Standard operating procedure

Title: Signal management

Status: PUBLIC Document no.: SOP/H/3065

Lead author Approver Effective date: 06-DEC-18
Name: Julie Durand Name: Peter Arlett Review date: 06-DEC-21
Signature: ON FILE Signature: ON FILE Supersedes:
SOP/H/3065 (07-MAR-13)
Date: 06-DEC-18 Date: 06-DEC-18 TrackWise record no.: 4273

1. Purpose
To describe the process by which identification and management of safety signals for active substances
contained in Centrally Authorised medicinal Products (CAPs) for human use is conducted periodically
based on electronic Reaction Monitoring Reports (eRMRs) generated from the EudraVigilance (EV)
database, as well as other sources of information such as the scientific literature. The SOP also
provides guidance on the handling by the Agency of signals validated and confirmed by national
competent authorities for nationally authorised products (NAPs). It also applies to confirmed signals
originating from marketing authorisation holder (MAHs). The purpose of this SOP is to ensure that
these activities, from signal detection to provision of support to the Pharmacovigilance Risk
Assessment Committee (PRAC) in its initial analysis, prioritisation and evaluation of signals, are
handled in an efficient and consistent way. This SOP applies to standard signal management as well as
specific situations such as a pandemic, however for such situations adapted processes and shorter
timelines may apply.

2. Scope
This SOP applies to the Signal and Incident Management Service of the Pharmacovigilance and
Epidemiology Department (P-PE-SIM).

3. Responsibilities
It is the responsibility of the Heads of Department and Service to ensure that this procedure is adhered
to within their own Department/Service. The responsibility for the execution of each step of this
procedure is identified in the right-hand column of 9. Procedure.

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, 2018. Reproduction is authorised provided the source is acknowledged.
4. Changes since last revision
This SOP has been updated to reflect organisational changes within the Agency, revision 1 of GVP
Module IX, the support provided by the Agency in relation to signals for nationally authorised products,
as well as various improvements to the process since the last revision.

5. Documents needed for this SOP

Best practice guidance on using PRAC plenary time efficiently and effectively
(PRAC/EMA/242096/2018)

EPITT User Guide (EMA/240784/2012)

EudraVigilance Data Analysis System (EVDAS) User manual (EMA/243244/2016)

Signal assessment report template

https://www.ema.europa.eu/documents/template-form/signal-assessment-report-template_en.doc

Signal assessment timetables

https://www.ema.europa.eu/documents/other/timetable-safety-signal-assessment-responses-request-
supplementary-information-rsi_en.pdf

Screening for adverse reactions in EudraVigilance

https://www.ema.europa.eu/documents/other/screening-adverse-reactions-eudravigilance_en.pdf

SOP/H/3382 - Handling of safety information from non-EEA regulatory authorities

SOP/H/3441 - Tracking and handling in SIAMED of SDA post-authorisation measures for centrally
authorised products

User Manual of the electronic Reaction Monitoring Report (eRMR) for National Competent Authorities
and EMA (EMA/746442/2017)

WIN/H/3268 - Maintenance of the Signal Detection tracking table

WIN/H/3287 – Validation of signals from the review of individual cases

WIN/H/3406 - Screening Electronic Reaction Monitoring Reports for new Signals

Supportive service guidance documents and templates:

 CAP + NAP signal process workflow (DREAM: Cabinets/14. Working areas/14.03 P-Division/03. P-
PE Activities/P-PE-SIM /Templates and guidances / PRAC communication templates and
instructions)

 Cover e-mail to PRAC Rapporteur when sending signal for confirmation (DREAM: Cabinets/14.
Working areas/14.03 P-Division/03. P-PE Activities/P-PE-SIM /Templates and guidances)

 Guidance on activities performed by Signal Leads while supporting the PRAC (DREAM: Cabinets/14.
Working areas/14.03 P-Division/03. P-PE Activities/P-PE-SIM /Templates and guidances)

 PRAC support workflow – Email templates (DREAM: Cabinets/14. Working areas/14.03 P-

Division/03. P-PE Activities/P-PE-SIM /Templates and guidances / PRAC communication templates
and instructions)

 PRAC support workflow guidance (DREAM: Cabinets/14. Working areas/14.03 P-Division/03. P-PE
Activities/P-PE-SIM /Templates and guidances / PRAC communication templates and instructions)

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 Publication of PRAC signal documents (DREAM: Cabinets/14. Working areas/14.03 P-Division/03.
P-PE Activities/P-PE-SIM /Templates and guidances / PRAC communication templates and
instructions)

 Signal AR redaction guideline (DREAM: Cabinets/14. Working areas/14.03 P-Division/03. P-PE

Activities/P-PE-SIM /Templates and guidances / PRAC communication templates and instructions)

 Signal description template (DREAM: Cabinets/14. Working areas/14.03 P-Division/03. P-PE

Activities/P-PE-SIM /Templates and guidances)

 Templates of communication to MAHs regarding signals (DREAM: Cabinets/14. Working

areas/14.03 P-Division/03. P-PE Activities/P-PE-SIM /Templates and guidances)

6. Related documents
Commission Implementing Regulation (EU) No 520/2012

Directive 2001/83/EC

Guideline on good pharmacovigilance practices (GVP) – Module IX – Signal management

https://www.ema.europa.eu/human-regulatory/post-authorisation/pharmacovigilance/good-
pharmacovigilance-practices

Addendum I – Methodological aspects of signal detection from spontaneous reports of suspected

adverse reactions
https://www.ema.europa.eu/human-regulatory/post-authorisation/pharmacovigilance/good-
pharmacovigilance-practices

Questions & answers on signal management

https://www.ema.europa.eu/documents/other/questions-answers-signal-management_en.pdf

Practical aspects of signal detection in pharmacovigilance. Report of CIOMS Working Group VIII

Regulation (EC) No 726/2004

WIN/H/3364 – Training for signal management leads

7. Definitions
Adverse reaction: According to Directive 2001/83/EC an adverse reaction is a response to a
medicinal product which is noxious and unintended.

Centrally Authorised Product (CAP): A medicinal product with a single marketing authorisation
issued by the European Commission and valid across the European Union.

DREAM (Documents Records Electronic Archive Management): electronic document management

system of the EMA.

Electronic Reaction Monitoring Report (eRMR): Report extracted from EudraVigilance which
provides an overview of the ICSRs transmitted to EV over a defined period of time. The eRMR contains
information on adverse drug reactions grouped according to the MedDRA hierarchy, per active
substance(s)/medicinal product(s) and allow filters and thresholds to be applied on several fields as
appropriate. Contents of the eRMR are further detailed in WIN/H/3406 - Screening Electronic Reaction
Monitoring Reports for new Signals.

EMA Product Lead (EPL): EMA staff member responsible for clinical and regulatory science input for
a given CAP from initial marketing authorisation and through post-authorisation.

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EPITT: European Pharmacovigilance Issues Tracking Tool. A database developed by the EMA to
promote the rapid communication of pharmacovigilance and risk management issues between the
EMA, all National Competent Authorities (NCAs) of the European Economic Area (EEA), the Committee
for Medicinal Products for Human use (CHMP), the Pharmacovigilance Risk Assessment Committee
(PRAC), the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human
[CMD(h)] and (Co-) Rapporteurs.

EudraVigilance (EV): the European data processing network and management system, which has
been developed according to internationally agreed standards and allows the EMA to manage the
electronic data exchange of Individual Case Safety Reports (ICSRs) and to support the
pharmacovigilance activities at Community level.

EudraVigilance data analysis system (EVDAS): component of EudraVigilance supporting EU

pharmacovigilance safety monitoring activities with a main focus on signal detection and evaluation of
ICSRs. EVDAS outputs in relation to pharmacovigilance include eRMRs, line listings of individual cases
of suspected adverse reactions and ICSR forms.

H-SD: EMA functional mailbox for signal management

Individual Case Safety Report (ICSR) form: output from EudraVigilance providing in a human
readable format those ICH-E2B(R3)1,2 data elements that are needed to assess individual case safety
reports.

Lead Member State for signal management: The Member State responsible for monitoring the
EudraVigilance database for an active substance or combination of active substances contained in
medicinal products authorised in more than one Member State through the national, mutual
recognition or decentralised procedures. The lead Member State shall validate and confirm signals on
behalf of the other Member States. If the active substance is authorised in only one Member State,
that Member State automatically assumes the responsibilities of the Lead Member State.

MedDRA: Medical Dictionary for Regulatory Activities.

MMD (Managing Meeting Document): system linked to DREAM and intending to support the
management of documents connected to EMA meetings.

NAP: nationally authorised medicinal product, including mutual recognition and decentralised
procedures

Peer-reviewers: signal management leads designated to review the conclusions for closed or
monitored signals. Two peer-reviewers are appointed every SVM week on a rota basis.

Periodic Safety Update Report (PSUR): Format and content for providing an evaluation of the risk-
benefit balance of a medicinal product for submission by the marketing authorisation holder at defined
time points during the post-authorisation phase. PSURs are defined in Module VII of the GVP.

Pharmacovigilance: The science and activities relating to the detection, assessment, understanding
and prevention of adverse effects or any other drug-related problems.

Pharmacovigilance Risk Assessment Committee (PRAC): Committee at the European Medicines

Agency responsible for assessing and monitoring safety issues related to medicines for human use.

1 The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) http://www.ich.org/
2 See ICH guideline E2B (R3) on electronic transmission of individual case safety reports (ICSRs) - data elements and

message specification - implementation guide

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PRAC rapporteur: Rapporteur appointed by the PRAC in the context of the centralised procedure.
Within the EU signal management process, the PRAC rapporteur is responsible for the confirmation of
signals concerning CAPs.

Risk Management Plan (RMP): Detailed description of a product’s risk management system. RMPs
are defined in Module V of the GVP.

SIAMED: EMA’s product information and application tracking system

Signal: Information that arises from one or multiple sources (including observation and experiments),
which suggests a new potentially causal association or a new aspect of a known association, between
an intervention and an event or set of related events, either adverse or beneficial, that is judged to be
of sufficient likelihood to justify verificatory action. In the context of signal detection in EV, only signals
related to adverse reactions are considered.

A potential signal is considered urgent if it may warrant expedited signal validation due to its potential
important impact on public health impact and/or on the benefit-risk profile of the medicinal product.

Signal confirmation: In the context of the EU signal management process (see GVP IX), process of
deciding whether or not a validated signal shall be transmitted to the PRAC for initial analysis and
prioritisation.

Signal detection tracking table: document where signals raised by SVT members are tracked with
their validation outcomes. See WIN/H/3268 - Maintenance of the Signal Detection tracking table.

Signal management lead (SML): P-PE member responsible for signal management activities related
to assigned medicinal products.

Signal tracking table: document where validated signals entered in EPITT (for both CAPs and NAPs)
are tracked from the confirmation step throughout PRAC evaluation.

Signal validation: Process of evaluating the data supporting the detected signal in order to verify that
the available documentation contains sufficient evidence demonstrating the existence of a new
potentially causal association or a new aspect of a known association, and therefore justifies further
analysis. General guidance on signal validation can be found in GVP IX, with more detailed instructions
in WIN/H/3287 - Validation of signals from the review of individual cases.

Signal validation meeting (SVM): Meeting of the SVT at which identified signals for substances
included in CAPs are discussed. SVMs take place three times a month. In addition, a meeting dedicated
to general scientific issues relevant to signal detection, or to organisational matters (ORGAM) is
organised once a month.

The chairperson of the SVM is the Service Head for Signal and Incident Management (P-PE-SIM), or, if
absent, a SML nominated by the P-PE-SIM Service Head.

SVMs are organised by P-PE-SIM assistants and usually take place on Thursday. Changes to the
schedule of SVM (cancellation, change of date or time, ad hoc meeting as necessary) may be proposed
by any SVT member and should be approved by the Chairperson and the P-PE-SIM assistant. All SMLs
should attend each meeting. In case a SML cannot attend a meeting, he/she should inform the P-PE-
SIM assistant, preferably before 12:00 noon on the day of the meeting, stating the reason for their
absence.

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Signal validation team (SVT): EMA team responsible for the detection and management of new
safety signals associated with the use of substances included in CAPs. The SVT includes:

 members of the P-PE-SIM service,

 other members of the P-PE department nominated by the Head of Department,

 other EMA staff member(s) as necessary.

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8. Process map(s)/ flow chart(s)

START

1.2. Retrieve
1.1. Identify or
confirmed signal
1. Screen eRMR receive signal from
originating from
other source
Member State

2.1. Inform SVT that 2. DECs

no DEC was No identified for
identified for review review? 1.2.1. Allocate to
SML

Yes

END 3. Send signal

notification
1.2.2. Enter signal in
signal tracking table

4. Update signal
detection tracking
table

Go to step 25.

5. Perform signal
validation

Go to step 6.

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 Continue from step 5.

6.1. Discuss with

6. Is signal
Yes service head and
urgent?
relevant colleagues

No

6.2. Is expedited
7. Circulate
No signal validation
validation report
required?

8. Update signal
detection tracking
table

9. Does the 9.1. Send closed/

signal require No monitored signals to
discussion? peer-reviewers

Yes 9.2. Review closed/

monitored signals

10. Circulate list of

9.3. Is discussion
signals to be Yes
required?
discussed

11. Present signal at

SVM

Yes

12. Is signal
validated?

Yes

13. Enter signal in

signal tracking table

No
No
14. Circulate draft
signal description
for internal
consultation

15. Update signal

detection tracking
table

Go to step 16.

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 Continue from step 15.

16. Circulate
minutes

17. Update eRMR

18. Is update of
signal
description
needed?

Yes

No 19. Update signal

description

20. Send signal

description to
service head / SVM
chair

21. Sign-off

22. Enter signal in

EPITT and send it to
PRAC Rapporteur

Go to step 23.

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 Continue from step 22.

23. Retrieve
confirmation
outcome

24.1 Include in
24. Is signal
update to PRAC No
confirmed?
members

Yes

24.2. Include in
communication to
25. Inform PRAC
QPPVs
secretariat
Continue from step
1.2.2.

24.3. Update signal 26. Include in

tracking table update to PRAC
members

27. Include in
communication to
END QPPVs

Go to step 28.

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 Continue from step 27.

28. Does signal

qualify for silent No
adoption?

Yes

28.1. Attend PRAC

29. Send draft PRAC
discussion
recommendation to
Rapporteur

28.2. Is direct
variation
Yes requested?
30. Send AR with
agreed
recommendation to Yes
all PRAC members
for silent adoption
28.3. Consult
MAH(s) on No
proposed wording

31. Is plenary
discussion
requested? 28.4. Send draft
PRAC
recommendation to
Rapporteur

No
28.5. Table AR for
adoption.

32. Table AR as 28.6. Attend PRAC

adopted. signal adoption slot

33. Update signal

tracking table

34. Send PRAC

recommendations
to CHMP and CMDh

Go to step 35.

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 Continue from step 34.

35. Is regulatory
action
recommended
for CAP(s)

Yes

No 36. CHMP
endorsement

37. Publish
recommendations
on EMA website

38.1. Request
38. Request for
38.1.1. Upload AR in for additional
No No additional data
EPITT data from other
from MAH(s)?
parties?

Yes Yes

END 39. Does the

38.2. Retrieve AR signal concern
CAPs?

Yes

40. Create entry in

38.3. Attend PRAC No SIAMED
discussion

38.4. Send draft 41. Redact AR for

PRAC confidential
recommendation to information
Rapporteur

42. Send AR
38.5. Table AR for including request to
adoption. MAH(s)

43. Is MAH
38.6. Attend PRAC 43.1. Reject
submission No
signal adoption slot submission
acceptable?

END

Go to step 38.7. Go to step 44.

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 Continue from step 38.6. Continue from step 43.

38.7. Table AR as 44. Retrieve AR

adopted

45. Redact AR for

confidential
38.8. Update signal information
tracking table

46. Send AR to
MAH(s) for
38.9. Send PRAC comments
recommendations
to CHMP and CMDh

47. Retrieve AR
38.10. Request
from additional
Yes
data from
MAH(s)?
Go to step 39.
No
48. Attend PRAC
38.11. Publish discussion
recommendations
on EMA website

49. Send draft PRAC

recommendation to
Rapporteur
38.12. Upload AR in
EPITT

50. Table AR for

adoption.

END

51. Attend PRAC

signal adoption slot

52. Table AR as
adopted

53. Update signal

tracking table

Go to step 54.

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 Continue from step 53.

54. Send PRAC

recommendations
to CHMP and CMDh

55. Is regulatory
action
recommended
for CAP(s)

Yes

No 56. CHMP
endorsement

57. Redact AR for

confidential
information

58. Send AR to
MAH(s)

59. Publish
recommendations
on EMA website

60. Does the

signal concern
CAP(s)?

Yes

61. Update SIAMED No

62. Upload AR in
EPITT

END

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9. Procedure
Step Action Responsibility

SIGNAL DETECTION AND VALIDATION

1. Screen electronic Reaction Monitoring Report. SML

As described in WIN/H/3406 - Screening Electronic Reaction

Monitoring Reports for new Signals.

Go to step 2.

1.1. Identify or receive potential signal from sources other than SML
EudraVigilance (e.g. literature, other regulatory authority,
emerging safety issue etc.)

Go to step 3.

Note: Handling of safety information from non-EEA regulatory

authorities is described in SOP/H/3382.

1.2. Retrieve signal validated and confirmed by Member State for Assistant
NAP(s) or CAP(s) from the H-SD / PRAC mailbox.

Go to step 1.2.1.

1.2.1. Assign SML for the signal. Service head

1.2.2. Enter signal in signal tracking table. Assistant

Go to step 25.

2. Is any drug-event combination (DEC) identified for further review? SML

If yes, go to step 3.

If not, go to step 2.1.

2.1 Send an e-mail to the H-SD mailbox stating that no DEC was SML
identified for further review for the reporting period.

End of procedure.

3. Send signal notification SML

Send the list of signals to be opened to the H-SD mailbox.

The notification of signals arising from the review of eRMRs is

described in WIN/H/3406 - Screening Electronic Reaction
Monitoring Reports for new Signals.

4. Update signal detection tracking table Assistant

As described in WIN/H/3268 - Maintenance of the Signal Detection

tracking table.

5. Perform signal validation SML

Review ICSR forms or Line Listings and other sources of

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 Step Action Responsibility

information, as relevant.

As described in WIN/H/3287 - Validation of signals from the review

of individual cases

Retrieval of line listings and ICSR forms is described in the EVDAS

User manual

6. Is the signal thought to be urgent? SML

If yes, go to step 6.1.

If not, go to step 7.

6.1. Discuss signal with service head and relevant colleagues as SML
applicable (e.g. EPL, regulatory affairs)

6.2. Is expedited signal validation required? SML / service head

Expedited validation should be considered if the signal cannot wait

until the next SVM.

If expedited validation is warranted, a draft signal description

should be circulated, go to step 14.

If the signal can be handled with standard timelines, go to step 7.

7. Circulate signal validation report SML

As described in WIN/H/3287 – Validation of signals from the review

of individual cases

8. Receive signal validation report and update signal detection Assistant

tracking table

As described in WIN/H/3268 - Maintenance of the Signal Detection

tracking table.

9. Does the signal require discussion? SML

If the SML concludes that the signal should be validated and/or

discussed at SVM, go to step 10.

If the SML concludes that the signal should be closed or monitored,

go to step 9.1.

Closed signals require no further immediate action. For monitored

signals, new cases reported to EudraVigilance should be reviewed
at a frequency determined by the SML.

See WIN/H/3406 - Screening Electronic Reaction Monitoring

Reports for new Signals for the handling of monitored signals when
screening Reaction Monitoring Reports.

9.1. Send proposed closed/monitored signals to peer-reviewers Assistant

Send extract of signal detection tracking table with signals to be

closed or monitored according to the SMLs to the designated peer-

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 Step Action Responsibility

reviewers, cc H-SD mailbox.

As described in WIN/H/3268 - Maintenance of the Signal Detection

tracking table.

9.2. Review proposed closed/monitored signals. Peer-reviewers

The two designated peer-reviewers review the conclusions for

closed and monitored signals and send comments, if applicable, to
individual SMLs, cc P-PE-SIM assistant and service head.

9.3. Is a discussion at SVM required? SML / peer-

reviewers
If comments raised during the peer-review warrant discussion at
SVM, inform P-PE-SIM assistant and go to step 10.

If not, go to step 15.

10. Send list of signals to be discussed at SVM (meeting agenda). Assistant

Prior to each SVM, the assistant sends an extract of the signal

detection tracking table with the signals to be discussed, including
those for which validation is proposed by the SML, together with
any presentation to the H-SD mailbox.

11. Present signal during SVM SML

The SML presents the information supporting the signal (e.g. EV

data, scientific literature, PSURs, RMP, regulatory procedures…)
together with proposed action(s).

As described in WIN/H/3287 – Validation of signal from the review

of individual cases.

12. Is the signal validated? SVT members

Based on the information presented by the SML, SVT members

discuss and agree on whether or not the signal is validated.

If yes, go to step 13.

If not, go to step 15.

Note: the SVT may also wish to see additional information before
making a decision and, if not already done, may request a more
formal and comprehensive presentation of the signal at the
following SVM, in which case steps 10 to 12 should be repeated.

13. Enter signal in signal tracking table. Assistant

14. Circulate draft signal description for internal consultation SML

A draft signal description is sent to H-SD and the EMA Product Lead
(EPL), copying the product shared mailbox(es), for comments. The
consultation period is in principle 2 working days, but may be
shortened in case of urgent signals. No response means agreement

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 Step Action Responsibility

with the signal description.

Note: a Word template replicating the EPITT signal description is

available for draft signal descriptions (see Section 5).

15. Update signal detection tracking table Assistant

As described in WIN/H/3268 - Maintenance of the Signal Detection

tracking table.

16. Send minutes to H-SD mailbox Assistant

As described in WIN/H/3268 - Maintenance of the Signal Detection

tracking table.

17. Update electronic Reaction Monitoring Report SML

Update the eRMR with the agreed action and conclusion for each
raised signal.

Follow WIN/H/3406 - Screening Electronic Reaction Monitoring

Reports for new Signals

18. Consider comments received from SVT members and EPL, as SML
applicable.

If an update of the signal description is required, go to step 19.

If no update is needed, go to step 20.

19. Update signal description taking into account comments received. SML

20. Send signal description to service head, or in their absence, to staff SML
member who chaired the SVM, copying the assistant.

Note: If controversial or numerous comments were made during

the consultation, the SML may be requested to provide an overview
of those, together with a brief explanation/justification of how they
have been addressed or not, as applicable.

21. Written sign-off by email within one working day provided by Service head /
service head or designated alternate, e.g. SML in charge of chairing SVM chair
relevant SVM.

For urgent signals, a shorter timeframe may apply.

22. Send signal description to PRAC rapporteur(s) SML

The SML enters the final signal description in EPITT and sends it by
e-mail to the PRAC rapporteur(s), copying:

- all PRAC members (using the PRAC functional mailbox: ‘All

Human Pharmacovigilance’),
- H-SD,
- the EPL,
- the product shared mailbox(es).

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 Step Action Responsibility

Follow EPITT User Guide.

A template for cover e-mails when sending signal descriptions to

PRAC rapporteurs is available (see section 5).

Note: if the signal is urgent, this should be clearly identified in the

subject of the e-mail.

SIGNAL CONFIRMATION

23. Monitor H-SD / PRAC mailbox and/or check EPITT, to retrieve the Assistant
outcome of the confirmation.

24. Is the signal confirmed? PRAC rapporteur /

Lead Member State
The PRAC rapporteur confirms or not the signal in EPITT within 30
days.

For confirmed signals, the rapporteur / Lead Member State

circulates a signal confirmation assessment report (AR) and
specifies whether or not the signal qualifies for silent adoption.

For non-confirmed signals, a justification should be included in

EPITT and circulated to all PRAC members.

If the signal is confirmed, go to step 25.

If the signal is not confirmed, go to step 24.1.

24.1. Include in list of signals extracted from EPITT circulated to PRAC Assistant
members prior to each PRAC meeting.

24.2. Include in list of non-confirmed signals circulated to all Qualified Assistant

Persons responsible for Pharmacovigilance (QPPVs) prior to each
PRAC meeting

24.3. Update signal tracking table. Assistant

End of procedure.

25. Inform PRAC secretariat. Assistant

The assistant liaises with the PRAC secretariat so that the

confirmed signal can be added to the PRAC agenda.

26. Include in list of signals extracted from EPITT circulated to PRAC Assistant
members prior to each PRAC meeting.

27. Include in advance notification to QPPVs regarding signals on PRAC Assistant

agenda.

SIGNAL ANALYSIS AND PRIORITISATION

28. Does the signal qualify for silent adoption? SML

Criteria for silent adoption are outlined in the ‘Best practice

guidance on using PRAC plenary time efficiently and effectively’.

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 Step Action Responsibility

If the signal qualifies for silent adoption, go to step 29.

If not, go to step 28.1.

28.1. Attend discussion on signal at PRAC plenary meeting. SML

28.2. Is a direct variation proposed? SML

In rare occurrences where PRAC recommends a variation without

first requesting data from the MAH(s), the MAH(s) should be
consulted on the proposed wording in an expedited manner; go to
step to step 28.3.

If not, go to step 28.4.

28.3. Send the proposed wording to the MAH(s). SML

MAH comments should be provided as soon as possible to allow for

finalisation of the PRAC recommendation during the meeting.

28.4. Send draft PRAC recommendation to PRAC rapporteur / (Lead) SML

Member State.

Guidance on PRAC recommendations is provided in ‘Guidance on

activities performed by Signal Leads while supporting the PRAC’.

28.5. Update assessment report if needed based on feedback from SML / assistant
rapporteur / (Lead) Member State and table it in MMD for adoption.

28.6. Attend PRAC plenary adoption slot for recommendations on signals Service head / SML
and update recommendation if needed.

Go to step 32.

29. Prepare and send draft PRAC recommendation to PRAC rapporteur SML
/ (Lead) Member State

The SML drafts the PRAC recommendation based on the proposal

outlined in the assessment report and sends it to the rapporteur /
(Lead) Member State for agreement. If required, the SML also
confirms with the rapporteur / (Lead) Member State that silent
adoption is appropriate.

Guidance on PRAC recommendations, including on the selection of

MAH(s) to be involved in procedure, is provided in ‘Guidance on
activities performed by Signal Leads while supporting the PRAC’.
Timetables for signal assessment are published on the EMA
website.

30. Send assessment report with agreed PRAC recommendation to all SML
PRAC members for silent adoption.

For signals related to NAPs, the proposed rapporteur for the signal
(usually the Member State that confirmed the signal) should also
be agreed at this stage.

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 Step Action Responsibility

The deadline for comments is usually the Friday preceding the

PRAC plenary meeting. In the absence of comments, the
recommendation is considered agreed.

31. Is plenary discussion requested by PRAC member(s)? PRAC member

If a PRAC member considers that plenary discussion is required, go

to step 28.1.

If not, go to step 32.

32. Table assessment report with PRAC recommendation (updated as SML / assistant
appropriate) in MMD as adopted.

33. Update signal tracking table. Assistant

34. Send PRAC recommendations on signals to CHMP and CMDh Assistant

members.

35. Is regulatory action recommended for CAP(s)? Assistant

For CAPs, requests for regulatory actions such as variations should

be formally endorsed by the CHMP, go to step 36.

If not, go to step 37.

36. The CHMP formally endorses the PRAC recommendation. CHMP / CHMP
secretariat
The signal is included on the agenda for the next CHMP meeting
and the recommendation is agreed via silent adoption.

37. Publish PRAC recommendations on EMA website. Assistant

The process for the publication of signal recommendations,

including translation of product information updates, is described in
the ‘Guidance on signal documents for publication’.

38. Are additional data requested from MAH(s) as part of the PRAC SML
recommendation?

If yes, go to step 39.

If not, go to step 38.1.

38.1. Are additional data requested from other parties? SML

If the PRAC recommendation includes questions addressed to e.g.

EMA, study authors etc., go to step 38.2.

If not, go to step 38.1.1.

38.1.1. Upload AR in EPITT Assistant

The signal procedure is considered closed when the signal is to be

further handled in another procedure (e.g. PSUR) or if routine
pharmacovigilance is considered sufficient.

End of procedure.

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 Step Action Responsibility

SIGNAL ASSESSMENT

38.2. Receives Rapporteur’s preliminary and updated assessment reports SML

on additional data or retrieve them from H-SD / PRAC mailbox.

38.3. Attend discussion on signal at PRAC plenary meeting. SML

38.4. Prepare and send draft PRAC recommendation to rapporteur. SML

38.5. Update assessment report if needed based on feedback from SML

rapporteur and table it in MMD for adoption.

38.6. Attend PRAC plenary adoption slot for recommendations on signals Service Head /
and update recommendation if needed. SML

38.7. Table assessment report with PRAC recommendation (updated as SML / assistant
appropriate) in MMD as adopted.

38.8. Update signal tracking table. Assistant

38.9. Send PRAC recommendations on signals to CHMP and CMDh Assistant

members.

38.10. Are additional data requested from MAH(s) as part of the PRAC SML
recommendation?

If yes, go to step 39.

If not, go to step 38.11.

38.11. Publish PRAC recommendations on EMA website. Assistant

38.12. Upload AR in EPITT Assistant

The signal procedure is considered closed when the signal is to be

further handled in another procedure (e.g. PSUR) or if routine
pharmacovigilance is considered sufficient.

End of procedure.

39. Are CAPs involved in the signal? Assistant

If yes, go to step 40.

If not, go to step 41.

40. Create an entry for the signal in SIAMED. Assistant

As described in SOP/H/3441 - Tracking and handling in SIAMED of

SDA post-authorisation measures for centrally authorised products.

41. Redact assessment report for confidential information. SML / assistant

As described in the ‘Signal AR redaction guideline’.

42. Send redacted assessment report, including PRAC request for Assistant
additional data to MAH(s).

43. Is MAH submission acceptable? SML / assistant

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 Step Action Responsibility

The assistant informs the SML that the MAH responses have been
received and should be checked. MAH submissions containing
revised annexes (dossier section 1.3.1.) should in principle be
rejected and resubmitted as variations.

If the submission is acceptable, go to step 44.

If not, go to step 43.1.

See SOP/H/3441 - Tracking and handling in SIAMED of SDA post-

authorisation measures for centrally authorised products.

43.1. Send rejection letter. Assistant

As described in SOP/H/3441 - Tracking and handling in SIAMED of

SDA post-authorisation measures for centrally authorised products.

44. Receive rapporteur’s preliminary assessment report on additional SML / assistant

data or retrieve it from the H-SD / PRAC mailbox.

45. Redact assessment report for confidential information. SML / assistant

As described in the ‘Signal AR redaction guideline’.

46. Send the redacted assessment report to MAH(s), stating the Assistant
deadline for comments.

47. Receive rapporteur’s updated assessment report or retrieve it from SML

the H-SD / PRAC mailbox.

48. Attend discussion on signal at PRAC plenary meeting. SML

49. Prepare and send draft PRAC recommendation to rapporteur. SML

50. Update assessment report if needed based on feedback from SML

rapporteur and table it in MMD for adoption.

51. Attend PRAC plenary adoption slot for recommendations on signals Service Head /
and update recommendation if needed. SML

52. Table assessment report with PRAC recommendation (updated as SML / assistant
appropriate) in MMD as adopted.

53. Update signal tracking table. Assistant

54. Send PRAC recommendations on signals to CHMP and CMDh Assistant

members.

55. Is regulatory action recommended for CAP(s)? Assistant

If yes, go to step 56.

If not, go to step 57.

56. Formal endorsement of PRAC recommendation. CHMP / CHMP

secretariat
The signal is included on the agenda for the next CHMP meeting
and the recommendation is agreed via silent adoption.

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 Step Action Responsibility

57. Redact assessment report for confidential information. SML / assistant

58. Send redacted assessment report to MAH(s). Assistant

59. Publish PRAC recommendations on EMA website. Assistant

60. Are CAPs involved in the signal? Assistant

If yes, go to step 61.

If not, go to step 62.

61. Update signal entry in SIAMED Assistant

As described in SOP/H/3441 - Tracking and handling in SIAMED of

SDA post-authorisation measures for centrally authorised products.

62. Upload assessment report in EPITT Assistant

End of procedure.

10. Records
 The Signal Detection Tracking Table called ‘SDMDB-IM_RM 2.xls’ is saved in DREAM: Cabinets/03.
Pharmacovigilance/PhV - Human/3.3 Signal detection activities/01 Signal detection tracking
tools/IM RM CAP list.

 The signal tracking table is saved in DREAM: Cabinets/03. Pharmacovigilance/PhV - Human/3.3

Signal detection activities/01 Signal detection tracking tools/IM RM CAP list.

 Signal Notifications are stored in electronic format in the mailbox Public Folders/All Public
Folders/Chrono In/EMAILS/H-SD

 Signal Validation Reports are stored in:

 the mailbox Public Folders/All Public Folders/Chrono In/EMAILS/H-SD

 DREAM: Cabinets/ 03. Pharmacovigilance/PhV - Human/3.3 Signal detection activities/03

Signal validation meeting/Intensively_Routinely Monitored Products/[Year]/[Month]/[Day]

 Signal descriptions of validated signals, justifications for non-confirmation and PRAC assessment
reports are stored in EPITT (fmp://fmapps3.eudra.org/EPITT.fmp12)

 Relevant documents on validated signals (e.g. further analyses, presentation, signal description…)
are archived in DREAM in the product folder in a dedicated subfolder (example: Cabinets/01.
Evaluation of Medicine/H-C/A-C/Abilify-000471/09 PHV/Signal Detection/[Signal X]).

 Relevant communications on validated signals concerning CAPs are stored in the product mailboxes.

 Electronic Reaction Monitoring Reports are named “IM or RM_[Name of SML]” and saved in DREAM:
Cabinets/03. Pharmacovigilance/PhV - Human/3.3 Signal detection activities/01 Signal detection
tracking tools/IM RM CAP list/eRMRs (IM or RM) since [date]

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