Work instructions
Title: Screening electronic reaction monitoring reports (eRMR) for new signals
Applies to: Scientific Administrators in the Signal Detection and Data Analysis Section,
Pharmacovigilance and Risk Management Sector
Status: PUBLIC
Document no.: WIN/H/3406
Lead Author
Approver
Effective Date: 19-SEP-12
Name: Cosimo Zaccaria
Name: Georgy Genov
Review Date: 19-SEP-15
Signature: ON FILE
Signature: ON FILE
Supersedes:
N/A
Date: 14-SEP-12
Date: 17-SEP-12
TrackWise record no.: 3379
1. Changes since last revision
New WIN.
2. Records
•
The non-formatted eRMR to be produced with the new data corresponding to the period of interest
(called the ‘reference period’ throughout this document) and saved in DREAM by a Data manager
of the Data Collection and Management (P-PV-DCM) section. The folder contains one file for each
Signal Validation Team (SVT) member. The files are named:

For every 2 weeks monitored products (IM): IM Name of validator version - date.XLS

For once-monthly monitored products (RM): RM Name of validator version - date.XLS
and saved in DREAM in the following location: Cabinets/13. Projects/EudraVigilance - NEW
STRUCTURE/Pharmacovigilance/Data Analysis/SAS analysis/Signal Validation Team - Reaction
Monitoring Reports/eRMR_SDA
•
The formatted Excel file to be used for the review of the ADRs reported (called the “Excel eRMR”
throughout this document) named:

For every 2 weeks monitored products (IM): “IM_Name of validator.xls”

For once-monthly monitored products (RM): “RM_Name of validator.xls”.
7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom
Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416
E-mail info@ema.europa.eu Website www.ema.europa.eu
An agency of the European Union
© European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
and saved in DREAM in the following location: “Cabinets\Old EDMS Structure\Operational
Units\Human\Post\PHVSE\H-Pharmacovigilance\Signal detection PhV and PASE\IM RM CAP
list\eRMRs since May 2011”
•
Signal Notifications sent by each SVT member are stored in electronic format in the mailbox: Public
Folder/Chrono In/EMAILS/H-SD (H-SD)
•
All signals are listed in the Signal Detection Tracking Table named “SDMB-IM_RM 2.xls” which is
located in DREAM in: “Cabinets\Old EDMS Structure\Operational Units\Human\Post\PHVSE\HPharmacovigilance\Signal detection PhV and PASE\IM RM CAP list”.
3. Instructions
This WIN provides a guidance on how to screen the eRMR and refers to:

SOP/H/3065 - Periodic signal detection for centrally authorised products based on reaction
monitoring reports - which states that the screening of the eRMR is performed by SVT
members.

WIN/H/3287 – Evaluation, validation, prioritisation, and reporting signals from the review of
CIOMS forms and line listings - after identification of signals screening the Reaction Monitoring
Report.
This WIN also provides instructions on how to send Signal Notifications in a standardised format to HSD mailbox for validation.
These instructions are applicable to once-monthly monitored (RM), every 2 weeks monitored (IM)
products and weekly monitored products in special situation (i.e. pandemic)
This WIN consists of six individual chapters:
I.
I.
Excel eRMR File management
II.
Structure of the Excel eRMR file
III.
Structure of the eRMR worksheet
IV.
Screening the eRMR
V.
Validation of new signals
VI.
Guidance for key activities in screening the eRMR
VII.
Processes in place in case of SVT member’s absence
Excel eRMR File Management
As described in SOP/H/3243 – Creation of the reaction monitoring reports for signal detection activities
eRMRs are generated by the P-PV-DCM section and forwarded by the Data Manager to the H-SD
mailbox on Wednesday of the week preceding the Signal Validation Meeting (SVM) for IM or RM
products. The SDA secretariat saves and imports the eRMR on behalf of SVT member following the
steps described below:
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1. Receiving the eRMR
When the new eRMRs are created by P-PV-DCM, an e-mail is sent to H-SD by the P-PV-DCM
manager. The message contains the locator to the folder in DREAM which contains all nonformatted eRMRs. The updated eRMRs include the new cases received in EudraVigilance during
the reference period (mentioned in the subject of the email). In case of a technical problem,
the Data Manager informs H-SD of the delay.
2. Importing the eRMRs in DREAM
SDA secretariat imports for each SVT member the non-formatted eRMRs in the formatted Excel
eRMR file saved in DREAM and then the files are all checked-in to be unlocked. Once the files
are prepared the SDA secretariat sends an e-mail to all SVT members and lets them know that
the Excel eRMRs files are ready for the screening.
3. Check-out and Check–in the Excel eRMR file in DREAM
Each SVT member checks-out the eRMR file in DREAM for editing. Once the screening is
finalised the SVT member checks-in the Excel eRMR file in DREAM. It is a good DREAM practice
and it is advisable that SVT members keep the Excel eRMR files checked-in while not working
on them to avoid any inconvenience in case of an absence.
4. Exporting the eRMRs in G:drive
The SDA secretariat sends the reminders via Outlook to each SVT member specifying by when
all Excel eRMR files have to be checked-in for the update (usually a day before P-PV-DCM
produces the new eRMR which is on a Monday, except when the Monday is a EMA holiday).
SDA secretariat double-checks whether or not all files are checked-in in DREAM; if this is not
the case, the SDA secretariat re-contacts the concerned SVT members with a new reminder.
Once all Excel eRMRs files are checked-in, the SDA secretariat saves them on the G:drive and
locks them out to prevent any editing while they are being updated.
II.
Structure of the eRMR
The Excel eRMR file is a formatted Excel file which contains 4 different worksheets named:
1. ‘eRMR’: contains ICSRs historically submitted to EV plus new ICSRs submitted during the
reference period.
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2. ‘EVDAS’: contains hyperlinks to the standard EVDAS simplified queries to support signal
detection activities such as direct access to electronic line listings, calculation of the dynamic
Proportional Reporting Ratio (PRR) etc.
3. ‘Drug info’: this worksheet is automatically updated every 6 months. It is populated with the
most used information related to a given active substance, as follows:
a.
Active substance
b.
Medicine name
c.
ATC code
d.
Marketing Authorisation Holder
e.
Status : authorised/withdrawn/suspended
f.
Authorisation date
g.
Indication
h.
Classification : conditional approval / exceptional circumstances / orphan / generic /
biosimilar
i.
EPAR: (optional) direct hyperlink to the latest SmPC published on the EMA website (manual
entry is required)
j.
PSUR-AR: (optional) direct hyperlink to the latest PSUR- assessment report (AR) in DREAM
(manual entry is required)
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4.
‘Legend’: contains the full list of SMQs (according to the latest version of MedDRA) sorted by
alphabetic order with the related acronyms and the legend for all drop-list menus.
III.
Structure of the ‘eRMR’ worksheet
The ‘eRMR’ worksheet is used to perform the screening of new potential signals or to check whether a
risk for a specific drug-event combination has changed. It allows a comparison between the reference
period and the cumulative history of all ICSRs submitted to EV (total) for a given active substance (or
combination of active substances).
The figures displayed in the columns of the eRMR are computed from the EudraVigilance PostAuthorisation Module (EVPM) and the EudraVigilance Clinical Trials Module (EVCTM).
Data in EVPM include reports classified as EVPM ICSRs 1, EVPM backlog ICSRs 2, EVPM Master ICSRs 3,
PSUR ICSRs 4, Master PMPSUR 5.
1
ICSRs transmitted to the EudraVigilance Post-Authorisation Module (EVPM)
2
ICSRs transmitted retrospectively to EVPM
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Data in EVCTM include reports classified as EVCTM ICSRs 6, EVCTM backlog ICSRs, ASR ICSRs 7, Master
CTICSR 8, Master CTASR 9.
The structure of the eRMR is as follows:
A.
‘PT Code’: MedDRA Preferred Term Code. These codes are used only for the production of the
eRMR and the column can be hidden;
B.
‘Active Substances’: This column contains the active substances (or combination of active
substances) allocated to each SVT member;
C.
‘SOCs’: MedDRA System Organ Class classification;
D.
‘HLGTs’: MedDRA High Group Level Term classification;
E.
‘HLTs’: MedDRA High Level Term classification;
F.
‘SMQ Narrow’: Standardised MedDRA Query (narrow) classification. This column contains:
a.
Empty cells when the MedDRA PT is not associated with any SMQ;
b.
One single SMQ per cell when the MedDRA PT is associated with one unique SMQ;
c.
Different SMQs in one single cell when the MedDRA PT belongs to more than one SMQ (the
different SMQs are separated by ‘ -- ‘).
G.
‘SMQ Broad’: Standardised MedDRA Query (broad) classification. This column is organised as
above for the SMQ narrow.
H.
‘PTs’: MedDRA Preferred Terms classification;
I.
‘IME/DME’: This column indicates “Important Medical Events” and “Designated Medical Events”;
J.
‘New EV’: Number of new cases received in EVPM and EVCTM for the concerned drug-event
combination during the reference period;
K.
‘Tot EV’: Total number of cases received in EVPM and EVCTM for the concerned drug-event
combination, including the reference period;
The columns from “L. New Fatal” to ‘Y. Tot Serious’ refer to the number of cases received in EVPM
and EVCT:
L.
‘New Fatal’: Number of fatal 10 cases received for the concerned drug-event combination during
the reference period;
3
Master ICSRs created after duplicate detection, transmitted to EVPM
4
ICSRs from Periodic Safety Update Reports transmitted to the EVPM
5
Master ICSRs from PSURs created after duplicate detection, transmitted to EVPM
ICSRs transmitted to the EudraVigilance Clinical Trial module (EVCTM)
6
7
8
ICSRs from Annual Safety Reports transmitted to the EVCTM
Master ICSRs created after duplicate detection, transmitted to EVCTM
9
Master ICSRs from Annual Safety Reports created after duplicate detection, transmitted to the EVCTM
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M.
‘Total Fatal’: Total number of fatal cases received for the concerned drug-event combination,
including the reference period. When the number of fatal cases is ≥ 1 the font automatically turns
red;
N.
‘New Med Err/Abus’: Number of cases received for the concerned drug-event combination
during the reference period and reported with at least one reaction contained in the ad-hoc SMQ
‘Medication Error/Abuse’. The ad-hoc SMQ is reported in the worksheet ‘Legend’ and contains the
following MedDRA PTs:
O.
a.
HLGT ‘Medication error’;
b.
Selected MedDRA PTs of the SMQ ‘Depression and suicide/self-injury’;
c.
Selected MedDRA PTs of the SMQ ‘Drug Abuse, dependence and withdrawal’;
‘Tot Med Err/Abus’: Total number of cases received for the concerned drug-event combination,
including the reference period and reported with at least one reaction contained in the ad-hoc
SMQ ‘Medication Error/Abuse’.
P.
‘New Paed’: Number of cases referring to patients aged < 18 years old and received for the
concerned drug-event combination during the reference period;
Q.
‘Total Paed’: Total number of cases referring to patients aged < 18 years old and received for
the concerned drug-event combination, including the reference period;
R.
‘New Geriatr’: Number of cases referring to patients aged > 65 years old and received for the
concerned drug-event combination during the reference period;
S.
‘Total Geriatr’: Total number of cases referring to patients aged > 65 years old and received for
the concerned drug-event combination, including the reference period;
T.
New EEA: Number of cases originating from the European Economic Area (EEA) 11 and received
for the concerned drug-event combination during the reference period;
U.
‘Total EEA’: Total number of cases originating from the EEA and received for the concerned drugevent combination, including the reference period;
V.
‘New HCP’: Number of cases originating from a Health Care Professional (HCP) 12 and received for
the concerned drug-event combination during the reference period;
W.
‘Total HCP’: Total number of cases originating from a HCP and received for the concerned drugevent combination, including the reference period;
X.
‘New Serious’: Number of cases reported as ‘Serious’ 13 and received for the concerned drugevent combination during the reference period;
10
A case is considered fatal if either the E2B field A.1.5.2 (Result in Death) has the value ‘Yes’ or the E2B field B.2.i.8
(Outcome) has the value ‘Fatal’
11
A case is considered originated from the European Economic Area if the E2B field A.1.1 (Primary Source Country) has a
country belonging to the European Economic Area (EEA)
12
A case is considered originated from a Health Care Professional if the E2B field A.2.1.4 (Qualification) has at least one of
the following values: ‘Physician’, ‘Pharmacist’ or ‘Other health professional’
13
A case is considered serious if the E2B field A.1.5.1 (Serious) has the value ‘Yes’
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Y.
‘Total Serious’: Total number of cases reported as ‘Serious’ and received for the concerned
drug-event combination, including the reference period;
Z.
‘New Spontaneous’: Number of spontaneous cases received in EVPM (including report types ‘not
available to sender (unknown)’ and ‘others’) for the concerned drug-event combination during the
reference period; this number does not include the new reports from observational studies (see
column AK. ‘New Obs’);
AA. ‘Total Spontaneous’: Total number of spontaneous cases received in EVPM (including report
type ‘not available to sender (unknown)’ and ‘others’) for the concerned drug-event combination,
including the reference period; this number does not include reports from observational studies
(see column AL. ‘Tot Obs’)
Note that:
• this number is used for the calculation of the ‘PRR’ and the ‘SDR’ columns;
AB. ‘PRR (-)’: 95% confidence interval lower bound of the PRR for the concerned drug-event
combination using all other drug-event combinations available in the database as reference. When
the SDR criterion is met 14, the cell is automatically highlighted in red;
AC. ‘PRR’: value of the Proportional Reporting Ratio (PRR) for the concerned drug-event combination,
using all other drug-events combination available in the database as reference;
AD. ‘Priority’: this column groups together filters belonging to the column ‘Changes’, ‘IME/DME’,
‘Paediatric’ and ‘SDR’. It facilitates the selection of drug-event combinations according to three
mutually-exclusive priority levels defined as follows:
b. Priority 1: highest priority. It indicates drug-event combinations received in the reference
period classified as DME;
c. Priority 2: It indicates drug-event combinations received in the reference period (not included
in the priority 1) classified as IME with an SDR;
d. Priority 3: It indicates drug-event combinations received in the reference period (not included
in the priority 1 and 2) with a fatal outcome as well as paediatric or parent-child reports.
AE. ‘Changes’: column that indicates all drug-event combinations for which new ICSRs (initial or
follow-up) were received in both EVPM and EVCT module during the reference period. By selecting
one of the values in the drop-down list, 3 different filters can be applied:
• “New”: drug-event combinations appearing in EV for the first time ;
• “Increased”: drug-event combination with an increased number of cases in the column ‘Tot EV’
or for which a follow-up report was received since the previous eRMR;
• “Increased fatal”: drug-event combinations with an increased number of fatal cases or for
which a follow-up for a fatal case has been received;
14
The Statistics of Disproportionate Reporting is calculated differently according to the periodicity of the eRMR. For biweekly eRMRs (IM) the criterion is met when the number of spontaneous cases is > 3 and the PRR (-) is > 1. For monthly
eRMRs (RM) the criterion is met when the number of spontaneous cases is > 5 and PRR (-) is > 1.
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AF. ‘SDR’: column that allows identifying drug-event combinations with a signal of disproportionate
reporting i.e. PRR (-) > 1 with 3 or more spontaneous cases for IM products, 5 or more
spontaneous cases for RM products. When these criteria are met, the term “SDR (n)” appears in
the column where ‘n’ is the number of instances the drug-event combination was recognised as an
SDR;
AG. ‘Signal Status’: This filter allows the SVT member qualifying a drug-event combination. Only the
following terms can be used:
•
Listed: MedDRA PT reported in the SmPC (section 4.8) for at least one brand name of a
concerned active substance. This entry is automatically updated every 6 months and it
concerns Centrally Authorised Products (CAPs) only.
•
US: MedDRA PT which is listed in the United States Prescribing Information (US-PI) of a
concerned active substance. This optional entry is manual.
•
Linked: MedDRA PT linked to another MedDRA PT already qualified in the column ‘Signal
Status’ as a validated signal or ‘Listed’. (See chapter IV: ‘how to link different MedDRA PTs’).
•
Ongoing: MedDRA PT under review from a previous screening of the eRMR.
•
Closed: MedDRA PT closed according to the decision at the Signal Validation Meeting (SVM).
This should be followed by populating the column ‘Comment’ with the conclusion sent to HSD.
•
Monitor: MedDRA PT under monitoring according to the decision at the SVM. This should be
followed by populating the column ‘Comment’ with the conclusion sent to H-SD.
•
PSUR: MedDRA PT monitored in PSURs and acknowledged as such by the Rapporteur. This
should be followed by populating the column ‘Comments’ with the Rapporteur’s conclusion of
the PSUR-AR.
•
RMP: MedDRA PT included in the Risk Management Plan as Identified or Potential Risk. This
entry is manual until the validated Annex 1 of the RMP will be automatically implemented.
•
Disease: MedDRA PT which is considered to be part of the underlying disease / indication;
•
Other: MedDRA PT flagged as Priority 1, 2 or 3 but according to the SVT member’s judgement
a review of the cases is unlikely to substantiate the signal.
•
Check: when none of the above-mentioned filters is applicable and therefore a review of the
cases / line listing is expected. This should be followed by populating the column ‘Comments’
with the date and the action expected (e.g. review of cases / line listing).
AH. ‘Comments’: General comments filled in by the SVT member as free text after qualifying a
MedDRA PT using the abovementioned filters options in the column ‘Signal Status’. (See chapter
VI: ‘how to populate the column comment’)
AI. ‘New Lit’: Number of cases originating from literature reports received in EV for the concerned
drug-event combinations during the reference period. When the number of cases is > 1 in the
column ‘New Lit’ the cell is automatically highlighted in blue;
AJ. ‘Tot Lit’: Total number of cases originating from literature reports received in EV (EVPM and
EVCTM) for the concerned drug-event combination including the reference period;
AK. ‘New Obs’: Number of cases originating from solicited reports received in EVPM for the concerned
drug-event combination during the reference period. (These cases are not included in the ‘New
Spontaneous’ cases);
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AL. ‘Tot Obs’: Total number of cases from solicited reports received in EVPM for the concerned drugevent combination including the reference period. (These cases are not included in the ‘Total
Spontaneous’ cases nor in the calculation of the PRR);
AM. ‘New CT’: Number of cases originating from interventional clinical trials received in EVCTM for
the concerned drug-event combination during reference period;
AN. ‘Total CT’: Total number of cases originating from interventional clinical trials received in EVCTM
for the concerned drug-event combination including the reference period. (These cases are not
included in the calculation of the PRR);
AO. ‘RoA 1’: Name of the most frequently reported route of administration for the concerned drugevent combination;
AP. ‘New RoA1’: Number of cases received in EV for the concerned drug-event combination and the
most frequently reported route of administration during the reference period;
AQ. ‘Tot RoA1’: Total number of cases received in EV for the concerned drug-event combination and
the most frequently reported route of administration, including the reference period;
The columns from ‘AR. Roa2’ to ‘AW.Tot RoA3’ (which are named ‘RoA2’, ‘New RoA2’, ‘Tot RoA2’,
‘RoA3’, ‘New RoA3’ and ‘Tot RoA3’) contain the second and the third most frequently reported
route of administrations for the concerned drug-event combination;
AX. ‘New RoA (n/a)’: Number of cases received in EV for the concerned drug-event combination in
which the route of administration was unknown (‘unk’) or missing (‘n.a.’) during the reference
period;
AY. ‘Tot RoA (n/a)’: Total number of cases received in EV for the concerned drug-event combination
in which the route of administration was unknown (‘unk’) or missing (‘n.a.’), including the
reference period;
AZ. ‘Brand Name 1’: Corresponding to the CAP 1. The column ‘Brand name 1’ contains the brand
name reported the most frequently;
BA. ‘New Brand 1’: Number of cases received in EV during the reference period for the concerned
brand name and the corresponding MedDRA PT;
BB. ‘Tot Brand 1’: Total number of cases received in EV for the concerned brand name and the
corresponding MedDRA PT including the reference period;
BC. ‘PRR(-) Brand 1: 95% confidence interval lower bound of the PRR for the concerned brand name
and the corresponding MedDRA PT, using all other brand names and all other MedDRA PTs
available in the database as reference. When the SDR criterion is met (see footnote 14 page 9),
the cell is automatically highlighted in red;
BD. ‘Freq SPC Brand 1’: as reported in the SmPC in 4.8 for the concerned brand name, when
available;
BE. ‘Brand Name (n)’: columns repeated as from AZ to BD according to the number of brand names
authorised in the EEA under the same active substance; the columns ‘Brand name (n)’ are sorted
following a decreasing order of reporting.
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IV.
Screening the eRMR
1. Step I = CHECKING-OUT THE EXCEL eRMR FILE: following the email sent-out by the SDA
secretariat (informing that the Excel eRMRs files are updated and ready for the screening) checkout the file in DREAM;
2. Step II = SELECTING THE REACTION MONITORING REPORT: to select the reaction monitor report
for the period of interest set the filters on not ‘Blanks’ in the column “Changes”, this filter shows all
drug-event combinations received during the reference period.
3. Step III = CHECKING MONITORED ISSUE: in the column “Signal Status” set the filters on
‘Monitor’ to double-check whether or not there are new cases or follow-ups related to the drugevent combination under monitoring. If this is the case replace the status ‘Monitor’ by ‘Check’
which means that only new cases will be reviewed. As a general principle each drug-event
combination marked as monitored in the column “Signal Status” should be replaced by ‘Check’ for
the review of any new case unless it is specified in the column “Comments” that a Follow-up in the
upcoming PSUR is expected.
4. Step IV = SCREENING DMEs: in the column named ‘Priority’, set the filter on ‘Pr1’ in order to
display all drug-event combinations classified with the highest level of priority (DMEs). Each DME
shall be either assigned a ‘Signal Status’ by selecting one of the available filter options (described
in chapter III) or justification for not assigning a ‘Signal Status’ shall be provided in the column
‘Comment’ (e.g. review when additional cases become available). THIS IS A MANDATORY STEP
FOR ALL eRMRs.
5. Step V= SCREENING THE REMAINING MedDRA PTs: in the column ‘Priority’ set the filters on ‘Pr2’
and ‘Pr3’ to perform the screening of the remaining drug-event combinations not included in step
IV. Investigation and justification of the MedDRA PTs classified with these two priority levels are
based on SVT member’s clinical judgement.
6. Step VI = TRANSMISSION OF SIGNAL NOTIFICATION TO H-SD: When the filter ‘Check’ is
applicable a review of the cases is expected specifying in the column “Comments” whether the
review of the cases or the line listing is needed. Set the filter on ‘Check’ in the column “Signal
Status” to select all drug-event combinations for which further investigation is required. If the
signal was previously reviewed specify in the column ‘Comments’ that only the review of new cases
is needed. Select the area of the table which includes all columns between ‘Active substance’ and
‘Comments’; copy and paste in an email to be sent to H-SD. In order to facilitate the work of the
SDA secretariat and the retrieval of messages, indicate in the Subject of the email: Signals - SVT
member’s name - RM or IM – Reference period.
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7. Step VII = UPDATING THE eRMR: after the SVM, update the eRMR in line with the conclusions
adopted for the concerned signals. The column “Signal Status” should reflect the decision taken at
the meeting using the filters ‘Closed’, ‘Monitor’ or ‘Rapp’. The column “Comments” should reflect
the conclusion sent to H-SD in the report.
8. Step VIII = CHECKING-IN THE eRMR IN DREAM: save the Excel eRMR file and check it in.
N.B. Identification of signals should be based on all available information which can be visualised
by selecting in the Menu bar: [Sort&Clear  Clear]. Judgment should be exercised and
information of clinical relevance should be identified, even if it does not represent an IME/DME or
a SDR.
V.
Validation of new signals
Once new signals have been identified, their validation is a matter of clinical judgment and the
following elements should be considered:
1. Clinical relevance
i. Severity of the reaction and its outcome: Depending on the suspected medicinal product and the
concerned adverse reaction, reactions leading to a fatal outcome or irreversible serious reactions
should be considered in priority for inclusion in the list of signals to be validated; unless there is a
suspected relationship with the underlying disease or if this outcome is already mentioned in the
product information.
ii. Novelty of the reaction: New and (medically) serious reactions should be reviewed, as well as
new aspects of a known issue. DMEs or events of special interest that are known to be rare,
serious, and highly attributable to drugs should be considered in priority as signals to be validated.
This is irrespective of the statistical criteria, or whether there is a high degree of biological
plausibility (for example an anaphylactic shock, or a toxic epidermal necrolysis).
iii. Clinical context: The reaction PT should always be considered in the broader context of a
possible drug-induced toxicity or more complex syndrome (e.g. interval QT prolonged may suggest
the occurrence of torsades de pointe, hepatitis may suggest the occurrence of other types of liver
injuries, JC virus infection may reflect the occurrence of progressive multifocal
leukoencephalopathy). The SVT member should (1) check in EudraVigilance whether other case
reports involving relevant terms associated with the syndrome or the system organ class have
previously been transmitted to EudraVigilance and, if this is the case, (2) assess whether these
clinical entities should be included in the signal identification process.
iv. Potential for drug-drug interactions: medicinal products susceptible to induce clinically relevant
drug-drug interactions should be subject of a specific, targeted monitoring. The (co)-suspected
medications could be checked for these medicinal products in the line listing.
v. Reactions in special populations, eg. paediatrics
vi. Events related to the indication of the medicinal product (e.g. thrombosis following an antithrombotic agent) should not, in principle, be considered as signal unless cases of lack of efficacy or
loss of efficacy need to be investigated.
2. Previous awareness
i. In principle, an adverse reaction which is already listed in section 4.4 or 4.8 of the Summary of
Product Characteristic (SPC) or which has already been assessed by the CHMP / Rapporteur in the
PSURs or RMP, does not represent a new signal. However, it may qualify as such if its apparent
frequency of reporting, its temporal persistence, its severity, or change in the outcome or reported
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fatality rate, suggests a new information as compared to the data included in the SPC or previously
assessed by the Rapporteur.
ii. The European Pharmacovigilance Issues Tracking Tool (EPITT) should be checked to verify if a
signal has already been addressed within the EU regulatory network.
iii. The SVT Member should also verify whether there is new information available from the MAH, or
recent decisions (e.g. request of additional information or ongoing type II variation) taken by the
Rapporteur or the CHMP, already addressing the signal. This can be done by searching in the
Product Cabinet in DREAM, in SIAMED or by enquiring with the Product Team Leader (PTL).
i.v. The granularity effect of the medical dictionaries utilised for data coding and the variability of
the terms employed among healthcare professionals to characterise the same symptoms or
diagnoses should be considered when appraising the novelty of a signal. The concerned safety issue
could well be reported under several distinctive PTs and included in the SPC as a more general term
as it is often the case for hepatic reactions or hypersensitivity for example.
v. If an adverse reaction is a monitored signal in the Signal Detection Tracking Table for a specific
active substance or medicinal product, every new case should in principle be appraised until the
signal has been closed.
3. Statistical criteria
i. In principle, a minimum of at least 3 (for IM) or 5 (for RM) spontaneous cases should have been
reported to EudraVigilance in order to consider the adverse reaction of interest as a signal. The
number of new cases should also be considered if the signal has already been reviewed and
included in the Signal Detection Tracking Table. This threshold may not apply for some reactions
(eg. anaphylactic shock) or for orphan drugs.
ii. A PRR (-) > 1 and 3 (for IM), 5 (for RM) or more reports defines a signal of disproportionate
reporting. In this case it simply expresses a higher reporting than expected of the adverse reaction
for the active substance of interest compared to all other active substances in the database.
iii. The disproportionality analyses are performed on spontaneous reporting system databases and
therefore are affected by the same strengths and weaknesses (including the therapeutic area in
which the medicinal product is used, the variability of use across countries of the medicinal product,
or the strong reporting association of the concerned adverse reaction with another medicinal
product (masking effect)). Various biases or reporting artefacts may affect the value of the PRR and
generate false positives or false negatives. Therefore, the absence of a Signal of Disproportionate
Reporting (SDR) does not necessarily exclude the possibility of a causal association between the
concerned medicinal product and the adverse reaction. Alternatively a high SDR does not always
reflect a causal association between a medicinal product and the adverse reaction.
VI.
1.
Guidance for key activities in screening the eRMR
How to select the Reaction Monitor Report
To display the reaction monitor report for the reference period use the ‘eRMR’ worksheet:
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The “eRMR” worksheet contains the Cumulative Summary Table of ADRs for the concerned active
substance (or combination of active substances) since the first ICSRs was received in EV. To display the
cases received during the reference period, select the column “Changes” and set the filters on not
’Blanks’. The eRMR will display all reports received during the period of interest for the three categories:
‘new’, ‘increased fatal’ and ‘increased’. The figures showed on the bottom left corner of the worksheet
are the number of ADRs received in the eRMR (which need to be screened) and the total number of
ADRs received in EV:
2.
How to group and ungroup columns
The eRMR contains many columns. To better organise the information in the eRMR and to simplify its
review it is possible to visualise only the columns which the SVT member is interested in. By default
the visualisation can be done as follow:
•
To ungroup and visualize all columns belonging to a specific category click on the symbol
above the header:
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•
To group again the columns click on the symbol
above the header:
The grouping and ungrouping of columns can be customised according to the preferences of the
SVT member or it can be deleted to allow the visualisation of the full categories: in Excel the
options are on the Data tab located in the Ribbon, under the Group or Ungroup button located in
the Outline Group.
3.
How to prioritise the review of drug-event combination without using the Column
‘Priority’
Grouping of drug-event combinations by applying filters allows the screening to focus on specific
types of ADRs. After displaying the reaction monitor report the following could be selected:
•
Pr1/Pr2/Pr3: the column ‘Priority’ groups together the filters that are applicable in the following
columns: ‘IME/IME’, ‘Changes’, ‘SDR’, ‘Fatal’, ‘Paediatric’. To select the priority of interest:
•
DME/IME = in the column “IME/DME” un-tick the filter ‘Ime’ and ‘Blank’ to select designated
medical events only and press ‘ok’:
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To prioritise by important medical event only, un-tick ‘Dme’ and ‘Blanks’ and keep ticked ‘Ime’
and ‘Ime/Dme’ and press ‘ok’. To select both ‘Ime’ and ‘Dme’ keep un-ticked only ‘Blanks’ and
press ‘ok’.
•
New ADRs = set the filter on ‘New’ in the column “Changes”. The eRMR will only show drugevent combinations which are appearing for the first time in EV in the column ‘Tot EV’:
•
Increased fatal ADRs = set the filter on ‘Increased fatal’ in the column “Changes”. Apply this
filter to select all drug-event combinations with a fatal outcome or for which a follow-up for a
fatal report has been received during the reference period;
•
Increased ADRs = set the filter on ‘Increased’ in the column “Changes” to select all drug-event
combinations with an increase in number of cases or with a new follow-up report received in
the reference period;
•
SDR = in the column “SDR” un-tick the filter ‘Blanks’ and press ‘ok’; the eRMR will show
automatically all drug-event combinations which have reached an SDR in the eRMR. This filter
can be combined with ‘Ime’ to prioritise by important medical event with an SDR:
•
Customised thresholds: in the column “Tot Spontaneous” or in any other column named “Tot…”
set the filter to display ADRs received with a minimum number of cases in EV:
[‘Number filter’ - > select ‘greater than or equal to’ and type a number for your threshold for
instance ‘5’ in the field option - > ok]
A simple way to do so is to un-tick all values which are not of interest in the column named
‘Tot…’:
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•
Brand names: The columns concerning brand names are useful when there is more than one
brand name centrally authorised for the same active substance. To filter by a specific brand
name un-tick the value ‘blanks’ in the column “Brand name” of interest:
If the eRMR is set on the reference period (using the column ‘Changes’ as shown above) it will
show only drug-event combinations received for the concerned brand name during the
reference period. In case you also want to display the historical submitted in EV keep the filter
in the column ‘brand name’ and tick ‘Select all’ in the column ‘Changes’.
4. How to filter by new literature reports received in EV
To group all MedDRA PTs for which there has been at least one literature case reported in EV
during the reference period, follow the step below:
a) [Un-tick the value ‘0’ in the column ‘New Lit’].
b) [Press ok]
The eRMR will show all new literature reports and the cell will automatically turn blue when the
value is > then 1:
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This approach can be used in any column named “New …” such as “New serious”, “New CT”, “New
Obs” etc. to select all new cases received under a specific category during the period of interest.
The column ‘New Lit’ is also useful during the screening of signals under monitoring (or closed) to
double-check whether or not new evidence is coming from the literature during the reference
period.
5. How to release all filters
Filters should be applied with caution in order to avoid missing relevant information.
To go back and visualise the totality of the data, select in the Menu bar [Sort&Filter ->Clear] as
shown below:
6.
Comparison of ‘Totals’:
The columns reporting the totals of each category allows a comparison with the total number of
cases received in EV (‘Tot EV’). To compare totals:
[Hide all columns containing “New …” and leave all columns containing “Tot… “]
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The eRMR will show for the concerned drug combination event the proportion of
fatal/paediatric/geriatric/serious/HCP etc cases against the Total number of cases received in EV.
7. How to extend a search and display information at the level of the SOC/HLGT/HLT
It may be useful to extend the search following the broader structure of MedDRA in order to show
all drug-event combinations reported historically in EV at different MedDRA levels. This allows
obtaining a wider overview of the issue under investigation as follow:
For example, extend at the level of the SOC:
a) Release all filter in the eRMR and identify the drug-event combination of interest. (The MedDRA
PTs under investigations are easily retrievable filtering by ‘Check’ in the column ‘Signal Status’:
b) Filter by the correspondent active substance and SOC to which the MedDRA PT belongs to:
The eRMR will show all MedDRA PTs reported in EV at the level of the SOC selected. The same
steps can be followed to filter at the level of the HLGT and HLT in the related columns.
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This functionality is useful to have a broader overview of the information included in the eRMR
such as SmPC, PSUR, RMP, previous review etc. when looking for possible explanations (links)
for a concerned drug-event combination. Justifying and linking MedDRA PTs at different
MedDRA level in the eRMR increase knowledge overtime facilitating future reviews.
8.
How to filter by SMQ when the MedDRA PT belongs to different SMQs
This step is necessary when the MedDRA PT is associated with more than one SMQ.
To filter by the SMQ of interest and include all MedDRA PTs:
[select the filter in the column ‘SMQ narrow’  type the name of the SMQ and press ‘ok’ ]
9.
How to link different MedDRA PTs
The availability of Signal Status in the eRMR allows linking MedDRA PTs. An example is proposed
below:
a) Identify a drug-event combination that requires further investigation
b) Extend the search at the level of the ‘SOC’ (as described above) and display the information
reported in the eRMR;
c) Release the filter in the column ‘Signal Status’ and check the listedness for the concerned
active substance.
d) Link the MedDRA PT of concern to any MedDRA PT either validated as a signal or listed in
the SmPC. A MedDRA PT may be linked to another MedDRA PT when the latter has been
already qualified in the column “Signal Status” as ‘listed’ or as ‘Rapp’ and covers the former
term according to the SVT member’s clinical judgment. For instance ‘suicidal ideation’ may be
linked to ‘completed suicide’ as shown below in the example as it covers a more severe medical
concept:
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10. How to populate the column ‘COMMENTS’ after the SVT meeting:
The column ‘Signal Status’ allows several filter options as described in chapter III. This column
should be populated with free text according to the status of the signal as it appears in the column
‘Signal Status’ and it should reflect the conclusion adopted at the SVM for each reviewed signal.
To facilitate future reviews, when the signal is to be closed/monitored it is convenient to populate
as follows:
•
‘date’ using the option [control+;] for the automatic entry of the today date);
•
Total number of cases reviewed
•
Total number of cases assessed as valid by the SVT member (i.e. unique cases, sufficiently
documented etc.)
•
Brief description of the signal as reported in the conclusion sent to H-SD
For signals which need to be monitored or followed-up in the upcoming PSUR-AR, populate the
column “Signal Status” with ‘Monitor’ and report in the column ‘Comments’ the conclusion sent to
H-SD. Specify ‘FU-PSUR’ if the signal has to be followed-up in the upcoming PSUR-AR:
11. How to display Listedness
The listedness of a concerned product is shown in the column “Signal Status”. This information is
updated automatically every six months by the P-PV-DCM manager. In order to display the
listedness of an active substance, follow the steps below:
a) Clear all filters in the eRMR;
b) Select the active substance of interest from the column “Active substance”;
c) Set the filter ‘Listed’ in the column “Signal Status”. This is the simple way to show the listed
reaction in the SmPC for the active substance of interest.
For a given active substance the MedDRA PT is marked automatically as ‘Listed’ in the column
“Signal Status” when there is at least one brand name with the concerned MedDRA PT listed in the
SmPC. To check in which brand name the MedDRA PT has been listed check the column
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“Frequency”. If the cell in the column “Frequency” is populated it means that the MedDRA PT of
interest is reported in the SmPC of the concerned brand name.
12. How to review changes in the risk:
Tracking all sources of information in the eRMR (i.e. recording outcomes of assessments, importing
listedness from the SmPC, PSUR and RMP potential risks) allows comparing new information
received with the previous knowledge gathered in the eRMR. This could be useful when the safety
profile may have significantly changed during the reference period. It is possible to ‘re-open’
signals previously assessed as ‘Closed’ by replacing the filter by ‘Check’ in the column ‘Signal
status’ meaning that a review of the new cases received since last assessment is expected. To
check whether or not the risk has changed since last screening of the eRMR some criteria may be
applied such as:
•
‘Seriousness’: checking the number of cases in the column ‘Total fatal’ compared to the ‘Tot
spontaneous’ / ‘Tot EV’.
•
‘New Evidence’: checking whether there are new cases in the column ‘New Lit’ meaning that
new publications may strengthen the evidence of a signal assessed as ‘closed’/’monitor’.
•
‘Disproportionality at the level of the Brand Name’: when the PRR (-) calculated at the level of
the brand name is > 1 the cell automatically turns red. This may indicate an increase in
reporting or change in the risk for the concerned product-event combination / route of
administration / indication.
The same principle can be applied reviewing the RMP information entered in the eRMR, in particular
for ‘potential risks’.
VII.
Processes in place in case of SVT member’s absence
This process applies when the SVT member is absent for one or more weeks. The SDA secretariat
saves in DREAM on a weekly basis the updated version of the Excel eRMR file sent to H-SD by the PPV-DCM manager. When the SVT member is absent during the review of a specific eRMR the retrieval
of previous versions is possible following one of the two options below:
1. Retrieval from DREAM = the SVT member visualises and selects from DREAM the version of
interest that needs to be screened.
[Right-click on the Excel eRMR File -> View -> Versions-> Select the version of interest]
2. Retrieval from email: prior to the absence, the SVT member informs the SDA secretariat
specifying which version of the Excel eRMR File has to be sent as an attachment by email.
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When the Excel eRMR File is updated in DREAM with the new data, the SDA secretariat then
sends an email to the absent SVT member with the attached version requested.
Once the SVT member is back, the different Excel eRMR File versions are retrieved and the screening
should be done separately. These versions can also be printed for the review on paper as follow:
[Select the area of interest -> file -> print area -> set print area -> control + p]
In order to report both ‘signal status’ and related ‘comments’ to the latest version of Excel eRMR saved
in DREAM, update it with the results obtained from the screening of the previous version/s of the
eRMR/s.
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