Work instructions
Title: Evaluation, validation, prioritisation and reporting signals from the review of CIOMS forms and
line listings
Applies to: Signal Validation Team in the Pharmacovigilance and Risk Management Sector
Status: PUBLIC
Document no.: WIN/H/3287
Lead Author
Approver
Effective Date: 15-SEP-11
Name: Gilles Touraille
Name: Peter Arlett
Review Date: 15-SEP-14
Signature: ON FILE
Signature: ON FILE
Supersedes:
WIN/H/3287 (08-MAR-2010)
Date: 14-SEP-11
Date: 14-SEP-11
TrackWise record no.: 3385
1. Changes since last revision
Update of the instructions for the validation and prioritisation of signals.
2. Records
The Signal Validation Reports are stored in electronic format in the mailbox Public Folders/Chrono
In/EMAILS/H-SD.
All validated signals are listed in the Signal Detection Tracking Table. This table is named “SDMBIM_RM
2.xls”
and
is
located
in
DREAM
in
“Cabinets\Old
EDMS
Structure\Operational
Units\Human\Post\PHVSE\H-Pharmacovigilance\Signal detection PhV and PASE\IM RM CAP list”.
3. Instructions
This WIN refers to the SOP/H/3065 – Periodic signal detection for centrally authorised
products based on reaction monitoring reports.
The objective of this WIN is to provide recommendations and instructions regarding the validation of
signals identified from the review of the Reaction Monitoring Report (RMR). WIN/H/3285 - Reviewing
reaction monitoring reports for new signals - provides guidance on how to identify signals in the RMR.
WIN/H/3406 - Screening electronic reaction monitoring reports for new Signals - should be consulted
for instructions on the use of the electronic RMR (e-RMR). The validation of signals is based on the
review of Line Listings or individual case safety reports (ICSRs). The review is performed by a member
of the Signal Validation Team (SVT) see SOP/H/3065).
7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom
Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416
E-mail [email protected] Website www.ema.europa.eu
An agency of the European Union
© European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged.
This WIN applies to both intensively and routinely monitored products.
It should be emphasised that the review of Line Listings and ICSRs aims to determine if, based on the
overall evaluation, the signal is validated and needs to be communicated to the Rapporteur. This
evaluation is based on clinical judgment and may require some degree of causality assessment of the
cases.
This WIN contains seven chapters:
I.
Source of information
II.
Reviewing Line Listings
III.
Reviewing ICSRs
IV.
Signal validation
V.
Signal prioritisation
VI.
Writing a signal evaluation report
VII.
Sending the report to the H-SD mailbox.
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 2/14
I. Source of information
Line Listings and ICSRs for the validation of signals are retrieved from EudraVigilance according
to WIN/H/3286 - Searching and Printing CIOMS forms and Line Listings.
A Line Listing contains the following information:
In the Header:


Name of the reviewer
Request made to the Signal Detection and Data Analysis (P-PV-SDA) secretary (e.g.
check cases)

MedDRA Preferred Term (PT) for the signal (e.g. Injection Site Abscess)

Active substance name

Medicinal product name (Optional)
In the Footer:

Frequency of monitoring of the concerned medicinal product : Intensively Monitored
(IM) or Routinely Monitored (RM) medicinal product
In the Table:

Case report identification number

Case version

Sender of the case

Report Type (spontaneous report, report from study, other, not available to sender)

EV Document Type (EVPM ICSRs, EVPM backlog ICSRs, EVPM Master ICSRs, PSUR
ICSRs, Master PMPSUR, as EVCTM ICSRs, EVCTM backlog ICSRs, ASR ICSRs, Master
CTICSR, Master CTASR)

Country of origin of the case

Gateway date of the case

Patient’s age

Patient’s birthdate

Patient’s gender

Whether the case is serious (Yes, No)

Whether the case is serious with a fatal outcome (Yes, No)

List of reported suspected, interacting, concomitant medicinal products

List of reported adverse reactions

List of recoded medicinal product name
In principle, the Line Listing always contains all the cases available in EudraVigilance. By
default the list is sorted in ascending order based on the gateway date. Different presentations
can be requested when submitting signal notification to the Signal Detection mail box (H-SD)
(see WIN 3285). When only a subset of the total number of cases has been requested (eg.
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 3/14
only the new cases or only cases reported since a certain date), these cases are highlighted or
shadowed.
The ICSRs corresponding to the requested signal are provided by default together with a Line
Listing, unless only the Line Listing has been requested (see WIN 3285). ICSRs are extracted
from EudraVigilance in the format defined by the Council for International Organizations of
Medical Sciences (CIOMS) - International Reporting of Adverse Drug Reactions - CIOMS I
reporting form (http://www.cioms.ch/cioms.pdf). Only CIOMS forms for cases to be reviewed
are provided.
II. Reviewing Line Listings
Line Listings provide an overview of a signal in terms of case identification, demographics,
fatality, associated medicinal products and associated adverse reactions. They are therefore
useful for an initial screening and filtering of the available cases.
They may be used to:

Identify other reported medicinal products that are known to be associated with the
suspected adverse reaction; for example, a signal of rhabdomyolysis may be explained
by concomitant intake of statins or by the occurrence of a drug-drug interaction;

Identify other reported MedDRA PTs, and explore whether the signal could be
associated to or caused by these other adverse reactions; for example, if CONVULSION
is a signal detected for a vaccine administered in children, the simultaneous reporting
of FEVER in the majority of cases suggests that the reports of convulsions may
correspond febrile convulsion and may not in itself represent a signal;

Identify whether the indication of the suspected medicinal product could be considered
as confounding factor; this is of importance if the medicinal product is authorised for
several indications in different therapeutic areas or if it is used in off label indications.

Get a first idea of the adverse reactions reported with a combination of terms;

Identify the age group of the population to which the product is prescribed (elderly,
children…);

Differentiate some routes of administration of specific interest for the suspected
medicinal product (e.g. topic or systemic);

Identify reports from healthcare professionals from non-healthcare professionals;

Identify the distribution of the period of reporting of the cases;

Identify duplicate cases.
For some signals, the review of the Line Listing may be sufficient to refute a signal. For others,
it allows to focus the review on a subset of cases, for example those in which there is no
identified confounding factors such as concomitant adverse reactions or medications. However,
the main limitation of Line Listings is that they do not allow to determine a temporal
relationship between the suspected medicinal product(s) and the
reaction(s).
suspected adverse
For example, it is not known whether the time to onset is compatible with the
suspected medicinal product mode of action, or whether other reported concomitant
medications were administered before, together or after the suspected medicinial product.
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 4/14
III. Reviewing ICSRs
The steps of the review of ICSRs include:

The identification of duplicates;

The review of the ICSRs for the clinical validation of the signal;

The determination of the causality assessment of the suspected medicinal product in
the ICSRs.
a. Identification of duplicates
When reviewing signals, it is important to exclude the duplicate reports. The duplicates can be
identified using the information on the patient, country of origin, reactions (nature and date of
occurrence), medicinal products and information contained in other fields in the ICSR (e.g.
narrative).
Duplication of reporting may occur in the following circumstances:

Copies of the same case with the same case report identification number have been
sent by the same company; these are initial and follow-up reports. The report received
on the most recent date should be kept.

The same case has been received from a National Competent Authority (NCA) and a
company. Check if the information is identical and check for possible differing causality
assessments.

Reports of the same case have been transmitted by different companies; this situation
may occur when the patient was exposed to several suspected medicinal products with
different Marketing Authorisation Holders (MAHs) and the case was reported by one or
several primary sources to the MAHs, all of them having the obligation to report the
case. Even if the patient and the adverse reactions are the same, each report should
be checked, as the available information may differ.

The case was identified in the literature and concerned a generic active substance or
several
medicinal
products for which several
MAHs have expedited
reporting
requirements.
b. Evaluation of ICSRs
A number of elements should be considered when evaluating the possible association between
the suspected medicinal product and the suspected adverse reaction:
i. Report:

Is the report appropriately documented?

Is a narrative available?

Does the narrative include sufficient information for an evaluation?
ii. Reporter:

Does the information originate from a healthcare professional?

If this is a consumer’s report, has the adverse reaction been confirmed by a healthcare
professional?
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 5/14
iii. Suspected active substance/medicinal product:

Is the medicinal product name available? Is the suspected medicinal product a
Centrally-Authorised Product (CAP)?

Are the dates of administration known? Is a precise start date specified?

Is the dosage sufficiently described, e.g. doses, route of administration, duration,
frequency?

Is the dosage in line with the Summary of Product Characteristics?

Is there any evidence of an overdose?
iv. Suspected adverse reaction:

Is the MedDRA term used to report the adverse reaction compatible with its
description?

Are the reported signs and symptoms compatible with the medical definition of the
diagnosis?

Does the report describe how the diagnosis was made? Was the diagnosis performed
according to standard medical practices?

Is there evidence that the suspect adverse reaction started after the initiation of the
suspected medicinal product?

Were differential diagnosis investigated? For example, for hepatitis, were viral tests
performed?

How was the suspected adverse reaction treated? Can the treatment and its outcome
contribute to confirming the diagnosis?
For example, a medical event cured by
antibiotics is more likely of infectious origin rather than drug induced.
v. Indication:

Is the indication specified?

Is the indication in line with the Summary of Product Characteristics (SPC)?

Is there any evidence of an off-label use?

Could the suspected adverse reaction be a consequence of or a complication to the
indication?
vi. Patient:

Age and gender: Is this information available? If so, are the age and gender compatible
with the suspected adverse reaction?

Could the age or gender of the patient be considered as triggering factor?

Is there an off-label use?
vii. Time relationship:

Did the first administration of the suspected medicinal product occur before the onset
of the suspected adverse reaction or signs/symptoms?

Is the time to onset (i.e. time from first suspected medicinal product intake to onset of
first symptoms or signs of the suspected adverse reaction) compatible with the patho-
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 6/14
physiological mechanism of occurrence of the suspected adverse reaction? For
example, if the adverse reaction is reported as anaphylactic reaction, did it occur within
minutes or hours after the start of the suspected medicinal product?
viii. Outcome:

What was the outcome of the suspected adverse reaction?

Was the suspected adverse reaction fatal?

Is this outcome compatible with what is known about the suspected adverse reaction?

If the suspected medicinal product was stopped (dechallenge), did the suspected
adverse reaction abate (positive dechallenge) or persist (negative dechallenge) without
corrective treatment?

If the suspected medicinal product was not stopped, did the adverse reaction abate or
persist, with or without corrective treatment?

If the suspected medicinal product was stopped and later restarted (rechallenge), did
the adverse reaction recur or aggravate when the product was re-administered under
the same conditions (positive rechallenge)?
ix. Concomitant disease(s):

Are there any concomitant underlying diseases?

Could these diseases have caused or aggravated the suspected adverse reaction and
be considered as alternative aetiology?
x. Concomitant medicinal products:

Was the patient taking other medicinal product(s) which are known to potentially
induce the suspected adverse reaction and which could be considered as confounder
factor?

Were these medicinal products started before the onset of the suspected adverse
reaction? Is the timing of administration compatible with an association with the
suspected adverse reaction?

Were these concomitant medicinal products stopped after the suspected adverse
reaction
occurred?
Were
they
restarted?
What
was
the
outcome
of
the
dechallenge/rechallenge?

Can the reaction be caused by an interaction between the co-suspected, interacting or
concomitant medicinal products? Is the suspected adverse reaction compatible with
this interaction? Are interactions mentioned in the SPC?

Does the available information point to a compatible mechanism of interaction between
the suspected and concomitant medicinal products?
xi. Biological and patho-physiological plausibility:

Is there a compatible biological or patho-physiological association between the
suspected medicinal product and the suspected adverse reaction?
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 7/14
c.
Causality assessment determination.
The time relationship is probably the only absolute criterion to be taken into account, as a
medicinal product could not be considered to have caused an event if its first administration
occurred after the onset of the adverse reaction. For this reason, it is important to look at the
date of occurrence of the first signs or symptoms of the adverse reaction. For example,
pulmonary hypertension is often diagnosed several weeks or months after the occurrence of
dyspnoea.
Based on the evaluation of the available information, the association between a suspected
medicinal product and a suspected adverse reaction or causality could be classified as follows,
according to the WHO-UMC classification as modified by GACVS ( 1,2 ):

Very likely/Certain: A clinical event occurring in a plausible time relationship to drug
administration, and which cannot be explained by concurrent disease or other drugs or
chemicals. The response to withdrawal of the drug (dechallenge) should be clinically
plausible. The event must be definitive pharmacologically or phenomenologically, using a
satisfactory rechallenge procedure if necessary.

Probable/Likely: A clinical event with a reasonable time sequence to drug administration,
and which is unlikely to be attributed to concurrent disease or other drugs or chemicals.
The
event
follows
a
clinically
reasonable
response
on
withdrawal
(dechallenge).
Rechallenge information is not required to fulfil this definition.

Possible: A clinical event with a reasonable time sequence to administrations of the drug,
but which could also be explained by concurrent disease or other drugs or chemicals.
Information on drug withdrawal may be lacking or unclear.

Unlikely: A clinical event whose time relationship to drug administration makes a causal
connection improbable, but which could be explained by an underlying disease or other
drugs or chemicals.

Unrelated: A clinical event with an incompatible time relationship and which could be
explained by underlying disease or other drugs or chemicals.

Unassessable/Unclassifiable:
A
clinical
event
with
insufficient
or
contradictory
information to permit assessment and identification of the cause.
For the purpose of signal validation, only the cases that are at least possibly related should be
considered. Cases with a probable or a very likely/certain relationship should be highlighted and
counted separately.
IV. Signal validation
A signal corresponds to “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” ( 3 ).
1
The Uppsala Monitoring Centre. WHO Collaborating Centre for International Drug Monitoring. Safety Monitoring of Medicinal
Products, Guidelines for setting up and running a Pharmacovigilance Centre, Uppsala, 2000 http://apps.who.int/medicinedocs/en/d/Jh2934e/
2
World-Health Organization. Adverse events following immunization (AEFI): causality assessment. http:/www.who.int/vaccinesdocuments/DocsPDF05/815.pdf.
3
Report of the CIOMS working group VIII, Practical Aspects of Signal Detection in Pharmacovigilance, Geneva 2010.
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 8/14
The concept of signal detection requires an evaluation of all the information available in the
ICSRs to determine whether a case series, less frequently one single case, which has raised
attention, can be validated as a signal. Once this step has been completed, the signal can
either be verified or remains indeterminate. The following elements should be taken into
consideration, as presented in the order of prioritisation, to determine whether a signal can be
considered as validated and should be transmitted to the Rapporteur for further verification:
a. Strength of the signal
i. There is a plausible temporal association in the majority of the reports with a compatible
time to onset in the occurrence of the suspected adverse reaction (including first signs or
symptoms) and the beginning of the suspected medicinal product.
ii. Some
clinically
relevant
positive
dechallenges
(without
corrective
treatment)
and
rechallenges are observed with compatible time intervals.
iii. A sufficient number of the cases do not present confounding factors such as co-morbidities,
co-medications, patients’ ages or environmental conditions.
iv. The signal is detected from noteworthy findings in the ICSRs submitted either as solicited or
spontaneous reports.
v. The reported signs and symptoms and the performed tests are compatible with the medical
definition and practices.
vi. There is a clear causal pharmacological, biological or pharmacokinetic link between the
suspected adverse reaction and the administration of the suspected medicinal product.
vii. A dose relationship is observed in several of the reported ICSRs.
viii. Some consistency is observed in the reported cases regarding the pattern of symptoms.
b. Novelty of the signal
i. Some clinical or non-clinical similar findings were observed during the development of the
medicinal product. This requires searching in the (Co-) Rapporteur’s assessment reports of
the initial opinion for the granting of the marketing authorisation whether the issue was
already identified in other areas of the development of the medicinal product.
ii. The suspected adverse reaction has also been described in relevant scientific articles in
relation to the suspected medicinal product (or active substance(s)), or medicinal products
of the same therapeutic class.
iii. The suspected adverse reaction is already listed in third countries product information.
V. Signal Prioritisation
Once the signal has been validated by the SVT, the following priority criteria should be applied,
in accordance with the WIN H/3288 - Using EPITT for Signal Management by the Signal
Validation Team - when communicating it to the Rapporteur (Co-) for its verification:
a. Important impact on public health:
This represents the highest level of urgency requiring immediate attention of the (Co-)
Rapporteur. The severity of the suspected adverse reaction modifies the benefit-risk balance
of the suspected medicinal product. The signal may lead to Rapid Alert or initiation of
Incident Management and may result in the introduction of Urgent Safety Restrictions or
suspension of the marketing authorisation of the medicinal product.
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 9/14
E.g. A number of the ICSRs reports a fatal outcome for the suspected adverse reaction,
which can not be related to the indication of the suspected medicinal product or to the
patients’ co-morbidities.
b. Potentially important impact on public health:
This is a medium level of urgency, which requires attention of the (Co-) Rapporteur in a
short term. It may trigger an ad-hoc evaluation by the CHMP, a Non Urgent Information
(NUI), the submission of a variation application within a short period of time and/or a
communication to health care professionals.
E.g. there is an identifiable patients group at higher risk of occurrence of the suspected
adverse reaction or with a risk of more severe adverse reaction. The suspected adverse
reaction could have a medical significance and an impact on public health or on the public
perception of the safety of the suspected medicinal product. The physio-pathological
mechanisms of occurrence of the suspected adverse reaction highlight the possibility of
implementation of preventive or risk minimisation measures, which necessitate an update of
the SPC.
c.
Serious unexpected adverse reactions that are likely to need labelling changes:
This characterises a low level of urgency. It concerns an identifiable signal of unexpected
serious adverse reaction that is reasonably well documented and worthy for further
verification by the Rapporteur (Co-). It may lead to labelling change through a variation.
The assessment may be managed through normal regulatory procedures such as PSUR
assessment.
E.g. Signal adds new information or changes the current available information of the safety
profile of the suspected medicinal product.
VI. Writing a signal evaluation report
For each signal evaluation, a short report should be written and sent to the H-SD mailbox.
The report should include three sections:
a.
Conclusion (including the proposed action)
b.
Case review
c.
additional evidence from other regulatory procedures and bibliography
a. Conclusion
The validator should identify, extract and summarise in the conclusion the core information
that justifies the reason of the proposed action. The conclusion will be included in the Signal
Detection Tracking table and needs to be concise. The conclusion should indicate:
i. The proposed action:
•
Signal closed (there is no signal or no further immediate action is needed).
•
Signal closed but requires follow-up (FU) (if some follow-up other than
monitoring is required (e.g. check next PSUR submission…), the nature of the
follow-up is clearly mentioned in the tracking table and the issue is flagged as
“Closed+FU”)
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 10/14
•
Signal monitored (this issue might represent a signal, but the available
information is currently limited (e.g. there are a small number of cases); new
cases reported to EudraVigilance will need to be evaluated).
•
Signal ongoing (further analyses or verifications are required before a
conclusion can be reached. The signal is rediscussed at the next relevant SVM).
•
Signal validated - Rapporteur needs to be informed (a proposal for a
regulatory action to be performed by the Rapporteur with the appropriate
timeframe should be suggested, e.g. cumulative review to be requested in next
PSUR).
ii. The total number of cases and the number of valid cases (eliminating duplicates, cases
lacking information, cases related to non-CAPs and other non-relevant cases, which
should not be broken down by reason for lack of validity).
iii. Relevant information supporting the proposed action (eg. alternative diagnosis, selected
case information, class effect, biological plausibility, literature, PSUR, SPC, RMP).
The following information should normally not be provided in the conclusion: details on nonvalid cases, ID numbers, demographic information (age and gender except if relevant),
outcomes and corrective treatments (unless relevant to understand the issue), history and
details of symptoms. If needed, the conclusion can be further explained in the case review.
In order to facilitate the work of the P-PV-SDA secretaries and the population of the Signal
Detection Tracking Table, it is recommended to separate the conclusion from the case review.
When only a cumulative overview of the ICSRs is provided, the conclusion and the overview
can be merged.
b. Case review
The extent of information to be provided in the case review is left to each SVT Member and will
generally depend on a number of factors, including the number of ICSRs to be reviewed,
previous evaluation of the same signal, severity of the signal, need for providing a
documentation of the cases to the Rapporteur, anticipated request for further information, etc.
Some signals may require a description of each ICSR, while an overview will be sufficient for
others. An overview will also be presented if only the Line Listing has been reviewed. Another
option is to describe only a subset of the cases, e.g. illustrative cases or cases with particular
severity.
The ICSRs reference numbers should always be indicated in order to avoid duplication of work
if further evaluation of the same signal is needed.
i. Cumulative overview of ICSRs:
The report should indicate the number of ICSRs reviewed, the date of the review and a
summary of the causality assessment of the suspected medicinal product for all the ICSRs
reviewed. This is to allow keeping track of this issue for a possible future re-evaluation.
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 11/14
Example of cumulative overview of ICSRs:
Signal: Substance X and cataract operation
There are 12 unique cases. All of them refer to patients treated with Product Y in oncology
indications. The cataract was not a primary concern in these reports, rather an incidental
finding. Half of the reports are coming from attorney in form of a class action Civil Complaint
due to Reaction W. There are plenty of contributory factors to cataract, given the age,
underlying
disease,
concomitant
chronic
corticoids,
chemotherapy,
oxygen
therapy
(hyperbaric). In some cases, the operation seemed to be rather a medical history rather than
an adverse reaction. 4 cases are unassessable (ICSRs Ref. Numb.), 2 are unrelated (ICSRs
Ref. Numb.) and 6 are unlikely (ICSRs Ref. Numb.). No new signal.
ii. Concise description of each ICSR:
It may provide further supportive evidence for the conclusion expressed by the SVT
Member. It is also useful if a further review of the same signal is anticipated, in order to
identify the cases already evaluated. Only relevant information for the evaluation of the
signal should be included in the case description. The following information may be useful
(but may not be necessary for all cases, with the exception of the ICSR reference number)
in the description of the individual cases:

ICSR reference number

Source of information (e.g. publication, health professional, consumer); if case series
from same article the total number of similar cases issued from the same source
should be provided,

Solicited or spontaneous report

Age and gender

Relevant information on the suspected medicinal product exposure (e.g. vaccine dose)
and its indication

Time to onset between the initiation of the suspected medicinal product and the
occurrence of the suspected adverse reaction

Method of diagnosis confirming the adverse reaction (if relevant e.g. skin biopsy for
Steven Johnson Syndrome)

Adverse reaction outcome, dechallenge (without corrective treatment) and rechallenge
information

Relevant concomitant medicinal products, and their time relationship to the suspected
medicinal product and the adverse reaction

Relevant concomitant diseases

Other factors that may be associated with the occurrence of the adverse reaction

Autopsy results if performed
The following information is NOT particularly useful:

Exact dates of medicinal product administration, unless seasonality is an important
factor
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 12/14

Detailed laboratory values, diagnostic methods and results of investigations, unless
relevant for the evaluation of the signal and confirmation of the adverse reaction

Non relevant past drug histories and medical histories

Complications of the adverse reaction

Non relevant concomitant medications or co-morbidities

Treatment of the suspected adverse reaction, unless the treatment provides useful
information about the adverse reaction itself (e.g. antibiotics).
Example of the individual review of each ICSRs:
Signal: Product A and Sudden death
- Case Ref. Numb.: 16F with type I diabetes mellitus who experienced pulmonary embolus and
died from cardiopulmonary collapse (autopsy findings) about three weeks after receiving
Product A. Causality: Possible
- Case Ref. Numb.: 18F who collapsed on the evening of the 3rd Product A dose, and died after
3 hours of reanimation. She had had a dental surgery about 2-3 weeks ago. Autopsy findings:
no sign of anaphylactic reaction, sepsis or inflammatory reasons, e.g. due to dental surgery.
Toxicological investigations did not find that the death was caused by any pharmacological
substance. All results of molecular genetic analyses were negative. No cause of death could be
established. Causality: Probable
- Case Ref. Numb. duplicate of Case Ref. Numb.: 19F died suddenly 10 days after receiving
Product A and meningococcal vaccine. She had complained of a headache and not feeling well
in the 24 hours prior to her death. No history of epilepsy, substance abuse, alcohol intake,
depression or mental health issue. No autopsy performed. Causality: Possible
- Case Ref. Numb.: 18F with overweight (120 kg), concomitant oral contraceptive and
smoking, who experienced sudden brutal cephalalgia and died despite cardiopulmonary
resuscitation, about 3 months after Product A. Autopsy did not find signs of pulmonary
embolism, myocardial infarction or meningeal or cerebral haemorrhage. Causality: Possible
- Case Ref. Numb: 20F with concomitant psychologic fragility and treated with Substance B,
Substance C, Substance D and oral contraceptive, who received Product A. She presented
hyperthermia and developed a malaise three days later. Two days later, she presented a
malaise again and developed cardiorespiratory arrest; she was diagnosed with arrhythmia and
atrial fibrillation; she was transferred to intensive care unit where she presented with bilateral
mydriasis, hypothermia, cyanosis and pneumopathy of right middle pulmonary lobe. She
developed multiorgan failure and died despite cardiopulmonary by-pass. HIV and other
serologies were negative. Autopsy performed but results not available. Causality: Possible
c.
Additional information from other relevant regulatory procedures and bibliography
The signal description should include a status of the information relating to the signal in other
(relevant) procedures, when applicable.
The signal description should also be accompanied by a review of relevant scientific literature
aimed at providing additional evidence (e.g. from clinical trials) in favour or against the
presence of a signal or convincing mechanistic evidence (e.g. validated pharmacodynamic
effect, pharmacokinetic information).
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 13/14
VII. Sending the report to the H-SD mailbox
The signal evaluation report should be sent by email to the H-SD mailbox. In order to retrieve
previously evaluated signals, the Subject field of the email should be populated as followed:
a. For intensively-monitored products:
PRODUCT NAME-signal-IM-date of Signal Validation Meeting (SVM) where the signal will be
discussed.
b. For routinely-monitored products:
PRODUCT NAME-signal-RM-date of SVM where the signal will be discussed.
Example :
MEDICINAL PRODUCT A-thrombocytopenia-IM-05032009
As the sorting function of the H-SD mailbox is case sensitive, retrieval of signals is facilitated
by using uniform rules for writing the email subject, with capital letters for the medicinal
product name and lower case letters for the signal. The medicinal product name may be
replaced by the active substance name as relevant.
The signal evaluation report may be copied in the message field of the email or included as an
attached document.
If the report is a follow-up or an update (i.e.: contains the reply from the Rapporteur) of a
previously evaluated signal, it may be practical to update the previous email in order to create
a single message containing cumulative information. In this situation, the Forward function of
the initial report could be used to send the updated version to the H-SD mailbox. The message
Object should then be modified by deleting the “Fw:” text and updating the date of the SVM
(indicating the date of the meeting when the updated signal will be discussed).
To ensure that the conclusion recorded in the tracking table are accurate and to
facilitate the work of the P-PV-SDA Secretary the Conclusion section with the
proposed action should be presented at the top of the e-mail.
Work instructions – PUBLIC
WIN/H/3287, 15-SEP-11
Page 14/14