIV <version no> <version no>

Populations not studied in clinical trials
<procedure number>
SV <version no> <version no>

Post-authorisation experience
<procedure number>
12
13
14
15

e.g. Enter only

for
v3.0
updated
II/14
e.g. v3.1
SVI <version no> <version no>

Additional EU requirements for the
<procedure number>
safety specification
SVII <version no> <version no>

Identified and potential risks
<procedure number>
SVIII <version no> <version no>

Summary of the safety concerns
<procedure number>
Part III <version no> <version no>

Pharmacovigilance
<procedure number>
Plan
Part IV <version no> <version no>

Plan for post-
<procedure number>
authorisation
efficacy studies
Part V <version no> <version no>

Risk Minimisation
<procedure number>
Measures
Part VI <version no> <version no>

Summary of RMP
<procedure number>
ANNEX 2 <version no> <version no>

Part VII
Tabulat <procedure number>
Annexes
ed summary of on-going and completed
pharmacoepidemiological study
programme.

Protocols for proposed, on-going and
<procedure number>
completed studies in the
pharmacovigilance plan

Specific adverse event follow-up forms
<procedure number>
16
17
18
19

e.g. Enter only

for
v3.0
updated
II/14
e.g. v3.1

Protocols for proposed and on-going
<procedure number>
studies in Part IV

Details of proposed additional risk
<procedure number>
minimisation activities

Other supporting data
<procedure number>
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67Some modules of the RMP may be omitted (see GVP V guidance and detailed
68guidance below); in these circumstances please write Not applicable
69in the approved version and procedure number table cell.
70
71It is expected that for a given product rarely more than one RMP
72version will be under assessment at the same time. But if two or more
73parallel procedures have RMP submissions, to facilitate assessment, it
74is advised to submit only one consolidated Word version of the RMP
75providing (colour coded) track changes, so that changes related to each
76procedure can be easily identified. This will also facilitate the
77finalisation of the RMP for each procedure.
78
79Others RMP versions under evaluation:
80This section is applicable for post-authorisation RMP updates when a
81different RMP version is still under assessment with another procedure.
82RMP Version number: <Insert number>
83Submitted on: <Enter a date>
84Procedure number: <indicate procedure number>
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86Table of content
87Table of content..........................................................................................6
88Part I: Product(s) Overview........................................................................8
89Part II: Module SI - Epidemiology of the indication(s) and target population
90...................................................................................................................9
91Part II: Module SII - Non-clinical part of the safety specification..............11
92Part II: Module SIII - Clinical trial exposure.............................................11
93SIII.1 Brief overview of development.........................................................................11
94SIII.2 Clinical Trial exposure.....................................................................................12
95Part II: Module SIV - Populations not studied in clinical trials...................13
96SIV.1 Exclusion criteria in pivotal clinical studies within the development programme......14
97SIV.2 Limitations of ADR detection common to clinical trial development programmes.....14
98SIV.3 Limitations in respect to populations typically under-represented in clinical trial
99development programmes..........................................................................................14
100Part II: Module SV - Post-authorisation experience...................................15
101SV.1 Post-authorisation exposure................................................................................15
102Part II: Module SVI - Additional EU requirements for the safety
103specification..............................................................................................16
104Part II: Module SVII - Identified and potential risks.................................16
105SVII.1 Identification of safety concerns in the initial RMP submission.............................18
106SVII.2 Identification of safety concerns with a submission of an updated RMP.................20
107SVII.3 Details of important identified potential risks and missing information..................21
108Part II: Module SVIII - Summary of the safety concerns...........................23
109Part III: Pharmacovigilance Plan..............................................................23
110III.1 Routine pharmacovigilance activities..................................................................23
111III.2 Additional pharmacovigilance activities...............................................................24
112III.3 Summary Table of additional Pharmacovigilance activities.....................................26
113Part IV: Plans for post-authorisation efficacy studies................................28

114Part V: Risk minimisation measures..........................................................29
115V.1. Routine Risk Minimisation Measures......................................................................29
116V.2. Additional Risk Minimisation Measures...................................................................30
117V.3 Summary table of pharmacovigilance and risk minimisation activities by safety concern
118 32
119Part VI: Summary of the risk management plan........................................33

1201.1. List of important risks and missing information.......................................................34
1211.2. Summary of important risks.................................................................................34
1221.3. Summary of missing information..........................................................................35
1231.4. Post-authorisation development plan.....................................................................35
1241.4.1. Studies which are conditions of the marketing authorisation..................................35
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1251.4.2. Other studies in post-authorisation development plan...........................................36

126Part VII: Annexes.....................................................................................37
127Annex 1 EudraVigilance Interface.............................................................................37
128Annex 2 Summary of on-going and completed pharmacoepidemiological study programme
129...............................................................................................................................37
130Annex 3 - Protocols for proposed and on-going studies in the pharmacovilance plan..........38
131Annex 4 - Specific adverse event follow-up forms..........................................................39
132Annex 5 - Protocols for proposed and on-going studies in RMP part IV.............................39
133Annex 6 - Details of proposed additional risk minimisation measures (if applicable)...........39
134Annex 7 - Other supporting data (including referenced material).....................................43
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136Part I: Product(s) Overview
137Table Part I.1 Product Overview

Invented name(s) in the European
Economic Area (EEA)
Procedure type (centrally or <Centrally authorised product> <nationally authorised

nationally authorised) product>, <decentralised>, <mutual recognition>,
Brief description of the product: Chemical class
Summary of mode of action
Important information about its composition (e.g. origin of

active substance of biological, relevant adjuvants or residues
for vaccines
Hyperlink to the Product This cell should include a link to the

Information: proposed PI in the eCTD sequence.
If no updated PI is submitted with the
procedure, the link should direct to the
latest approved PI.
Indication(s) in the EEA Current (if applicable):
Proposed (if applicable):
Dosage in the EEA Current (if applicable):
Summarise information only related to

main population; not a duplication of
SmPC section 4.2.
Summarise information only related to

main population; not a duplication of
SmPC section 4.2.
Pharmaceutical form(s) and Current (if applicable):

strengths
Is/will the product be subject to Yes/No

additional monitoring in the EU?
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142Part II:
143For generic medicinal products (applications under Article 10 (1) of
144Directive 2001/83/EC:
145For generics where there is a RMP available for the reference medicinal
146product or when the originator does not have an RMP but the safety
147profile of the originator is published on the CMDh website:
148 - Modules SI-SVII should be omitted
149 - Modules SVIII should be included based on the safety profile
150 published either on the CMDh website (http://www.hma.eu/464.html) or
151 EMA website1.
152If the Applicant considers that the available evidence justifies the
153removal or the change of a safety concern, a discussion can also be
154included in Module SVII. Similarly, if the Applicant has identified a
155new safety concern specific to the product (e.g. risks associated with
156a new formulation, route of administration or due to a new excipient,
157or a new safety concern raised from any clinical data generated), this
158should be discussed and the new safety concern detailed in Module SVII.
159For generics where there is no RMP available for the reference
160medicinal product:
161 - Modules SI-SVI should be omitted
162 - Modules SVII and SVIII should be provided.
163For fixed dose combination medicinal products (applications under
164Article 10b of Directive 2001/83/EC), if the combination contains a new
165active substance, a full RMP, which follows the requirements as for
166initial MAA for a new active substance, should be submitted. Modules
167SI-SVI should focus on the new active substance. If the indication
168targets a subpopulation of those with the disease, provide the
169information for the target population.
170Part II: Module SI - Epidemiology of the indication(s) and

171target population
172This module should be omitted for:

173 RMPs submitted with initial MAAs involving
174 o generic medicinal products,
175 o hybrid medicinal products,
176 o fixed combination medicinal products which do not contain a
177 new active substance,
361 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124
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178 o medicinal products with new indications where the marketing

179 authorisation applicant has products with the same active
180 substance authorised for 10 or more years without RMP in
181 place,
182 o well established medicinal use medicinal products,
183This section should only contain data relevant for the identification
184of the safety concerns (see module SVII).
185Information on inter-regional (e.g. EU, US, Asia, Africa etc.)
186variations may be provided when relevant, but the prime focus should be
187on the European population. A high level and brief summary of
188epidemiology is expected to be provided which should provide an
189interpretive, high level view of the information avoiding detailed
190discussion on specific epidemiology studies, published articles, etc
191When the medicinal product has/is expected to have several authorised
192indications, the data for the different indications should be
193integrated where this is sensible from a clinical perspective. When
194there are clinically relevant differences in user characteristics
195between the authorised indications, separate tables are however
196expected (e.g. Crohns disease and rheumatoid arthritis).
197Indication: <...>
198Incidence:
199Prevalence:
200Demographics of the population in the <authorised> <proposed> indication age, gender, ethnic
201origin, and risk factors for the disease:
202Natural history of the indicated condition including mortality and morbidity:
203This should include a discussion of the possible stages of disease
204progression to be treated and applies strictly to the natural history
205of the indication. It should also describe concisely the relevant
206adverse events to be anticipated in the target population, their
207frequency and characteristics.
208Important co-morbidities:
209This should include, where clinically relevant, diseases distinct from
210the indication that occur frequently in patients with the indicated
211condition (e.g. hypertension is a co-morbidity for hyperlipidaemia). A
212simple list is sufficient.
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214
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215Part II: Module SII - Non-clinical part of the safety

216specification
217This Module should be omitted in the same situations as Module SI,

218described above.
219This module should present a summary of the important non-clinical
220safety findings. Where studies have negative results or no findings,
221these should be mentioned if relevant to the target population (e.g. no
222signs of developmental or reproductive toxicity).
223For initial MAAs where no non-clinical data was generated by the
224Applicant, relevant data available from bibliographical sources should
225be presented.
226Final conclusions on this section should be aligned with the content of
227Module SVII and any important safety concerns should be carried forward
228to Part II Module SVIII.
229The topics should normally include, but do not need to be limited to:
230Table SII.1: Key safety findings from non-clinical studies
Key Safety findings from non- clinical studies Relevance to human
usage
Toxicity:
Acute toxicity including important results from safety pharmacology
studies (e.g. cardiovascular including potential for QT prolongation,
CNS)
Repeat-dose toxicity (by target organ for toxicity )
Genotoxicity
Carcinogenicity
Developmental and reproductive (must be discussed if medicine
might be used in women of child-bearing potential)
Other toxicity-related information or data
231Part II: Module SIII - Clinical trial exposure
232This Module should be omitted in the same situations as Module SI and

233SII, described above.
234SIII.1 Brief overview of development
235Provide a short overview of how the authorised indications and target

236populations have developed during the lifecycle for the product(s).
237This should include:
238 Original indication /product name(s)
239 New populations: e.g. extensions of indications/ new products
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240 Any other significant developments: e.g. route of administration
241SIII.2 Clinical Trial exposure
242Tables could be omitted for applications where the applicant does not
243have access to original trials data (e.g. well established use). In
244such cases, please include any relevant data the Applicant has access
245to, e.g. data from published studies.
246When the RMP is being submitted with an application for a new
247indication, a new pharmaceutical form or route, the clinical trial data
248specific to the application should be presented separately at the start
249of the module as well as being included in the summary tables
250representing pooled data across all indications.
251Data should be pooled and not shown per trial unless there are clear,
252justified reasons why some data cannot be pooled or combined. Data
253should be provided in an appropriate format either in a table or
254graphically.
255If the RMP includes more than one medicinal product, the total
256population table should be provided for each product as well as a table
257that combines the information on total patients exposed for all
258products, as appropriate.
259The categories below are suggestions and tables/graphs should be
260tailored to the product.
261Table SIII.1: Duration of exposure
Cumulative for all indications (person time)

Duration of exposure Patients Person time
To be tailored to the product
e.g. <1 m
1 to <3 m
3 to <6 m
6 m etc.
Total person time
<Indication>
Duration of exposure Patients Person time
e.g. <1 m
1 to <3 m
3 to <6 m
6 m etc.
Total person time for indication
262
263When providing data by age group, the age group should be relevant to
264the target population; this should be reflected in the choice of age
265categories for this table. Paediatric data should be divided by age
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266categories (e.g. ICH-E11); similarly the data on older people should be

267stratified into age categories reflecting the target population (e.g.
26865-74, 75-84 and 85 years and above). For teratogenic drugs,
269stratification into age categories relating to childbearing potential
270might be appropriate.
271Table SIII.2: Age group and gender
272As appropriate, based on available data

Age group Patients Person time
M F M F
Preterm newborn infants
Term newborn infants (0 to 27 days)
Infants and toddlers (28 days to 23 months)
Children (2 to e.g. 11 years)
Adolescents (e.g. 12 to 17 years)
Adults (e.g. 18 to 64 years)
Elderly people
65-74 years
75-84 years
75-84 years
85 + years
Total
Indication 1
Age group Patients Person time
M F M F
Age group 1
Age group 2 etc.
Total
273Table SIII.3: Dose
Dose of exposure Patients Person time

Dose level 1
Dose level 2 etc.
Total
Indication 1
Dose of exposure
Dose level 1
Dose level 2 etc.
Total
274 Part II: Module SIV - Populations not studied in clinical trials
275This Module should be omitted in the same situations as Modules SI-

276SIII, described above.
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277This section should focus on the aspects which justify and lead to the
278identification of the missing information in the safety specification.
279This module should discuss the limitations of the clinical trial
280population in relation to predicting the safety of the medicinal
281product(s) in real life use. If difficult to populate for e.g. for
282bibliographic applications or where the applicant does not have access
283to original trial data, the Applicant is encouraged to include any
284relevant data that the Applicant has access to, even if these are
285limited to the inclusion/exclusion criteria listed in published
286studies.
287SIV.1 Exclusion criteria in pivotal clinical studies within the

288development programme
289Discuss the important exclusion criteria in the pivotal clinical

290studies across the development programme.
291Important exclusion criteria in pivotal studies in the development programme:
292<Criterion>
293Reason for exclusion
294Is it considered to be included as missing information? <Yes>/<No>
295Rationale (if not included as missing information)
296SIV.2 Limitations of ADR detection common to clinical trial development

297programmes
298Normally, clinical trial development programmes are unlikely to detect

299certain types of adverse reactions (ADRs) such as rare ADRs, ADRs with
300a long latency period, or caused by prolonged or cumulative exposure.
301It is assumed that the clinical trial development programme is unable
302to detect these kinds of ADRs. However, if this assumption is not
303correct, briefly discuss the level of detection for the clinical trial
304programme conducted.
305SIV.3 Limitations in respect to populations typically under-represented

306in clinical trial development programmes
307Some populations are often not included in clinical trials. For each of
308the line in the table below, indicate the number of subjects included
309and total person years of follow-up in the clinical development program
310for the product(s) covered in this RMP
311Table SIV.1: List of populations included or not in clinical trial development programmes
Type of special population (Any included in pre-authorisation Exposure
clinical development program yes/no)
Total number of
subjects and person
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60
time
Pregnant women In most cases,

person time exposure
Breastfeeding women data can be omitted
for this population
Patients with relevant comorbidities:
Patients with hepatic impairment
Patients with renal impairment
Patients with other relevant co-morbidity such as cardiovascular

disease or immunocompromised patients
Patients with a disease severity different from inclusion criteria in

clinical trials.
Immuno-compromised patients
Population with relevant different ethnic origin
Subpopulations carrying known and relevant genetic polymorphisms
Other
Other special population under-represented in

clinical trials which are relevant for the
targeted indication if the safety profile is
expected to be different to the general
population.
312Part II: Module SV - Post-authorisation experience
313This Module should be omitted in the same situations as Modules SI-SIV,

314described above.
315This section is normally empty before the granting of the Marketing
316Authorisation except if there is available post-marketing data from an
317approved product containing the same active substance or from post-
318authorisation experience in other regions where the product is already
319authorised.
320This section should only provide an overview of experience in the post
321authorisation phase for risk management planning purposes. It is not
322the intention to duplicate information from PSURs. High-level
323information on the number of patients exposed post authorisation.
324SV.1 Post-authorisation exposure
325When available, worldwide data on patients exposed post marketing

326should be provided. Details and justification of the method used to
327calculate person- and person-time exposure should be briefly presented.
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328SV.1.1 Method used to calculate exposure
329If different methods have been used to calculate exposure for some
330tables, this section should be repeated before each of the relevant
331table(s).
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334SV.1.2 Exposure
335It is acknowledged that post-marketing data will most likely not be

336available by age group or by gender, but when available, the table
337template below should be used. Total expose and exposure by indication
338should always be presented.
339Table SV.1: Exposure table by indication, age group and gender
All indications Patients (e.g. packs or
Exposure
person time)
Age Group M F M F
<Age group>
Total
<Indication> Patients (e.g. packs or
Exposure
person time)
Age Group M F M F
<Age group>
Total
340
341Note the categories provided, are suggestions only and other relevant
342variables can be used e.g. oral versus I.V., duration of treatment etc.
343Table SV.2: Exposure table by country and indication
<Indication>
Exposure (e.g. packs or person
Patients
years)
<EU Country/sales area>
Non-EU exposure
344If possible, EU use should be broken down by country or sales area.
345Part II: Module SVI - Additional EU requirements for the

346safety specification
347This Module should be omitted in the same situations as Modules SI-SV,

348described above.
349Potential for misuse for illegal purposes
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350Discuss the potential for misuse, e.g. as a recreational drug or to

351facilitate assault. Discuss the means of limiting this in the risk
352minimisation plan where appropriate.
353Part II: Module SVII - Identified and potential risks
354This module is mandatory for all initial MAAs except for:

355 applications for generic medicinal products,
356 applications for hybrid medicinal products,
357 applications for fixed dose combination medicinal products that
358 do not contain a new active substance combination,
359 full MA applications while there has been a product with the same
360 active substance authorised for 10 or more years,
361This module should present the safety profile of the product, as it is
362known at the time of the RMPs data lock point. Relevant information
363for the identification of important identified and potential risks, and
364missing information should be discussed in this module. If they have
365not already been provided in the previous sections, provide appropriate
366references to the primary data informing the discussion here (e.g. eCTD
367hyperlinks).
368The identification of the risks to be addressed in the RMP should not
369be a copy paste of the sections 4.4 and 4.8 of the SmPC as the safety
370concerns to be included in the RMP should be considered important.
371Namely, important identified or potential risk is a risk that could
372have an impact on the benefit-risk balance of the product when further
373characterised and/or if not managed appropriately in daily clinical
374practice, and which therefore would usually lead to further evaluation
375as part of the Pharmacovigilance Plan or will require risk minimisation
376activities beyond routine risk communication.
377Identified risks, potential risks and missing information are defined
378according to GVP Module V, as follows:
379Identified risk: An undesirable outcome for which there is sufficient
380scientific evidence that it is caused by the medicinal product.
381Potential risk: An undesirable outcome for which there is a scientific
382basis for supposition of a causal relation with the medicinal product
383(e.g. a signal, a class effect plausible also for the new product,
384findings from (non-) clinical studies) but where there is insufficient
385support to conclude there is a causal association.
386Missing information: Gaps in knowledge about a medicinal product,
387related to the anticipated utilisation patterns such as long term use
388or use in particular patient populations, which could be clinically
389significant.
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390For RMPs covering multiple substances or products where there may be

391significant differences in the important identified and important
392potential risks or missing information for different substances/
393products (e.g. fixed dose combination products), it is appropriate to
394make it clear which safety concerns relate to which substance/ product.
395According to GVP module V section V.B.7.7., the following safety topics
396are of particular interest for consideration when deciding which risks
397to classify as important.
398 The risks from overdose, whether intentional or accidental and
399its consequences (i.e. AEs.)
400 The risks resulting from medication errors
401 The risks of transmission of infectious agents because of the
402nature of the manufacturing process or the materials involved.
403 The risks when used off-label;
404 Safety concerns identified for the drug class should be
405considered for inclusion if considered relevant for the drug in
406questions;
407 The risks associated with drug interactions for commonly used
408medicines in the target population.
409 Risks associated with the disposal of the used product (e.g.
410transdermal patches with remaining active substance or remains of
411radioactive diagnostics).
412 Risks related to the administration procedure (e.g. risks related
413to the use of a medical device (malfunction which impacts on the dose
414administered, risk of variability in complex administrations).
415 Specific paediatric safety information in the authorised
416indication should also be discussed according to section 5 of Annex I
417of the PIP opinion (Potential long-term safety/efficacy issues in
418relation to paediatric use for consideration in the
419RMP/Pharmacovigilance activities).
420For RMPs of advanced therapy medicinal products (ATMPs), the following
421risks should also be considered according to the Guideline on Safety
422and Efficacy Follow-up Risk Management of Advanced Therapy Medicinal
423Products2: risks to living donors, risks to patients related to quality
424characteristics of the product, risks to patients related to the
425storage and distribution of the product, risks to patients and HCPs
426related to administration procedures, risks related to interaction of
427the product and the patient or the healthcare professional, risks
428related to scaffolds, matrices and biomaterials (e.g. biodegradation,
429mechanical factors), risks related to persistence of the product in the
732 EMEA/149995/2008; available on EMA website:
74http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500006326.p
75df
76
77
78
79
80
430patient, risks related to re-administration, risks to close contacts,

431for instance, specific parent-child risks.
432Please remember this section should be concise and should not be a data
433dump of tables or lists of adverse reactions from clinical trials, or
434the proposed content of section 4.8 of the summary of product
435characteristics.
436SVII.1 Identification of safety concerns in the initial RMP submission
437SVII.1.1. Risk considered important for inclusion in the safety specification

438For risks included in the list of safety concerns of the product(s),
439the scientific evidence that has led to the inclusion should be
440discussed, and further details on the safety concerns should be
441provided in section Details of important identified and important
442potential risks.
443Important identified risks:
444<Risk>:
445Level of scientific evidence for <risk> to be added in the safety specification as an important identified
446risk:
447Seriousness:
448Frequency:
449Clinical and benefit/risk impact:
450Important potential risks
451<Risk>
452Level of scientific evidence for <risk> to be added in the safety specification as an important potential
453risk:
454Seriousness:
455Frequency:
457Missing information
458<Risk>
459Level of scientific evidence for <risk> to be added in the safety specification as an missing information:
460Seriousness:
461Frequency:
463
464SVII.1.2 Risk not considered important for inclusion in the safety specification
81
82
83
84
465For risks not taken forward as an important identified or important

466potential risk, or missing information the justification for not
467including them as a safety concern should be provided.
468<Risk(s):
469Seriousness:
470Frequency:
472Scientific evidence for <risk(s)> not to be added in the safety specification:
473
474SVII.2 Identification of safety concerns with a submission of an updated

475RMP
476This section applies to RMP updates after the granting of the MA.
477The section should contain a discussion on the new, revised or removed

478identified risks, potential risks, missing information in the same way
479as in section SVII.1:
480SVII.2.1. Newly identified risks of the product

481SVII.2.1.1. Newly identified risk considered safety concerns
482When the safety finding comes from non-clinical or clinical studies,
483references (eCTD hyperlinks) should be included to the primary study
484reports (i.e. clinical trial, epidemiological studies, case
485reports/series, non-clinical data, mechanistic hypothesis, etc.) from
486which the suggested safety findings were observed.
487Important identified risks:
488<Risk>
489Level of scientific evidence for <risk> to be added in the safety specification as an important identified
490risk:
491Seriousness:
492Frequency:
494Important potential risks
495<Risk>
496Level of scientific evidence for <risk> to be added in the safety specification as an important potential
497risk:
498Seriousness:
499Frequency:
85
86
87
88

501Missing information
502<Risk>
503Level of scientific evidence for <risk> to be added in the safety specification as an missing information:
504Seriousness:
505Frequency:
507
508SVII.2.1.2. Newly identified risks not considered as safety concerns:
509<Risk>
510Seriousness:
511Frequency:
513Scientific evidence for <risk> not to be added in the safety specification:
514SVII.2.2.Justification on the new risk classification (deletion, addition, downgrade and/or
515upgrade):
516When an important risk or missing information is removed, a

517justification of removal should be provided e.g. by provision of a
518discussion on relevant results of post-authorisation studies.
519<<Risk> previously classified as important identified/potential risk or missing information is classified

520to be <an important <identified> <potential> risk or <missing information> or <removed from the list
521of safety concerns>>.
522Level of scientific evidence for <risk> to be reclassified or removed:
523Seriousness:
524Frequency:
526For example, the rationale for removing the missing information can be
527that the results of a study are provided and no concerns safety were
528raised.
529SVII.3 Details of important identified potential risks and missing

530information
531This section applies to all stages of the products life cycle.

532For RMPs covering multiple products where there may be important
533differences in the identified and potential risks or missing
534information for different products, it is appropriate to make it clear
89
90
91
92
535which relate to which product. Categories to be considered include

536safety concerns relating to the active substance, safety concerns
537related to a specific formulation or route of administration and safety
538concerns associated with a switch to non-prescription status.
539
540SVII.3.1. Presentation of important identified and potential risks
541Name of the risk (using MedDRA terms when appropriate)
542Frequency with 95 % CI:
543State clearly:
544- Frequency parameter used e.g. incidence rate or incidence risk
545- Data source e.g. blinded clinical trial population, epidemiological
546study.
547For identified risks incidence should be presented for the whole
548population and relevant subpopulation with differences discussed.
549Potential mechanisms:
550Provide plausible biological mechanisms on how the administration of
551the medicinal product could lead to the event, if available.
552Evidence source and strength of evidence:
553Provide a brief summary of the main reasons for considering the risk as
554an important identified or important potential risk. Please consider
555that this text will be included verbatim in the RMP public summary.
556Impact on the individual patient:
557Describe the relative risk, severity/seriousness, reversibility, long-
558term outcomes, and quality of life, as applicable.
559Risk factors and risk groups
560Describe patient factors, dose-related, at risk period, additive or
561synergistic factors. Please consider that this text will be included
562verbatim in the RMP public summary.
563Preventability
564Provide data on predictability of the risk; risk factors identified
565which could be minimised by risk minimisation activities other than
566general awareness using the PI; possibility of detection at an early
567stage which could mitigate seriousness
568When additional risk minimisation measures are proposed or are in
569place, make reference to the specific section in Part V where the
570measures are being described.
571Impact on the benefit-risk balance of the product:
93
94
95
96
572Describe the actual impact and the expected impact if, when the risk is
573further characterised and with RMMs in place, the data confirms the
574presumed concerns.
575Public health impact:
576Describe the absolute risk (incidence rate) in relation to the size of
577the target population as well as the attributable risk. Describe the
578overall expected outcome on the population level.
579SVII.3.2. Presentation of the missing information
580Include only the missing information which has been selected to be part
581of the safety specifications.
582Name of missing information (Use MedDRA terms when appropriate)
583Anticipated risk/consequence of the missing information: (or the population in need for
584further characterisation if risks cannot be defined based on available
585evidence)
586Describe the risk anticipated in the population not studied.
587Describe the population followed up for further characterisation:
588Evidence source and strength of evidence:
589Describe the evidence that the safety profile is expected to be
590different from that in the general target population
591Impact on the benefit-risk balance of the product:
592Describe the expected impact on the B/R balance if a causal association
593between a further characterised risk and the product is found to be
594strong (i.e. worst case scenario)
595Part II: Module SVIII - Summary of the safety concerns
596This module is mandatory for all initial MAAs.

597A summary should be provided of the safety concerns identified in previous Module SVII of Part II.
598Table SVIII.1: Summary of safety concerns
Summary of safety concerns
Important identified risks <List>

Important potential risks <List>
Missing information <List>
599Part III: Pharmacovigilance Plan
600This part is mandatory for all initial MAAs.

601For well characterised safety concerns, routine Pharmacovigilance may
602be sufficient.
97
98
99
100
603The Pharmacovigilance plan should provide details of pharmacovigilance

604activities/studies intended to identify and/or further characterise
605safety concerns and studies measuring the effectiveness of risk
606minimisation measures where such study is required.
607The Pharmacovigilance Plan may include epidemiological (non-
608interventional or interventional) studies, non-clinical activities or
609clinical studies. Further information on post authorisation safety
610studies is given in GVP Module VIII.
611For each safety concern in Part II SVIII, provide details of specific
612areas that still need confirmation or further investigation e.g.
613confirmation of incidence, investigation of risk factors by routine or
614additional Pharmacovigilance activities. This information may be
615provided in tabular or text format, whichever is considered to be most
616informative and concise.
617III.1 Routine pharmacovigilance activities
618Routine pharmacovigilance is the set of activities required to fulfil

619the legal requirements for pharmacovigilance contained within Directive
6202001/83/EC and Regulation (EC) No 726/2004. The Pharmacovigilance
621System Master File (describing these activities is not required in the
622RMP). Signal detection, which is part of routine pharmacovigilance,
623will be an important element in identifying new risks for all products
624but should not be discussed here.
625Part III.1 should only include a brief description of the routine
626pharmacovigilance activities beyond ADRs reporting and signal
627detection.
628Routine pharmacovigilance activities beyond ADRs reporting and signal detection:
629 Specific adverse reaction follow-up questionnaires for <risk(s)>:
630Provide a description of the materials used when specific

631questionnaires to obtain structured information on reported suspected
632adverse reactions of special interest are required.
633The forms should be provided in Annex 4 of the RMP. .
634 Other forms of routine pharmacovigilance activities for <risk (s)>
635This includes for example enhanced passive surveillance, monitoring and

636special reporting in the PSURs, and one-off cumulative reviews of
637adverse events of interest (other legally binding post-authorisation
638measures).
639Please include the description of such activities including objectives
640and milestones.
101
102
103
104
641III.2 Additional pharmacovigilance activities
642Applicants/MAHs should describe additional pharmacovigilance activities

643such as non-clinical studies, clinical trials or non-interventional
644studies, and explain why they are needed. Examples of additional
645pharmacovigilance activities include long-term follow-up of clinical
646trial(s), studies to provide additional characterisation of the long
647term safety of the medicinal product or when a potential risk with an
648individual medicinal product has a significant background incidence in
649the target population(s), leading to difficulties in distinguishing
650between the effects of the medicinal product and the normal
651incidence. When any doubt exists about the need for additional
652pharmacovigilance activities, consultation with a competent authority
653should be considered.
654Studies in the pharmacovigilance plan should relate to the safety
655concerns identified in the safety specification irrespective of whether
656the studies are to identify and characterise risks, or to assess the
657effectiveness of additional risk minimisation activities. Exceptions
658are studies aimed at measuring the effectiveness of vaccines, they do
659not normally relate to any identified or potential safety issue, but
660they need to be included and described in the Pharmacovigilance Plan.
661Pharmacoepidemiology studies included in the pharmacovigilance plan
662should be designed and conducted according to the respective
663legislation in place, recommendations in the Guidelines for Good
664Pharmacoepidemiology Practices (GPP)3 and the ENCePP Guide on
665Methodological Standards in Pharmacoepidemiology4. For studies
666involving children, the Guideline on Conduct of Pharmacovigilance for
667Medicines Used by the Paediatric Population5 should be consulted. MAAs
668and MAHs can submit PASS protocols for Scientific Advice.
669Further guidance on the conduct of post-authorisation safety studies
670(PASS) is provided in the GVP module VIII.
671Protocols for studies in the pharmacovigilance plan should be provided
672in RMP Annex 3 until completion of the study and submission to the
673competent authorities of the final study report.
674If no additional Pharmacovigilance activities are deemed necessary, the
675applicant/MAH can justify that routine pharmacovigilance activities is
676considered sufficient to address all safety concerns with the aim to
677get and analyse relevant safety data from post-marketing experience to
678fully assess the safety of the product.
1053 International Society for Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (GPP).
106Pharmacoepidemiol Drug Saf. 2005; 14 (8): 589-595; available on the ISPE website
107http://www.pharmacoepi.org/resources/guidelines_08027.cfm.
1084 ENCePP Guide on Methodological Standards in Pharmacoepidemiology EMA/95098/2010; available on
109http://www.encepp.eu.
1105 EMEA/CHMP/PhVWP/235910/2005; available on http://www.ema.europa.eu/ema/index.jsp?
111curl=pages/regulation/document_listing/document_listing_000087.jsp&mid=WC0b01ac0580025b90&jsenabled=true.
112
113
114
115
679For all studies imposed as condition of the MA (category 1), as

680specific obligations in the context of a marketing authorisation under
681exceptional circumstances or condition MA (category 2), or required by
682the competent authority (category 3) complete the following:
683<PASS short name> summary
684The study summary should be consistent with the study description
685provided in table III.3 and should include:
686Study title: Please consider that the text in this section will be included
688Rationale and study objectives: Please consider that the text in this section
689will be included verbatim in the RMP public summary.
690The rationale for conducting the study should be included. Present
691briefly the study objectives.
692Study design:
693State the study design.
694Study populations:
695Present briefly the population included in the study, in line with the
696inclusion and exclusion criteria.
697Milestones:
698Include all milestones for reporting to the regulatory authorities
699(i.e. protocol, interim reports, and final report submission) as well
700as major milestones from study protocol (e.g. registration in the EU
701PAS register, start/end of data collection, interim progress reports,
702final study report completion, date of publication).
703The summary should not be duplication of the protocol synopsis, but it
704should be detailed enough to be able to inform what the study will add
705to further characterise the safety profile of the product.
706III.3 Summary Table of additional Pharmacovigilance activities
707This section should be a complete overview of all on-going and planned

708categories 1-3 studies included in the Pharmacovigilance Plan,
709regardless of whether they were designed to assess the safety or
710effectiveness of the medicinal product, or the effectiveness of the
711risk minimisation measures.
712With regards to milestones, it is mandatory to provide the submission
713date of the final results. Submission of interim results is not
714expected unless explicitly requested by the PRAC and CHMP. Clear due
715dates should be provided (e.g. the clinical study report should be
716submitted by 31 January 2018). Final report dues dates included in the
717table below are enforceable.
116
117
118
119
718If a study aims to evaluate the effectiveness of risk minimisation

719measures, this needs to be made explicit in the study summary of
720objectives.
721Table Part III.1: On-going and planned additional pharmacovigilance activities
722Examples of activities are provided in green in the table, to guide on the level of the detail expected.
723Not all milestones are applicable for all studies, and not all products will have studies from all
724categories.
Study(study
short name,
and title) Safety concerns Milesto Due
Summary of objectives
Status addressed nes dates
(planned/on-
going)
Category 1 - Imposed mandatory additional pharmacovigilance activities which are conditions of the
marketing authorisation (key to benefit risk)
LE observational To evaluate over a minimum of - serious infections Protoco 31-01-
cohort safety 1 year the incidence of all- (including non-serious l 2016
study (study cause mortality and adverse and serious submiss
LE123) events of special interest in opportunistic ion
patients with lupus infections and PML)
Planned erythematosus. - malignancies Final 31-12-
(including non-melanoma report 2018
skin cancer)
- serious infusion
- hypersensitivity
reactions
- serious psychiatric
events (mood disorders,
anxiety and suicide).
Long-term safety To evaluate the incidence of - serious infections Protoco 28/02/201
registry (Study all-cause mortality and (including opportunistic l 6
REG4321) adverse events of special infections and PML) submiss
interest in patients with - selected serious ion
Planned systemic lupus erythematosus, psychiatric events Final 30/10/202
using data from a long-term - malignancies report 3
safety registry where all (including
patients are followed for a non-melanoma skin
minimum of 5 years, cancer).
Category 2 Imposed mandatory additional pharmacovigilance activities which are Specific Obligations
in the context of a conditional marketing authorisation or a marketing authorisation under exceptional
circumstances (key to benefit risk)
Long term safety Primary - Long term safety Annual To be
PASS EPIOA005 To further evaluate the - Use in populations not reports submitted
long-term safety profile of studied in clinical with
Planned <product> in the treatment of trials: pregnancy and annual
patients with <..> when used lactation, elderly, re-
under conditions of routine children under 14 years assessmen
clinical care of age, hepatic ts
impairment, renal
Secondary impairment
To further evaluate the
long-term effectiveness of <>
in the treatment of patients
with <> when used under
conditions of routine clinical
care
To quantify discontinuation
of treatment due to adverse
events or due to lack of or
loss of therapeutic response.
To further elucidate the
risk of abnormal liver
function tests and hepatitis
120
121
122
123
Category 3 - Required additional pharmacovigilance activities (by the CHMP/PRAC or NCA)

Post-marketing To investigate the association - Cardiac risk Annual Progress
multi-centre between the <product> induced update reports
registry study QTc prolongation and possible on
REGAR02 predictive factors, and enrolment
estimate the incidence of and
On-going treatment-emergent adverse intermedi
events of special interest. ate
The study will also monitor analysis
the patterns of drug results
utilization for <product>. will be
provided
yearly.
Final 31/03/202
report 0
Drug utilisation To document the real-life use - Safety in renal Final 31/01/201
study for of the product. impaired patients report 9
<product> To measure the effectiveness
DUS-01 of routine risk minimisation
measures, i.e. the compliance
Planned with the SmPC recommendations
on dose reduction in renal
impaired patients
Vaccine To measure the seasonal flu - No safety concern Annual 3 months
Effectiveness vaccine effectiveness after addressed reports after the
Study every strain change after seasons
MOVE-15-19 strain end, for
change seasons
Planned following
a strain
change
Final 31/12/202
report 0
Post-approval To evaluate any potential Changes in the frequency Final 2 years
safety change in the frequency of of hypersensitivity and report following
surveillance hypersensitivity, immunogenicity events the
program for lot- immunogenicity or lack of drug with the altered expiry of
specific adverse effect events. manufacturing process the first
events Q-450-E01 released
finished
Planned batch
31/01/202
0
725Part IV: Plans for post-authorisation efficacy studies
726This part is mandatory for all initial MAAs.

727The purpose of this section is to have an overview of the planned and
728on-going imposed efficacy studies. i.e. post-authorisation efficacy
729studies imposed by the CHMP/NCA as a condition of marketing
730authorisation or which are Specific Obligations in the context of MA
731under exceptional circumstances or conditional MA. A synopsis of the
732protocol(s) should be provided in Annex 5.
733Table Part IV.1: Planned and on-going post-authorisation imposed efficacy studies
734Examples of activities are provided in green in the table, to guide on
735the level of the detail expected. Not all milestones are applicable for
736all studies.
737Please consider that text from the table below will be included
124
125
126
127
739
Study(study
short name and
Efficacy
title), Objectives uncertainties Milestones Due Date
(planned,
Status addressed
on-going)
Efficacy studies which are conditions of the marketing authorisation
Extension of To examine the Long term Final 30/06/2022>
clinical trial for 5-year efficacy efficacy and report
<product>(SUMACI) and safety of safety
<product>, compared
(on-going) with reference treatment, in
patients who
received study
treatment in the
pivotal sponsored study
for treatment of
<>.
Efficacy studies which are Specific Obligations in the context of a conditional marketing authorisation or a
marketing authorisation under exceptional circumstances
External natural To further investigate the Long-term Protocol 28/02/2017
history controlled, benefits of <product> in the efficacy submission
open-label treatment of <>,
interventional
Interim To be
study to assess the
reports submitted
efficacy and safety
and with annual
of <product> in the
re-assessment
treatment of
<indication>,
Final 31/12/2022
including long-term
report
treatment (CLINI-
EXT-05)
On-going
740
741Part V: Risk minimisation measures
742This part is mandatory for all initial MAA.

743For initial MAA for generic or hybrid medicinal products, where the
744originator does not have additional risk minimisation activities, a
745statement in Part V that the safety information in the proposed PI is
746aligned to the originator product is sufficient. However, if new risks
747have been identified for the new product, the risk minimisation
748activities for such safety concerns should be presented in Part V,
749following the same requirements as for a new active substance.
750For each safety concern identified in module SVIII summary of the
751safety specification, a summary of routine minimisation measures
752should be provided in Table Part V.1. The complete text from the
753product information should not be included, only reference to the
754section should be provided. Where none are proposed, then None should
755be entered against the safety concern.
128
129
130
131
756Further guidance on risk minimisation measures can be found in GVP

757Module XVI.
758
759Risk Minimisation Plan
760V.1. Routine Risk Minimisation Measures

761Include all safety concerns from Module SVIII.
762Table Part V.1: Description of routine risk minimisation measures by safety concern
Safety concern Routine risk minimisation activities
<Safety Please provide the following information, as applicable:

concern>
Routine risk communication:
Provide only SmPC/PL section (do not copy the exact

SmPC/PL wording).
e.g. <SmPC section 4.8.>
e.g. <PL section 2.>
Risk minimisation activities in the Product Information beyond routine risk

communication:
e.g. Specific monitoring information for healthcare

professionals in SmPC these may include warnings,
precautions, and advice on correct use:
<SmPC section 4.4 where advice is given on monitoring
the liver function>
Other risk minimisation measures beyond the Product Information:
Pack size:
e.g. when the amount of medicine in a pack helps

ensuring that the product is used correctly.
Medicines legal status:
Restricted medical prescription, special medical

prescription, categorisation at member states level,
etc)
<Safety <None>
concern >
763V.2. Additional Risk Minimisation Measures
764This section should present additional risk minimisation measures by

765type of measure. If no additional risk minimisation activities are
766proposed, a statement that routine risk minimisation activities as
132
133
134
135
767described in Part V.2. are sufficient to manage the safety concerns of

768the product.
769<Additional risk minimisation 1>
770It is recommended to use one of the names described below, as
771applicable.
772Objectives including a list of risks addressed:
773Rationale for the additional risk minimisation activity:
774Include justification on why the named additional risk minimisation is
775considered needed.
776Target audience and planned distribution path:
777Include very brief summary of planned communication plan.
778Plans for evaluating the effectiveness of the interventions and criteria for success:
779Specify how effectiveness will be measured and provide the criteria for
780judging success. Milestones for reporting should be included when
781effectiveness is evaluated using only routine pharmacovigilance
782activities.
783Further extensive guidance on additional risk minimisation measures is
784provided in GVP Module XVI, but examples of materials most frequently
785used are included below, for information only.
786Examples of additional risk minimisation measures:
787Healthcare Professional and patient/carer Guide
788Terms such as brochure, leaflet should be avoided and the term
789guide should be used instead. The media, format, specific content, and
790other aspects of the implementation of an educational tool are under
791the responsibilities of the NCA. The term guide can refer to any
792descriptive material that educates Healthcare Professional and/or
793patients about specific risks, and/or their early symptoms, and/or the
794best course of action to be taken when these appear. The aim to raise
795awareness about an on-going (imposed) registry / study can be also
796expected, as well as reference to the general value of reporting
797adverse events.
798Training material for Healthcare Professional
799The purpose of this tool is to train Healthcare Professional when new
800complicated administration procedures (e.g. intra-vitreal injections,
801imaging diagnostics, ATMPs, etc) are introduced or diagnostics
802products are first authorised, in order to minimise the potential risks
803associated with performing such procedures (e.g. medication error).
804Prescriber checklist
805The purpose of this tool is to facilitate patients selection when
806initiating therapy or repeat prescription is issued, as appropriate.
807The checklist should remind prescribers of the contraindications,
136
137
138
139
808warnings and precautions needed for the use of a product particularly

809relating to important safety concerns in the RMP and to facilitate the
810need for examination of specific aspects of the patients health (e.g.
811assess cardiovascular risk; perform and check results of liver
812function, etc) before initiating treatment and/or during continuous
813monitoring as appropriate.
814Patient reminder card
815A patient reminder card or (diary) can be used for the patient to
816record the date and/or outcome of specific tests needed during the
817continuous treatment with a product in order to facilitate regular
818monitoring of the patients health status with respect to product
819related safety concerns.
820Patient alert card
821The purpose of this tool is to ensure that special information about
822the on-going treatment with a product and its important risks (e.g.
823potential important interactions) is held by the patient at all time
824and reaches the relevant healthcare professional in any circumstances,
825including patients incapacity to communicate. Portability (small
826wallet size, hence concise and focused messages) is the key feature of
827this tool.
828<Rationale for proposing to remove additional risk minimisation measures>
829Include justification.
830V.3 Summary table of pharmacovigilance and risk minimisation activities

831by safety concern
832Table Part V.3: Summary table of pharmacovigilance activities and risk minimisation activities by safety
833concern
834Include all safety concerns from Module SVIII. Examples below are
835provided in green in the table, to guide on the level of the detail
836expected.
837Please consider that text from the table below will be included
839
Safety concern Risk minimisation measures Pharmacovigilance activities
Include only a list of Include only a list of routine

elements activities beyond ADR reporting
and SD, and a list of
additional pharmacovigilance
activities
<safety SmPC section 4.1 AE follow-up form

concern>
SmPC section 4.4 where Study short name
advice is given on
monitoring the liver
140
141
142
143
Safety concern Risk minimisation measures Pharmacovigilance activities
Include only a list of Include only a list of routine

elements activities beyond ADR reporting
and SD, and a list of
additional pharmacovigilance
activities
function
PL section 2
Pack size
Leaflet for Physicians
Patients brochure
<safety SmPC section 4.2 and none

concern> 4.8
Surgeons checklist
Rehabilitation Manual
144
145
146
147
840Part VI: Summary of the risk management plan
841This section should be submitted for all initial marketing

842authorisation applications and all post-authorisation RMP updates.
843A separate RMP Part VI should be provided for each product in the RMP.
844 Summary of risk management plan for <invented name>

845(<INN>)
846
847This summary should be updated to reflect any important change to the
848RMP6
849This is a summary of the risk management plan (RMP) for <X>. The RMP details important risks of
850<X>, how these risks can be minimised, and how more information will be obtained about <X>'s risks
851and uncertainties (missing information).
852<X>'s summary of product characteristics (SmPC) and its package leaflet give essential information to
853healthcare professionals and patients on how <X> should be used. This summary of the RMP for <X>
854should be read in the context of all this information including the assessment report of the evaluation
855and its plain-language summary, all which is part of the EPAR.
856Important new concerns or changes to the current ones will be included in updates of <X>'s RMP.
857
858I. The medicine and what it is used for
859<X> is authorised for <indication outline> (see SmPC for the full indication). It contains <Y> as the
860active substance and it is given by <route of administration>.
861Clinical studies have shown <X> to be effective for treating <patients/individuals> with <disorder>.
862Further information about the evaluation of <Xs> benefits can be found in <Xs> EPAR, including in its
863plain-language summary, available on the EMA website, under the medicines webpage <link to the
864EPAR summary landing page>.
865
866II. Risks associated with the medicine and activities to
867minimise or further characterise the risks
868Important risks of <X>, together with measures to minimise such risks and the proposed studies for
869learning more about <X>'s risks, are outlined below.
870Measures to minimise the risks identified for medicinal products can be:
1486 Changes are considered important if they relate to the following: new indications, new or updated contraindications, new safety
149concerns or important changes to a known safety concerns, any additional risk minimisation measure which is added or removed
150
151
152
153
154
871 Specific Information, such as warnings, precautions, and advice on correct use, in the package
872 leaflet and SmPC addressed to patients and healthcare professionals, such as warnings,
873 precautions, and advice on correct use;
874 Important advice on the medicines packaging;
875 The authorised pack size the amount of medicine in a pack is chosen so to ensure that the
876 medicine is used correctly;
877 The medicines legal status the way a medicine is supplied to the public (e.g. with or
878 without prescription) can help to minimises its risks.
879Together, these measures constitute routine risk minimisation measures. <In the case of <X>, these
880measures are supplemented with additional risk minimisation measures mentioned under relevant
881risks, below>.
882Include the second sentence, above, if the RMP (Part V.2) includes
883additional risk minimisation measures.
884In addition to these measures, information about adverse events is collected continuously and
885regularly analysed<, including PSUR assessment,> so that immediate action can be taken as
886necessary. These measures constitute routine pharmacovigilance activities.
887Include PSUR statement only if product has PSUR requirements.
888<If important information that may affect the safe use of <X> is not yet available, it is listed under
889missing information below>.
890The above sentence should be included if the RMP does contains missing
891information in the summary of safety concerns.
8921.1. List of important risks and missing information
893Important risks of <X> can be regarded as identified or potential. Identified risks are concerns for
894which there is sufficient proof of a link with the use of <X>. Potential risks are concerns for which an
895association with the use of this medicine is possible based on some preliminary data, but this
896association has not been fully proven and needs further evaluation.
List of important risks and missing information (from Part 2 Module SVIII)
Important identified risks <>

Important potential risks <>
Missing information <>
897
898Provide relevant information for each risk using only text sections
899form RMP Part II SVII.3.
9001.2. Summary of important risks
901<Risk>
Evidence for linking the Use text from RMP Part II SVII.3.1 under
risk to the medicine Evidence source and strength of evidence
155
156
157
158
Risk factors and risk Use text from Part II SVII.3.1 under Risk
groups factors and risk groups
Risk minimisation <Routine risk minimisation measures>

measures
Use text from table Part V.3.
<Additional risk minimisation measures>
<No risk minimisation measures>
Additional Additional pharmacovigilance activities:

pharmacovigilance
<Short study name>
activities
Use study short name from table Part V.2.
This row should
be removed in See section 2.3 of this summary for an overview of the post-
case there are no authorisation development plan.
pharmacovigilance
activities
9021.3. Summary of missing information
903<Missing information>
Risk minimisation <Routine risk minimisation measures>

measures
<Additional risk minimisation measures>
<No risk minimisation measures>
Additional Additional pharmacovigilance activities:

pharmacovigilance
<Short study name>
activities
Use study short name from table Part V.2.
This row should be
removed in case See section 2.3 of this summary for an overview of the post-
there are no authorisation development plan.
pharmacovigilance
activities
9041.4. Post-authorisation development plan
9051.4.1. Studies which are conditions of the marketing authorisation
906<The following studies are conditions of the marketing authorisation :>

907Include studies category 1 and 2 from table Part III.1: On-going and
908planned additional pharmacovigilance activities.
159
160
161
162
909Include all studied from table Part IV.1: Planned and on-going post-
910authorisation imposed efficacy studies.
911<study short name>
912Study title: Include text from Part III.3 and/or Part IV.
913Rationale and study objectives: Include text from Part III.3 and/or Part IV.
914<There are no studies which are conditions of the marketing authorisation or specific obligation of
915<X>>
9161.4.2. Other studies in post-authorisation development plan
917Include studies category 3 from table Part III.1: On-going and planned
918additional pharmacovigilance activities.
919<<study short name>
920Study title: Include text from Part III.3.
921Rationale and study objectives: Include text from Part III.3.
922<There are no studies required for <X>>
163
164
165
166
923Part VII: Annexes
924For generic (Article 10 (1)) and hybrid (Article 10 (3)) medicinal

925products, the same requirements as for initial MAA for a new active
926substance apply. For annexes 3 and 5, the Applicant is strongly
927encouraged to use the same forms and materials as the originator
928product. If materials are not available in the public domain, the MAH
929of the originator product should share them upon the Applicants
930request. If sharing the materials is not possible, the Competent
931Authority or the NCA in the MS where the originator product is used
932should provide the materials to the Applicant.
933Table of contentsInclude TOC of Annexes
934Annex 1 EudraVigilance Interface
935Annex 1 of the RMP is not required to be submitted in eCTD; the

936electronic file should be submitted in accordance to GVP module V
937chapter V.C.4 and the guidance on the EudraVigilance website
938(http://eudravigilance.ema.europa.eu/human/EURiskManagementPlans.asp)
939Leave Annex 1 empty.
940Annex 2 Summary of on-going and completed pharmacoepidemiological

941study programme
942List all studies included in the Pharmacovigilance Plan (current or in

943previously approved RMP versions). It is recommended to group the
944studies by status (e.g. on-going, completed)
945Table of contents
946Include ToC
947<Study 1>
948Status:
949For status, choose one of the following:
950 Planned
951 Protocol under development
952 Protocol agreed
953 Data collection started
954 Data collection ended
955 Study completed
956Objectives:
957Safety concerns addressed:
958< Milestones (for ongoing studies) :>
959<Date of final results regulatory submission (for completed studies) :>
167
168
169
170
960(effective, planned, or state the reason for not submitting the

961results)
962Protocol link: Include link to full protocol (included in RMP annexes or

963eCTD)
964Include a list of names and planned/actual date of final study report

965for studies conducted by the MAH, but not included in the
966Pharmacovigilance Plan (i.e. not category 1,2, or 3)
967Other studies conducted by the MAH:
968Table ANX2.1 Other studies conducted by the MAH
Name of study Date of final study report
969
970Annex 3 - Protocols for proposed and on-going studies in the

971pharmacovilance plan
972Annex 3 should include protocols of imposed studies (categories 1 and

9732) and protocols for those required studies (category 3). Protocols of
974studies not imposed or not required should not be included.
975This annex may include the links to other modules of the eCTD dossier
976where the protocols are included, instead of the full protocol
977documents.
979Include ToC
980Part A: Protocols of proposed studies, submitted for regulatory review with this updated version of the
981RMP
982This section should include the protocols that are proposed for
983assessment within the same procedure the RMP has been submitted in.
984This section should be completed only when the study protocol has been
985requested to be submitted for review by the competent authority, and
986when there is an agreed regulatory submission path that can allow the
987submission of study protocols together with an updated RMP.
988When a protocol not yet approved is submitted to address a request for
989supplementary information, an executive summary of how outstanding
990points have been addressed should be included in this section of the
991annex. A track changes version of any updated protocol should always be
992submitted.
993Full protocols or links to eCTD documents
994Part B: Updates of previously approved protocols, submitted for regulatory review with this updated
995version of the RMP
171
172
173
174
996This section should be completed only when the study protocol update
997has been requested to be submitted for review by the competent
998authority, and when there is an agreed regulatory submission path that
999can allow the submission of study protocols together with an updated
1000RMP.
1001Once approved, protocols from parts A or B should be moved to part C.
1002Full protocols or links to eCTD documents
1003Part C: Protocols for on-going studies previously agreed by the competent authority.
1004This section should include approved protocols for studies included in
1005the Pharmacovigilance Plan (current or in previously approved RMP
1006versions) and category 3 PASS protocols that were not requested to be
1007reviewed.
1008For approved protocols, they should be accompanied by the name of the
1009procedure when the protocol was approved and date of the Opinion.
1010Protocols not requested and not approved by the competent authorities
1011should be clearly marked when included in Annex 3 Part C for
1012information.
1013This section may include the links to other modules of the eCTD dossier
1014where the protocols have been previously submitted, instead of the full
1015protocol documents.
1016Protocols of completed studies should be removed from this annex once
1017the final study reports are submitted to the competent authority for
1018assessment.
1019Full protocols or links to eCTD documents, type of protocol (i.e. approved or submitted for information
1020only)
1021Annex 4 - Specific adverse event follow-up forms
1023Provide forms
1024Annex 5 - Protocols for proposed and on-going studies in RMP part IV
1025This section should include links to other parts of the eCTD dossier,
1026where the efficacy study protocols were submitted. This information is
1027meant to facilitate the assessment by maintaining an overview of the
1028post-authorisation efficacy and safety development plans.
1029Annex 6 - Details of proposed additional risk minimisation measures (if

1030applicable)
1031Part A: <Draft> key messages of the additional risk minimisation measures
175
176
177
178
1032This section should include the proposed draft key messages (and
1033approved if applicable) of the additional risk minimisation measures
1034(e.g. key messages of the educational materials).
1035Example: Key messages are included before initial approval of the
1036product (D1- D181) for review and assessment. For Centrally Authorised
1037Products, the PRAC and EMA will review and agree a final version that
1038will be included in Annex II of the MA. If the product requires a
1039revision of the key messages post-marketing, an amended set of key
1040messages can be proposed for assessment in Annex 5 Part A by the MAH
1041(tracked changes).
The following main tools are generally considered in the educational
programmes:
Educational tools targeting healthcare professionals with
specific recommendations on what to do and/or what not to do
and/or how to manage adverse reactions associated with a certain
drug
Educational tools targeting patients and/or caregivers to enhance
the awareness of patients or their caregivers on the signs and
symptoms relevant to the early recognition of specific adverse
events, for instance early recognition of lack of effect or
increased plasma levels in patients with specific polymorphism
For pregnancy prevention programmes, educational tools to inform
on the teratogenic risk and required actions to minimise this
risk (e.g. guidance regarding the need for contraception methods;
information for the patient on how long to avoid pregnancy after
treatment is stopped; information for when the male partner is
treated; counselling in case of inadvertent pregnancy)
Patients alert card to ensure that special information regarding
the patients current therapy and its risks is held by the
patient at all times and reaches the relevant healthcare
professional as appropriate
1042
1043Examples of key messages for different types of risk minimisation
1044materials
1045Physician educational material:
1046 <The Summary of Product Characteristics>
1047In addition to the Summary of Product Characteristics select all tools

1048that apply:
1049 <Guide for healthcare professionals>
1050 <Healthcare professionals training material>
1051 <Prescriber checklist>
179
180
181
182
1052 <Patient alert card>
1053Based on the choice on the above listing, select all relevant elements
1054and edit as required.
1055 Guide for healthcare professionals:
1056 o <Relevant information of the safety concern(s) addressed by the aRMM (e.g. seriousness,
1057 severity, frequency, time to onset, reversibility of the AE as applicable)>
1058 o <Details of the population at higher risk for the safety concern addressed by the aRMM
1059 (i.e. contraindications, risk factors, increased risk by interactions with certain medicine)>
1060 o <Details on how to minimise the safety concern addressed by the aRMM through
1061 appropriate monitoring and management (i.e. what to do, what not do, and who is most
1062 likely be impacted according to different scenarios, like when to limit or stop
1063 prescribing/ingestion, how to administer the medicine, when to increase/decrease the
1064 dosage according to laboratory measurements, signs and symptoms)>
1065 o <Key message to convey in patients counselling >
1066 o <Instructions how to handle possible adverse events>
1067 o <Information about the <name of> <study> <registry> and the importance of
1068 contributing to such a study>
1069 o <Remarks on the importance of reporting on specific ADRs, namely: < ADR 1, ADR 2 etc
1070 >
1071 o <Other to be specified>
1072 Healthcare professionals training material:
1073 o <Information on <product name>, including the approved indication according to the
1074 SmPC>
1075 o <Detailed description of the administration procedures of <PRODUCT NAME>>
1076 o <Patients preparation for the procedure and subsequent monitoring>
1077 o <Management of early signs and symptoms of selected safety concerns, namely: safety
1078 concern 1, safety concern 2, etc.>
1080For diagnostic products, select additional information:

1081 o <Limitations of <PRODUCT NAME> use, interpretation errors, safety information and the
1082 results of clinical trials informing on the diagnostic use of <PRODUCT NAME>>
1083 o <Review of the imaging reading criteria, including method of image review, criteria for
1084 interpretation, and images demonstrating the binary read methodology>
1085 o <Demonstration cases with correct imaging interpretation by an experienced reader and a
1086 number of clearly positive and negative cases as well as less clear-cut cases>
1087 Prescriber checklist:
1088 o <Lists of tests to be conducted for the initial screening of the patient>
183
184
185
186
1089 o <Vaccination/treatment course to be completed/withdrawn before/after treatment>
1090 o <Premedication, general health, and pregnancy and contraception checks immediately
1091 before/during/after treatment>
1092 o <Monitoring activities during treatment and for X years after last treatment>
1093 o <A specific reference to the fact that the patient has been informed and understands the
1094 <potential> <teratogenic> risks of <specify risk(s)> and the measures to minimize
1095 them>
1097 Patient alert card:
1098 o <A warning message for HCPs treating the patient at any time, including in conditions of
1099 emergency, that the patient is using <PRODUCT NAME>>
1100 o That <PRODUCT NAME> treatment may increase the <potential> risk of: <Risk 1, Risk2,
1101 etc.>
1102 o Signs or symptoms of the safety concern and when to seek attention from a HCP
1103 o Contact details of the <PRODUCT NAME> prescriber
1104The patient information pack:

1105 o Patient information leaflet
1106In addition to the patient information leaflet select all that applies:
1107 <A patient/carer guide>
1108 <A patient reminder card>
1109Based on the choice on the above listing, select all relevant elements
1110and edit as required. The suggested key elements are not strictly
1111supposed to be used only for the related specific tool (see example
1112above).
1113 The Patient/carer guide:
1114 o <A description of the <potential> <teratogenic> risks(s) associated with the use of
1115 <PRODUCT NAME> namely: <Risk 1, Risk2, etc.>
1116 o <A description of the correct use of <product name> and the <potential> risks associated
1117 with its use, namely: <Risk 1, Risk2, etc.>
1118 o <Detailed description of the modalities used for the self-administration of <PRODUCT
1119 NAME>>
1120 o <A description of the <early> sign and symptoms of the <potential> risk of <specify
1121 risk(s)>
1122 o <A description of the best course of action if sign and symptoms of those risks present
1123 themselves (e.g. How to reach your doctors)>
1124 o <Recommendations for the planning of the monitoring schedule>
1125 o <Information about the <name of> <study> <registry>>
187
188
189
190
1126 o <Remarks on the importance of reporting on specific ADRs, namely: < ADR 1, ADR 2 etc
1127 >
1129For pregnancy-related risks, select additional information:

1130 o <Recommendation to not take <PRODUCT NAME> in case of pregnancy>
1131 o <For women of child bearing potential recommendation to use effective contraception
1132 methods>
1133 o <Recommendation for regular pregnancy testing>
1134 The patients reminder card:
1135 o <Patient identification (e.g. name, date of birth, <national insurance number> <fiscal
1136 code><NHS number>)>
1137 o <Purpose and relevance of recording date <and outcome> of specific monitoring, namely:
1138 <test 1, test 2> <other monitoring>
1139 o <Potential> risk of <safety concern(s)> and need of <monthly> <regular> <pregnancy
1140 tests> <blood test> <liver function monitoring> <other testing required to be specified>
1142
1143Part B: Examples of the additional risk minimisation measures
1144This section should include, for information only, the additional risk
1145minimisation materials as they were distributed in the Member States.
1146Materials included in this annex are not assessed and are not
1147considered endorsed as part of the RMP assessment. They are not
1148considered as approved by the PRAC/CHMP since the detailed additional
1149risk minimisation measures should be approved at a national level.
1150 Annex 7 - Other supporting data (including referenced material)
1151List of references (include eCTD links)
191
192
193

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125 February 2016

4Guidance on format of the risk management plan (RMP)

30 Churchill Place Canary Wharf London E14 5EU United Kingdom

34types of initial marketing authorisation are described within each

36EU Risk Management Plan for <Invented name> (INN or

Active substance(s) (INN or common name):

Name of Marketing Authorisation Holder or

Names of medicinal products to which this RMP

Product(s) concerned (brand name(s)):

39Details of the currently approved RMP:

49RMP version to be assessed as part of this application:

60Date of final sign off: <Enter a date>

61Procedure number: <indicate procedure number>

62Rationale for submitting an updated RMP

e.g. Enter only

Part II SI <version no> <version no>

SII <version no> <version no>

SIII <version no> <version no>

SIV <version no> <version no>

SV <version no> <version no>

Part Module/annex Module version and Module

e.g. Enter only

SVI <version no> <version no>

SVII <version no> <version no>

SVIII <version no> <version no>

Part III <version no> <version no>

Part IV <version no> <version no>

Part V <version no> <version no>

Part VI <version no> <version no>

ANNEX 2 <version no> <version no>

ANNEX 3 <version no> <version no>

ANNEX 4 <version no> <version no>

Part Module/annex Module version and Module

e.g. Enter only

ANNEX 5 <version no> <version no>

ANNEX 6 <version no> <version no>

ANNEX 7 <version no> <version no>

113Part IV: Plans for post-authorisation efficacy studies................................28

119Part VI: Summary of the risk management plan........................................33

1251.4.2. Other studies in post-authorisation development plan...........................................36

136Part I: Product(s) Overview

137Table Part I.1 Product Overview

Procedure type (centrally or <Centrally authorised product> <nationally authorised

Brief description of the product: Chemical class

Summary of mode of action

Important information about its composition (e.g. origin of

Hyperlink to the Product This cell should include a link to the

Indication(s) in the EEA Current (if applicable):

Proposed (if applicable):

Dosage in the EEA Current (if applicable):

Summarise information only related to

Proposed (if applicable):

Summarise information only related to

Pharmaceutical form(s) and Current (if applicable):

Is/will the product be subject to Yes/No

170Part II: Module SI - Epidemiology of the indication(s) and

172This module should be omitted for:

178 o medicinal products with new indications where the marketing

215Part II: Module SII - Non-clinical part of the safety

217This Module should be omitted in the same situations as Module SI,

231Part II: Module SIII - Clinical trial exposure

232This Module should be omitted in the same situations as Module SI and

234SIII.1 Brief overview of development