Download GUIDE TO INDIVIDUAL CASE SAFETY REPORTING

JUNE 2015
GUIDE TO INDIVIDUAL CASE
SAFETY REPORTING
Guide to industry
GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
Guide to industry
© Danish Health and Medicines Authority, 2015
This publication may be freely cited with a clear indication that
the text comes from the Danish Health and Medicines Authority.
You are not allowed to reuse photos from this publication.
Danish Health and Medicines Authority
Axel Heides Gade 1
2300 Copenhagen S
dhma.dk
Keywords
E2B, ICSR, ADR
Language
English
Version
1.0
Version date
June 2015
Published by
Danish Health and Medicines Authority
CONTENTS
1
2
Introduction
Background
2.1 Background
2.2 References
2.3 Feedback
3 Valid adverse drug reaction
4 Reporting requirements
4.1 Reporting requirements
4.2 Creating one or more individual cases
4.3 Reporting of overdose, abuse, misuse, off-label use and occupational
exposure
4.4 Reporting of medication errors
4.5 Reports of lack of efficacy
4.6 Product complaints
5 ICSR submission based on cases received from DHMA
6 ICSR submissions based on cases received directly from other
companies
7 General data entry guidance
8 Patient characteristics
9 Drug information
9.1 Drug information
9.2 Additional drug information
9.3 Drug dosage
9.4 Pharmaceutical form
9.5 Route of administration and parent administration route
9.6 Indication
9.7 Dates
9.8 Action taken with drug
10 Reaction information
10.1 MedDRA
10.2 Reaction outcomes
10.3 Adverse drug reactions versus adverse events
10.4 Withdrawal reaction classification
10.5 Reaction occurring at multiple body sites
10.6 Duplication of reaction terms
10.6.1 Drug interactions
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
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10.6.2 Definitive and provisional diagnosis with signs and symptoms
10.6.3 Other patient outcomes
10.6.4 No adverse effect
10.6.5 Product substitution
10.6.6 Unexpected benefit
Case narrative
Test results
Fatal reactions
13.1 Reports of death
13.2 Patient death details
Reports of drug exposure during pregnancy
14.1 Reports of drug exposure during pregnancy
14.2 Parent-child reports
14.3 Pregnancy with contraceptive medicines
Literature reports
Reporter details
Administrative information
17.1 Worldwide unique case identification number and senders safety report
unique identifier
17.2 Report type
17.3 Seriousness criteria and medically confirmed selection
17.4 Duplicates and nullifications
17.5 Dates
17.6 Follow-up reports
17.7 Sender and receiver details
Appendix 1 – Abbreviations
Appendix 2 – Useful webpages
Appendix 3 – Glossary
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1
INTRODUCTION
WHO defines Pharmacovigilance (PV) as “the science and activities
relating to the detection, assessment, understanding and prevention of
adverse effects or any other drug-related problem.”
The reporting of adverse drug reactions (ADR) is a cornerstone in the post-marketing
surveillance of medicines. Accurate and structured collection of information on ADRs is
important to support accurate detection and analysis of drug safety signals. From the
analysis and assessment of such signals, we gain an understanding of ADRs and thereby
have the possibility to communicate knowledge about ADRs and possibly prevent ADRs.
Industry and authorities need to work together to ensure that the high quality of electronic
reports is maintained. By way of electronic transmission, ADR reports from industry are
transmitted directly into the Danish Health and Medicines Authority (DHMA) ADR database
and therefore it is essential to use a common understanding and methodology for best
practice in coding and data classification.
Based on experience over the last five years since the implementation of the current
database, DHMA has identified a need for a ‘Best Practice’ guide to the reporting of
Individual Case Safety Reports (ICSRs) using the E2B standard. This guide aims to
remove the various differences that occur in reporting when companies use different
classification and coding practices. The guide also provides guidance on other topics that
we have identified as problem areas or reasons for dispute and ambiguity.
We hope the guide will contribute to delivering high standards in ADR reporting by
providing direction and specific examples of good practice in this area.
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2
BACKGROUND
2.1 BACKGROUND
Electronic exchange of information on suspected ADR reports between regulators and
industry allows the data to be made immediately available for qualitative signal detection
and evaluation. The E2B standard ensures that this information is easily transferred and
facilitates uniformity and high quality with regard to the content and format of ICSRs.
At DHMA, the procedure for handling reports received from other reporters than industry
involves internal coding and quality review in the workflow to ensure that data are correctly
coded before they are committed to the database and made available in outputs to
industry, Drug Analysis Prints (DAPs), and signal detection. However, usually electronic
reports received from industry are automatically committed to the database without manual
intervention, and therefore reports from industry are often available in the public domain as
initially coded by the Marketing Authorisation Holder (MAH). Sometimes reports from
industry are not committed directly to the database due to various reasons. DHMA has to
handle these reports manually, which is a significant administrative burden that does not
necessarily add any scientific value to the reports.
Errors and low-quality reports in the DHMA database could have serious consequences,
such as missing signals or creating false signals where ADRs are duplicated. Furthermore,
such errors and quality issues also generate a large volume of enquiries. This results in
further work to update the case and/or contact the originator company to request an update
to their case. Each enquiry that requires a case update will generate an updated version of
the report, which is also a significant administrative burden for both industry and DHMA.
This guide is published to increase the number of high-quality valid reports from industry
that are committed to the DHMA database without requiring additional manual handling.
Validation rules have been built to ensure that basic quality standards are met.
2.2 REFERENCES
It is intended that this guide will complement current EU legislation and guidance and
provide practical advice to industry on the coding of ICSRs. It is important to note that the
guide is not intended to replace the existing legislation and guidance.
Appendix 1 provides a list of the abbreviations used in this guide.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
This guide has been based on the current pharmacovigilance framework. New EU
pharmacovigilance legislation will have an impact on the guidance provided.
Appendix 2 provides a list of references.
2.3 FEEDBACK
For general enquiries about the topics of this guide, contact DHMA by e-mail to
[email protected].
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3
VALID ADVERSE DRUG REACTION
The minimum criteria for reporting a valid case to DHMA are:
•
•
•
•
an identifiable patient
a suspect drug or active substance
a suspected ADR
an identifiable and contactable reporter
For more guidance on the four minimum criteria, see the relevant chapters (chapters 8, 9,
10 and 16).
If one or more of these criteria are missing, the MAH must follow up on the case in order to
validate the report. The report should not be submitted until all criteria are met.
Module VI and national legislation state that if ICSRs, which do not qualify for reporting,
contain information that may lead to a change in the known risk-benefit balance for the
product, the Competent Authorities should be notified without delay. If reports are received
with details of a drug and a reaction term but not an identifiable patient and/or reporter, the
MAH should enter the cases in their safety database and submit the cases when validating
information is received. Invalid reports should be reviewed regularly to consider how these
reports might provide information on the known risk-benefit balance for the product. The
MAH should also take appropriate action to investigate the possibility of an emerging
pattern, e.g. reports from the same source or a cluster of similar adverse events.
A valid ADR for reporting to DHMA must include an identifiable patient, a
suspect drug, a suspect reaction and an identifiable and contactable reporter.
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4
REPORTING REQUIREMENTS
4.1 REPORTING REQUIREMENTS
European reporting requirements are covered in Module VI, incl. annex. Additional details
are provided in national legislation.
It should be noted that although some reports may not meet the reporting requirements,
they should be recorded in the MAH’s pharmacovigilance system as they may provide
useful information on the overall risk-benefit balance of the medicinal product. These
reports should be included for risk-benefit evaluation during signal detection and PSUR
preparation, e.g. reports of overdose, abuse and misuse that are not associated with an
ADR (see section 4.3).
The following cases should be submitted to DHMA:
a)
Spontaneous:
 All DK serious reports should be submitted within 15 days. DHMA will forward
all serious DK reports to the EMA and therefore companies must not submit
these cases to the EMA
 All DK cases are forwarded to WHO
 All DK non-serious reports should be reported within 90 days
 ADRs seen during clinical trials, but only related to the non-IMP, should be
reported as spontaneous
It is important to note that reports derived from post-marketing studies are subject to the
same reporting requirements as spontaneous reports.
b)
8
Clinical trial sponsors are obliged to immediately report suspected unexpected
serious adverse reactions (SUSARs) to DHMA in the following cases:
 SUSARs arising from clinical trials in Denmark whose conduct have been
authorised by DHMA
 SUSARs arising from clinical trials in other EU countries, but with a site in
Denmark having the same EudraCT number
 SUSARs should only be submitted by the sponsor or investigator
 Non-SUSARs from clinical trials where IMP is suspect drug should not be
submitted to DHMA.
GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
All DK SUSARS should also be sent to EudraVigilance Clinical Trial Module (EVCTM)
(receiverID: EVCTMPROD).
4.2 CREATING ONE OR MORE INDIVIDUAL CASES
The suspect drug(s) in a case should be related to all reported ADRs and vice versa. If a
patient has received several suspect drugs and experienced several ADRs and it can be
clearly identified which drug and ADR combinations are related, this should be handled in
individual reports. Judgment should be applied.
Example 1:

The following example describes a patient who received drug A and drug B. The patient
experienced bleeding following treatment with drug A and hypokalaemia following
treatment with drug B. In this case, two individual cases should be reported; one with
suspect drug A and bleeding, and one with suspect drug B and hypokalaemia.
Example 2:

The following example describes a patient who received drug A and drug B. The patient
experienced bleeding following treatment with drug A and hypokalaemia following
treatment with drug B. The patient also experienced dizziness as an ADR to both drug A
and drug B. In this case, three individual cases should be reported; one with suspect drug
A and bleeding, one with suspect drug B and hypokalaemia and one with suspect drugs A
and B and dizziness.
4.3 REPORTING OF OVERDOSE, ABUSE, MISUSE, OFF-LABEL USE AND
OCCUPATIONAL EXPOSURE
In line with Module VI, the MAH should continuously monitor and evaluate the potential
impact of overdose, abuse, misuse, off-label use and occupational exposure on the overall
risk-benefit balance of the medicinal product.
Only cases of overdose, abuse, misuse, off-label use or occupational exposure that lead to
adverse reactions should be reported to DHMA. Reports should be routinely followed up on
to ensure that information is as complete as possible with regard to early symptoms,
treatment and outcome. This includes cases of intended suicide.
Reports of overdose, abuse, misuse, off-label use and occupational exposure that are not
associated with an ADR should be recorded in the MAH’s pharmacovigilance system as
they provide useful information on the overall risk-benefit balance of the medicinal product
and should be included for risk-benefit evaluation during signal detection and PSUR
preparation.
The most appropriate MedDRA term to describe the overdose should be selected, e.g.
whether the overdose is accidental or intentional or involves a multiple drug overdose.
Reports that indicate that the taking of the suspect drug led to a suicidal intention and
subsequent overdose of the suspect drug or other medication should be reported.
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Example 1:

In the following example, the patient was hospitalised following an overdose, however, this
case should not be submitted because there was no reaction associated with the
overdose. The MAH should consider whether the drug may have contributed to the
overdose and the report should be followed up on for further information.
<narrativeincludeclinical> Spontaneous report, reported by a nurse,
received on 06OCT2014. A 21 year old female patient has taken
an overdose of XXXXXX of 40 mg on 24SEP2014 at 11am. She
also took an overdose of 20 mg XXXXXXX. The patient rang the
hospital at 6pm and discharged herself at 3 am. No side effects
were experienced by the patient. The reporting nurse did not
provide a causality assessment and outcome.
</narrativeincludeclinical>
4.4 REPORTING OF MEDICATION ERRORS
Reports of medication errors – such as wrong route of administration or wrong drug
administered – should only be reported to DHMA if they are accompanied by an ADR.
4.5 REPORTS OF LACK OF EFFICACY
Module VI states that reports of lack of efficacy (without additional ADRs) should not
normally be reported, but should be recorded in the MAH’s pharmacovigilance system and
discussed in the relevant PSUR. However, in certain circumstances, reports of lack of
efficacy should be reported; medicinal products used for the treatment of life-threatening
diseases, vaccines and contraceptives are examples of classes of medicinal products
where lack of efficacy should be considered for reporting. It is important to provide batch
numbers for vaccines and biological medicinal products.
Judgment should be applied when considering if cases of lack of efficacy qualify for
reporting. For example, antibiotics used in life-threatening situations where the medicinal
product was not in fact appropriate for the infective agent should not be reported. However,
a life-threatening infection where the lack of efficacy seems to be due to the development
of a newly resistant strain of a bacterium previously regarded as susceptible should be
reported.
Companies should apply medical judgment on a case-by-case basis to decide if the reports
raise a concern of lack of efficacy.
4.6 PRODUCT COMPLAINTS
Product complaints should be reviewed for efficacy-related issues or problems with the
manufacturing process in accordance with good manufacturing practice requirements.
Reports of product technical complaints should also be reviewed on an ongoing basis to
ensure that any reports associated with an ADR are recorded on the MAH’s database so
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that they are included for risk-benefit evaluation during signal detection and PSUR
preparation. Any report that includes an ADR and fulfil the requirements for reporting
should be submitted within the regulatory time frames.
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5
ICSR SUBMISSION BASED ON CASES
RECEIVED FROM DHMA
Expedited reporting of ICSRs also applies to EU Competent Authorities. EU Competent
Authorities are required to provide reports within 15 days of receipt of all serious adverse
reactions occurring in their country to relevant MAHs and to the EMA. DHMA provides this
information to MAHs. The date on which the information is made available to the MAH
should be considered day 0.
ICSRs based on cases received from DHMA should not be reported back to DHMA, unless
the company has received significant new information.
According to Module VI, significant new information relates to altered medical interpretation
of the case. This includes, but is not limited to, additional patient identifiers, new ADRs or
new drugs.
When cases are returned to DHMA, the report is often committed directly into the DHMA
database and the original DHMA case is entirely overwritten.
This often results in reporter details and patient characteristics being deleted or replaced
with e.g. “PRIVACY”/”UNKNOWN”/ due to company procedures. This impairs data quality
and complicates contact to reporters, identification of duplicates, searches and signal
detection.
If it is deemed necessary to submit an update to an ICSR originating from DHMA, it is
essential to use the correct format of the worldwide unique case identification number
(WWRN) in order to prevent the generation of duplicates. WWRN is the value in one of the
following tags in the E2B file: <authoritynumb> (A.1.10.1) or <companynumb>
(A.1.10.2).
As a general rule, do not return ICSRs received from DHMA.
The following are examples, which should not have been reported to DHMA, as they are
based on DHMA cases.
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Example 1:

DHMA sends an initial case to a company. The company returns the case with a new
WWRN (companynumber) and the original WWRN as a duplicate number. The reporter is
listed as DHMA in the narrative.
<reportduplicate >
<duplicatesource>DK-DKMA</duplicatesource>
<duplicatenumb>DK-DKMA-ADR 12345678</duplicatenumb>
</reportduplicate>
<narrativeincludeclinical>Serious spontaneous case received on
20Jan-2014 from the Danish Authorities (ADR
12345678)</narrativeincludeclinical>
Example 2:

In this example, the ICSR maintains the DHMA assigned WWR number. An update case
was created in the DHMA database, with no additional information reported.
<authoritynumb>DK-DKMA-ADR 12345678</authoritynumb>
<narrativeincludeclinical>This report was received via authority and
originated in Denmark...</narrativeincludeclinical>
Example 3:

A company has received a case from DHMA where a batch number is included. The
company returns this case with the only addition being the expiry date of the reported
batch. In most cases, the expiry date will not affect the causality assessment or medical
interpretation of the case. The case should not be reported back to DHMA.
Example 4:

Company A has received a case from DHMA. Company A returns this case after having
added only company A causality assessment and company B case number.
<authoritynumb>DK-DKMA-ADR 12345678</authoritynumb>
<duplicate>1</duplicate>
<reportduplicate>
<duplicatesource>Company B</duplicatesource>
<duplicatenumb>DK-xxx-0123456</duplicatenumb>
</reportduplicate>
<drugreactionassesmeddraversion>18.0</drugreactionassesmeddraversion>
<drugreactionasses>10046735</drugreactionasses>
<drugassessmentsource>Company A</drugassessmentsource>
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<drugresult>Unlikely</drugresult>
<sendercomment>Events are assessed as possible after vaccination
except lymph node enlarged and immune imbalance due to the
fact that reporter states it to be present every time he gets sick.
Urticaria because it is directly stated that is occurs after
sunlotion contact.</sendercomment>
Example 5:

The DHMA has sent a case originating from DHMA to a company with the following
WWRN:
<authoritynumb>DK-DKMA-EFO1234</authoritynumb>
The company returned the case with a wrong WWRN number. In this example, part of the
WWRN has been replaced with the DHMA “Safety Report ID” (Sender’s (case) Safety
Report Unique Identifier (A.1.0.1)):
<authoritynumb>DK-DKMA-ADR 12345678</authoritynumb>
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ICSR SUBMISSIONS BASED ON CASES
RECEIVED DIRECTLY FROM OTHER
COMPANIES
Only the MAH for the suspect drug should report the case to DHMA. Companies should
make internal agreements to ensure that the case is only reported to DHMA once.
Example 1:

Company A sends a case with several suspect drugs to DHMA and two other companies B
and C. Company B and company C should not report this case to DHMA as it has already
been reported to DHMA by company A. The case will be sent to company B and company
C by DHMA.
Example 2:

Company A receives a case on a suspect drug where company B is MAH. Company A
should not report the case to DHMA as company A does not have reporting obligations.
Company A should send the case to company B and ask them to report the case to DHMA.
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7
GENERAL DATA ENTRY GUIDANCE
The guidance in this and the following chapters are based on common findings from E2B
reports (further information and examples can be found in the following chapters).
It is important to provide as much information as possible in the structured fields. Some
reports include information on the age or gender in the case narrative but not in the
structured E2B age or gender fields. It is also important to provide as accurate information
as possible, including coding on brand names instead of substances where a brand name
is provided.
Coding in structured fields with accurate information will increase data quality, facilitate
signal analysis processes, duplicate detection and consistent data retrieval.
As much information as possible should be correctly coded in the relevant
structured fields.
Only reports of ADRs should be submitted to DHMA, not adverse events (see section 10.3
on ‘Adverse drug reaction versus adverse events’).
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8
PATIENT CHARACTERISTICS
For a report to be considered valid, it must contain at least one of the following
criteria: age, age group, sex, initials, date of birth, CPR number, gestation
period or identification number.
The <patientinitial> tag can be populated with the patient’s initials. If patient initials are
not known, the tag should be left blank. Entries such as XXX, N/A, UNK, UNKNOWN,
PRIVACY and --- should be avoided. If the <patientinitial> tag is blank, then one of the
other criteria for patient characteristics should be populated in order for the report to be
considered valid, e.g. date of birth.
Entries such as ‘Patient 1’ should not be entered in the patient initials. Such entries should
be captured in the patient investigation number field (B.1.1.1d). The Investigation number
must refer to an identifiable patient.
The following should be avoided:
<patientinitial>XXX</patientinitial>

<patientinitial>PRIVACY</patientinitial>

<patientinitial>UNKNOWN</patientinitial>

or
or
The information provided should be as complete as possible.
Danish legislation allows inclusion of patient initials and date of birth. Therefore, include
this information if it is known.
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Include patient initials and date of birth in structured fields, if known.
Patient age group should be used as defined in ICH Guideline E11:





Preterm newborn infants
Term newborn infants (0 to 27 days incl)
Infants and toddlers (28 days to 23 months incl.)
Children (2 to 11 years incl.)
Adolescents (12 to 16-18 years (dependent on region))
DHMA further defines:
 Adolescent (12-17 years incl.)
 Adult (18 to 65 years incl.)
 Elderly (>65 years)
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9
DRUG INFORMATION
9.1 DRUG INFORMATION
This section covers coding on suspect drugs/vaccines and concomitant and past
medication. It is important to ensure that drug information is correctly coded. Coding on
active substance should only be used if it is not possible to obtain a drug name.
The drug characterisation indicates whether a drug is classified as suspect, concomitant or
interacting. Interacting should be used when an interaction LLT is selected, e.g. ‘Drug
interaction’, ‘Food interaction’ or ‘Alcohol interaction’.
Suspect drug(s)
Only the drug(s) suspected of causing the reaction should be listed as the suspect drug(s).
Concomitant medication
Any drug(s) that are not suspected of causing the reaction should be listed as concomitant
medication if taken at the time of the reaction. If the medication is initiated after the reaction
start date, it should not be classified as concomitant. It is important to note that any
medication given as treatment for the ADR should not be classified as concomitant
medication, but may be included in case narrative if relevant.
If a drug has been recently discontinued prior to the reaction, the MAH should consider
whether the drug should be coded as concomitant medication or patient past drug history
and document their working practices.
Patient Past Drug Therapy
All drugs that were completed/discontinued before the start of the treatment with the
suspect(ed) drug(s) should be included in the relevant section, Patient Past Drug Therapy
(unless it was recently discontinued prior to the reaction and therefore coded as
concomitant medication).
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DHMA requires either the medicinal product or active substance name to be
completed. If the drug name is known, it should always be coded instead of
only active substance.
It is important to note that the strength and dosage should not be captured in the drug
name fields. Neither should substance be included in the drug name if the drug name is
known, unless the substance is part of the drug name.
Any information regarding the formulation and route of administration should be captured
with the correct code or text and in the relevant tags; <drugdosageform> (B.4.k.7) and
<routeadministration> (B.4.k.8). DHMA will not provide leading zeros in the following
tags, but will receive values with or without leading zeros: <drugstructuredosageunit>,
<drugadministrationroute>, <drugparadministration>.
Do not use prefixes or suffixes in the classification of these drugs, unless they are part of
the specific product name.
Example 1:
For example, “Panodil 500 mg tablets” contains drug name, dosage and pharmaceutical
form; however, structured fields are available in E2B for the dose and pharmaceutical form.
The following is an example of correct coding:

<drugcharacterization>1</drugcharacterization>
<drug>
<medicinalproduct>PANODIL</medicinalproduct>
<drugstructuredosagenumb>500</drugstructuredosagenumb>
<drugstructuredosageunit>3</drugstructuredosageunit>
<drugadministrationroute>48</drugadministrationroute>
<drugdosageform>245</drugdosageform>
<activesubstance>
<activesubstancename>PARACETAMOL</activesubstancename>
</activesubstance>
</drug>
The following is an example of incorrect coding:

<drugcharacterization>1</drugcharacterization>
<drug>
<medicinalproduct>PANODIL 500mg tablets</medicinalproduct>
<drugstructuredosagenumb></drugstructuredosagenumb>
<drugstructuredosageunit></drugstructuredosageunit>
<drugdosageform>Tablets</drugdosageform>
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<activesubstance>
<activesubstancename>PARACETAMOL</activesubstancename>
</activesubstance>
</drug>
Example 2:
“DELEPSINE (VALPROATE SODIUM)” contains the drug name and substance; however,
a structured field is available in E2B for the substance name.
The following is an example of correct coding:

<drugcharacterization>1</drugcharacterization>
<drug>
<medicinalproduct>DELEPSINE</medicinalproduct>
<drugadministrationroute>48</drugadministrationroute>
<drugdosageform>245</drugdosageform>
<activesubstance>
<activesubstancename>VALPROATE
SODIUM</activesubstancename>
</activesubstance>
</drug>
The following is an example of incorrect coding:
<drugcharacterization>1</drugcharacterization>
<drug>
<medicinalproduct> DELEPSINE (VALPROATE
SODIUM)</medicinalproduct>
<drugstructuredosagenumb></drugstructuredosagenumb>
<drugstructuredosageunit></drugstructuredosageunit>
<drugadministrationroute></drugadministrationroute>
<drugdosageform>Tablet</drugdosageform>
<activesubstance>
<activesubstancename> VALPROATE
SODIUM</activesubstancename>
</activesubstance>
</drug>
In summary – only the drug name should be classified in the
<medicinalproduct> tag and active substances in the <activesubstance> tag.
Any additional information should be captured in the relevant structured fields
and not included as prefixes and suffixes in the medicinal product tags.
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
9.2 ADDITIONAL DRUG INFORMATION
All details regarding the suspect and concomitant drugs should be captured in the
structured fields. For example, the dosage information should be captured as shown
below:
<drugstructuredosagenumb>200</drugstructuredosagenumb>
<drugstructuredosageunit>21</drugstructuredosageunit>
This rule applies to other fields within the drug information. As a general rule, when a
number is provided, the corresponding unit also needs to be populated. Conversely, if a
unit is provided, then a corresponding number needs to be populated. If this information is
not known, e.g. there is no information on units (simvastatin 20), then this information
should be captured in the <drugdosagetext> field.
When the <drugstructuredosagenumb> is populated, it is mandatory to
provide the <drugstructuredosageunit> as well. Failure to do so will result
in a case failure.
A correctly coded example is shown below:

<drugseparatedosagenumb>200</ drugseparatedosagenumb>
<drugstructuredosageunit>21</ drugstructuredosageunit>
<drugcumulativedosagenumb>500</drugcumulativedosagenumb>
<drugcumulativedosageunit>3</drugcumulativedosageunit>
The following example would cause the report to be rejected.

<drugtreatmentduration></drugtreatmentduration>
<drugtreatmentdurationunit>804</drugtreatmentdurationunit>
<drugstartperiod>5</drugstartperiod>
<drugstartperiodunit></drugstartperiodunit>
9.3 DRUG DOSAGE
All the drug dosage information should be captured in the structured fields whenever
possible. The <drugdosagetext> field can be used to supplement the dosage data.
9.4 PHARMACEUTICAL FORM
The pharmaceutical form of the drug should be entered in the <drugdosageform> field
and the route of administration route should always be captured in the
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
<drugadministrationroute> field. It is important to note that the pharmaceutical form
should not be captured in the drug name fields.
The pharmaceutical form xml tag <drugdosageform> can be populated with either a
code or a text term – the list of accepted terms has been adopted from the European
Pharmacopoeia (see Appendix 2).
<drugdosageform>65</drugdosageform>
or
<drugdosageform>capsule</drugdosageform>


The following example would cause reports to be handled and recoded manually at DHMA:
<drugdosageform>capsules</drugdosageform>

9.5 ROUTE OF ADMINISTRATION AND PARENT ADMINISTRATION ROUTE
Both route of administration and parent administration route should be populated as a code
in the xml file using the predefined list in the E2B standard (see Appendix 2). Text terms
are not accepted in this field. DHMA can receive xml files with or without leading zeros but
will send xml files without leading zeros.
<drugadministrationroute>48</drugadministrationroute>

or
<drugadministrationroute>048</drugadministrationroute>

9.6 INDICATION
The indication of the drug should be captured in the <drugindication> field. The MedDRA
LLT ‘ill-defined disorder’ should not be coded as an indication. If the indication of the drug
is unknown, this field can be left blank or populated with LLT ‘Drug use for unknown
indication’. It is possible to submit cases to DHMA where the drug has more than one
indication.
9.7 DATES
The start and stop dates should all be captured in the structured date fields within the drug
tags. It is important to note that DHMA accepts all formats of dates in these fields, including
full and partial dates.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
<drugstartdateformat>610</drugstartdateformat>
<drugstartdate>201305</drugstartdate>
<drugenddateformat>102</drugenddateformat>
<drugenddate>20130603<drugenddate>
DHMA has a validation in place so that the start date of the suspect drug
cannot be later than the end date of the drug. Instances where the suspect
drug end date is earlier than the start date will result in case failure.
DHMA has a validation so that reactions reported to have started before the
suspect drug was administered are rejected.
9.8 ACTION TAKEN WITH DRUG
The action taken with the drug as a result of the reaction should be captured in the
<actiondrug> field. This field should be populated with ‘unknown’ rather than left blank if
the action taken is unknown. A separate drug entry should not be entered for any changes
to the dosage as a result of the reaction.
Example 1:
50mg of the suspect drug was taken before the reaction and as a result of the reaction it
was decreased to 25mg. The information regarding the reduced dose of 25mg should not
be captured as a separate suspect drug entry as this did not contribute to the reaction.
Instead, the <actiondrug> field (B.4.k.16) of the 50mg entry should state ‘dose decreased’
and the specific reduced dose (25mg) should be captured in the case narrative.
The rechallenge fields should be used when identical symptoms are experienced on both
exposures to the suspect drug.
Any rechallenge information should be captured in the <drugrecurreadministration>
and <drugrecuraction> fields. A separate drug entry should not be populated for the
rechallenge information.
Example 2:
A patient was taking suspect drug Y and developed an itchy rash. Suspect drug Y was
withdrawn on 01/01/2014 and the patient recovered. Suspect drug Y was re-introduced on
01/02/2014 and the patient developed an itchy rash again.
•
24
Only the first drug date should be entered with the action taken with drug set as
‘drug withdrawn’.
GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
•
•
Only the first instance of the itchy rash should be captured as a reaction term.
The <drugrecurreadministration> and <drugrecuraction> fields should be
completed with the itchy rash that occurred on rechallenge.
If the patient experiences a different reaction on rechallenge or a more serious reaction,
this should be recorded as a reaction term and not a rechallenge.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
10
REACTION INFORMATION
10.1 MEDDRA
MAHs are required to code reports using the ‘Medical Dictionary for Regulatory Activities’
(MedDRA) terminology. For further information on coding, please refer to the “MedDRA
Term Selection: Points to Consider” (MTS: PTC) document. This is an ICH-endorsed guide
for MedDRA users promoting accurate and consistent MedDRA term selection, which is
available from the Maintenance and Support Services Organization (MSSO) website and
the ICH website (see Appendix 2).
In line with the guidance from the EMA and MSSO, DHMA will implement new MedDRA
versions on the first Monday of the second month after release.
Any cases submitted with the new version of MedDRA prior this date will be rejected.
On implementation, DHMA will continue to support the current and the previous version of
MedDRA.
Reaction terms should be classified using the LLT available to accurately reflect the
reporter’s wording of the reaction. This is important to allow consistent and accurate
classification of ICSRs. Medical judgment should be used if an exact match cannot be
found and the most appropriate existing term should be selected. Terms should be
selected for every ADR reported.
Only current MedDRA LLTs should be selected. Non-current LLTs should not be used for
term selection.
Either the diagnosis of the ADR or the diagnosis of the ADR and accompanying symptoms
may be coded as adverse reactions. Procedures may also be coded as ADRs (see
example 5).
In the following examples, more specific reaction terms should have been selected.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
Example 1:

In this example, the MAH should have coded ‘loss of vision in his left eye’ as LLT
‘Unilateral vision loss’ rather than LLT ‘Visual acuity reduced’.
<reaction>
<primarysourcereaction>Loss of vision in his left eye
</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10047531</reactionmeddrallt>
<termhighlighted>3</termhighlighted>
<reactionstartdateformat>102</reactionstartdateformat>
<reactionstartdate>20140129</reactionstartdate>
<reactionenddateformat>102</reactionenddateformat>
<reactionenddate>20140129</reactionenddate>
<reactionduration>1</reactionduration>
<reactiondurationunit>804</reactiondurationunit>
<reactionfirsttime>1</reactionfirsttime>
<reactionfirsttimeunit>804</reactionfirsttimeunit>
<reactionoutcome>1</reactionoutcome>
</reaction>
Coded to MedDRA LLT ‘Visual acuity
reduced’
Example 2:

In this example, the MAH should have coded ‘drug interaction with pomegranate juice’ as
LLT ‘Food interaction’ rather than LLT ‘Drug interaction’.
<reaction>
<primarysourcereaction lang="en">DRUG INTERACTION WITH
POMEGRANATE JUICE</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10013710</reactionmeddrallt>
<reactionmeddraversionpt>18.0</reactionmeddraversionpt>
<reactionmeddrapt>10013710</reactionmeddrapt>
<termhighlighted>3</termhighlighted>
<reactionoutcome>2</reactionoutcome>
</reaction>
Coded to MedDRA LLT ‘Drug Interaction’
Reports that are ambiguous or confusing should be followed up for clarification. Terms
such as LLT ‘Ill-defined disorder’ and LLT ‘Adverse drug reaction’ should not be reported to
DHMA.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
There is also an option – in addition to the LLT – to select the corresponding MedDRA
preferred term (PT); however, DHMA does not require both of these to be completed. For
any MedDRA term that is provided, a corresponding MedDRA version is required. Failure
to provide the MedDRA version will result in rejection of the report.
The exact wording used by the reporter should be captured in the
<primarysourcereaction> field. This is a free text option and does not require a
MedDRA term to be used.
For any MedDRA term that is provided, a corresponding MedDRA version is
also required. Failure to do so will result in case rejection.
Example 3:

This example demonstrates the use of the <primarysourcereaction>. In this example,
the verbatim term has been selected as ‘øget blæremuskel tonus’ and the LLT selected
(10048994) ‘bladder spasm’. If the reported verbatim is translated into English, this should
be done as accurately as possible.
<reaction>
<primarysourcereaction>ØGET BLÆREMUSKEL
TONUS</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10048994</reactionmeddrallt>
<reactionmeddraversionpt>18.0</reactionmeddraversionpt>
<reactionmeddrapt>10048994</reactionmeddrapt>
<termhighlighted>4</termhighlighted>
<reactionstartdateformat>102</reactionstartdateformat>
<reactionstartdate>20140302</reactionstartdate>
<reactionenddateformat>102</reactionenddateformat>
<reactionenddate>20140302</reactionenddate>
<reactionduration>1</ reactionduration>
<reactiondurationunit>804</ reactiondurationunit>
<reactionfirsttime></reactionfirsttime>
<reactionfirsttimeunit></reactionfirsttimeunit>
<reactionlasttime></reactionlasttime>
<reactionlasttimeunit></reactionlasttimeunit>
<reactionoutcome>1</reactionoutcome>
</reaction>
Example 4:

It is important to pay particular attention to avoid potential coding of past medical history as
suspected ADRs. The following is an example where deep vein thrombosis was incorrectly
coded in the structured reaction fields. Swollen legs should be coded as the reaction.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
<narrativeincludeclinical>Initial report received from a physician….
The reporter stated that the patient had mild heart disease with
symptoms of swollen ankles etc, believed to be linked to her old
age. In the past the patient had also suffered from deep vein
thrombosis….The patient received XXXXXX 12.5 mg in Feb 2014.
Other suspect drug included XXXXXXX for depression. The
patient developed swollen legs on 04 Mar (exact date
unspecified)…The outcome and causality details for the other
events were not provided at the time of this report.
</narrativeincludeclinical>
Pre-existing medical conditions that have not changed should generally be classified as
medical history. Pre-existing medical conditions that have changed should be classified
using the most specific term, e.g. if “exacerbation of myasthenia gravis” is reported,
“Myasthenia gravis aggravated” should be selected.
In the absence of such a term, DHMA’s internal practice is to select a term for the condition
and an additional term to describe the modification of the condition, e.g. “Condition
aggravated”, “Disease progression”. For example, if “progression of Addison’s disease” is
reported, “Addison’s disease” and “Disease progression” should be selected. It is important
to note that the pre-existing medical condition should also be coded as medical history.
However, in case of several ADRs it may not be possible to identify which condition is
aggravated. In this scenario, the use of “Condition aggravated” or “Disease progression”
should be avoided. This information should be captured in case narrative.
Example 5:

In general, procedures should not be coded as ADRs, unless the procedure provides
significant information on the severity of the adverse reaction.
<reaction>
<primarysourcereaction>Heart failure</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10019279</reactionmeddrallt>
<reactionmeddraversionpt>17.1</reactionmeddraversionpt>
<reactionmeddrapt>Cardiac failure</reactionmeddrapt>
<reactionoutcome>6</reactionoutcome>
</reaction>
<reaction>
<primarysourcereaction>Dyspnø</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10013963</reactionmeddrallt>
<reactionmeddraversionpt>17.1</reactionmeddraversionpt>
<reactionmeddrapt>10013968</reactionmeddrapt>
<reactionoutcome>1</reactionoutcome>
</reaction>
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
<reaction>
<primarysourcereaction>Heart transplant</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10019314</reactionmeddrallt>
<reactionmeddraversionpt>18.0</reactionmeddraversionpt>
<reactionmeddrapt>Heart transplant</reactionmeddrapt>
<reactionoutcome>6</reactionoutcome>
</reaction>
<narrativeincludeclinical>Information was received from a
healthcare professional regarding a 64-year-old female patient
who received xxxxxxx therapy and experienced heart failure.
MEDICAL HISTORY: The patient's concurrent illness includes
hormone replacement therapy. PRODUCT DETAILS: Indication for
xxxxxx was rheumatoid arthritis. The dose regimen was 50 mg 1
time per day from an unspecified date to an unspecified date and
then was unknown from an unspecified date to Apr-2013.
Therapy was permanently discontinued. EVENT DETAILS: The
patient started experiencing dyspnea in Apr-2013 and was
diagnosed with heart failure in July-2013. In May 20014 she had
a heart transplant due to her heart failure. OUTCOME: At the time
of report the outcome of the operation was unknown.
</narrativeincludeclinical>
Each organisation should document their preference in their working practices.
DHMA has a validation in place so that reactions that are reported to have
started before the suspect drug was administered are rejected.
10.2 REACTION OUTCOMES
It is important to ensure that the reaction outcomes are consistent with the information in
the case narrative. For example, coding the outcome field as ‘Unknown’ is incorrect if the
reaction has been coded as ‘Death unexplained’.
Reaction outcomes should be consistent with the dates provided (e.g. if a stop date is
provided, then the outcome field must be populated as ‘Recovered/resolved’).
DHMA requires all reactions to have an outcome populated. If the outcome is
unknown, then the outcome field should be populated with ‘Unknown’ and not
be left blank.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
10.3 ADVERSE DRUG REACTIONS VERSUS ADVERSE EVENTS
All reaction terms classified in a case report must be suspected to have a causal
relationship to the drug. An ‘adverse event’ is an undesirable experience that occurs during
or after treatment with a medicine but is not necessarily caused by the medicine. Module VI
provides definitions on ‘adverse drug reactions’ and ‘adverse events’ (see Appendixes for
details).
It is important to apply judgment when reporting ADRs.
Common errors include the reporting of:
 surgical procedures, unless the procedure is related to the reaction and describes
severity
 treatments
 events occurring at the same time as the reaction
 outcomes, such as ‘hospitalisation’ as the reaction.
Cases should be assessed individually and followed up for further information, e.g. to
confirm whether the surgery was a result of the ADR or is unrelated to the reaction.
If a report contains a reaction and an event, the reaction should be reported and the event
captured in the case narrative (see the following example).
Example 1:

In this report, the patient suffered from constipation after taking medication and was given
an enema as treatment for this. The MAH has incorrectly coded ‘Enema administration’ as
the reaction. The only reaction term to be captured should be ‘Constipation’ and the
subsequent treatment with an enema should be stated in the case narrative.
<reaction>
<primarysourcereaction>Enema</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10050314</reactionmeddrallt>
<termhighlighted>3</termhighlighted>
<reactionoutcome>6</reactionoutcome>
</reaction>
Example 2:

<reaction>
<primarysourcereaction>Knee surgery</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10049662</reactionmeddrallt>
<termhighlighted>3</termhighlighted>
<reactionoutcome>6</reactionoutcome>
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</reaction>
<narrativeincludeclinical>Initial report received from the nurse on
xxxxxx :This patient was treated with xxxxxx for an unspecified
indication since an unknown date. The patient underwent knee
surgery on an unknown date and suffered cardiac arrest,
according to his wife the patient 'almost died'. Following this
incident, the patient suffered severe bradycardia and knee pain
and xxxxx was discontinued. The outcome of the event was not
reported.</narrativeincludeclinical>
In this example, the LLTs ‘Bradycardia’ & ‘Cardiac arrest’ should be selected, not ‘Knee
surgery’ or ‘Knee pain’.
Example 3

<reaction>
<primarysourcereaction>Nedsat
nyrefunktion</primarysourcereaction>
<reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10021523</reactionmeddrallt>
<reactionmeddraversionpt>12.1</reactionmeddraversionpt>
<reactionmeddrapt>10062237</reactionmeddrapt>
<reactionoutcome>6</reactionoutcome>
</reaction>
<narrativeincludeclinical>Information was received from a
healthcare professional regarding a 64-year-old female patient
who received xxxxxxx therapy and experienced decreased kidney
function. MEDICAL HISTORY: The patient's concurrent illness
includes hormone replacement therapy. PRODUCT DETAILS:
Indication for xxxxxx was rheumatoid arthritis. The dose
regimen was 50 mg 1 time per day from an unspecified date to
an unspecified date and then was unknown from an unspecified
date to Feb-2014. Therapy was permanently discontinued.
CONCOMITANT THERAPY: Concomitant therapy included xxxxxx.
EVENT DETAILS: The patient experienced decreased kidney
function in Apr-2013 and the patient received dialysis. OUTCOME:
At the time of report the outcome of the dialysis was unknown.
</narrativeincludeclinical>
In this example, the ‘Dialysis’ can be coded with the ‘Renal impairment’ as it described the
severity of the reaction.
10.4 WITHDRAWAL REACTION CLASSIFICATION
Drug withdrawal reactions are reports where the reporter describes reactions, which occur
after withdrawal of the suspect drug.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
 The MedDRA LLT ‘Withdrawal reaction’ should only be used to classify a reaction
when the reporter has stated this. In addition, all the symptoms associated with the
withdrawal should also be classified and coded as reactions.
 In instances where the reporter states ‘Withdrawal reaction’ as the only reaction and
gives no detail on the reactions suffered, the cases are still considered valid and
should be reported if they meet the minimum criteria for expediting reporting. However,
these cases should also be followed up for symptoms of the withdrawal reaction.
10.5 REACTION OCCURRING AT MULTIPLE BODY SITES
The MTS: PTC suggests that if a reaction is reported to occur at more than one body site,
and if all of those LLTs link to the same PT, then a single LLT that most accurately reflects
the reaction should be selected. For example, if the reaction is described as “Skin rash on
face and neck”, then the LLT ‘Skin rash’ should be selected (rather than ‘Rash on face’ and
‘Neck rash’ as both of these LLTs link to the PT ‘Rash’).
10.6 DUPLICATION OF REACTION TERMS
MedDRA terms should not be duplicated, unless the dates indicate two separate events.
A separate case should be created if a patient experienced the same reaction on different
dates where the interval between reactions is significant. Judgment should be applied. This
is not a positive rechallenge if the patient did not stop taking the suspect drug.
10.6.1 Drug interactions
At least two suspect drugs should be classified for reports involving a drug interaction.
When the reporter specifically states that an interaction occurred, an appropriate
interaction term should be selected in addition to term(s) for any reaction(s) described.
10.6.2 Definitive and provisional diagnosis with signs and symptoms
If a definitive diagnosis and a set of symptoms are given, DHMA’s internal practice is to
code the diagnosis and signs/symptoms to ensure that the most detailed information is
available for signal detection. It should be noted that DHMA’s internal practice in this
regard is not mandatory and each organisation should document their preference in their
working practices.
Example 1:

If ‘rhabdomyolysis with myalgia and acute Renal Failure’ is reported, the LLTs
‘Rhabdomyolysis’, ‘Myalgia’ and ‘Acute Renal Failure’ should be selected.
A provisional diagnosis may be described as “suspicion of”, “probable”, “presumed”, likely”,
“rule out”, “questionable”, “differential”, etc. If a provisional diagnosis and a set of
symptoms are given, DHMA’s internal practice is to code the provisional diagnosis and
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
signs/symptoms. If provisional diagnosis is later disconfirmed, this should be deleted from
the case.
Example 2:

If ‘Shortness of breath, with chest pain and coughing up blood, most likely pulmonary
embolism?’ is reported, the LLTs ‘Shortness of breath’, ‘Chest pain’ and ‘Coughing blood’
should be selected. DHMA internal procedure is to code ‘Pulmonary embolism’ as a
provisional diagnosis.
The MTS: PTC provides guidance on term selection and examples on options for definitive
and provisional diagnoses with or without sign/symptoms.
10.6.3 Other patient outcomes
Consequences of a reaction such as hospitalisation and disability are generally not
considered to be ADRs and should not be reported to DHMA. Reports that only state an
outcome – e.g., hospitalisation – but do not describe an ADR, should be followed up for
further information before submission.
10.6.4 No adverse effect
The LLT ‘No adverse effect’ may be used to maintain records for administrative purposes
in the MAH’s pharmacovigilance database, e.g. for pregnancy registries, overdoses and
medication errors; however, such cases should not be submitted as there is no reaction.
10.6.5 Product substitution
If a report states that the reaction occurred after the patient switched to taking a different
drug, having previously been taking a different drug containing the same active substance,
it may be useful to code this by using an appropriate MedDRA term such as: ‘Product
substitution issue’, ‘Product substitution issue brand to brand’,’ Product substitution issue
brand to generic’, ‘Product substitution issue generic to brand’ or ‘Product substitution
issue generic to generic’.
10.6.6 Unexpected benefit
MAHs should record reports of ‘unexpected therapeutic effects’ in their pharmacovigilance
database for risk-benefit evaluation during PSUR preparation; however, these reports
should not be reported to DHMA. These reports may describe a beneficial effect of a drug
aside from the use for which it had been given.
Example: If “a bald patient was pleased that he grew hair while using a product” is
reported, the term “Hair growth increased” can be selected. In addition, “Unexpected
therapeutic effect” can be selected.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
11
CASE NARRATIVE
Cases originating from DHMA contain case narratives in Danish. This information must be
maintained and additional information should be added. New information should be clearly
identifiable in the case narrative and provided in a structured format in the applicable data
elements. Changes should be summarized along with the receipt date in the end of the
case narrative.
In accordance with Module VI, the case narrative should be a medical report containing all
known relevant clinical and related information, including patient characteristics, therapy
details, medical history, clinical course of the event(s), diagnosis, adverse reactions,
including the outcome, relevant laboratory evidence (including normal ranges) and any
other information that supports or refutes an adverse reaction.
The narrative should serve as a comprehensive, stand-alone “medical report”. The
information should be presented in a logical time sequence; ideally with the source of the
report and presented in the chronology of the patient’s experience.
The information in the case narrative should also be captured in the relevant structured
fields. The correct coding of this information has a significant impact on the ability to
perform qualitative signal detection and evaluation.
CIOMS V provides an example of a standard narrative template (Appendix 2).
Example 1:

The following is an example of a clearly presented case narrative for an initial case:
<narrativeincludeclinical>This case was considered medically
important. Information was received from a healthcare
professional regarding a 29-year-old male patient who received
xxxxx and experienced hypertension. MEDICAL HISTORY:
Relevant medical history was xxxxx. PRODUCT DETAILS:
Indication for xxxxx was rheumatoid arthritis. Therapy began in
Oct-2012 and was permanently discontinued in Apr-2013. Dose
regimen was 50 mg, frequency unknown. CONCOMITANT
THERAPY: Concomitant medications included xxxxx. EVENT
DETAILS: The patient had been experiencing hypertension since
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
he started the xxxxx therapy in Oct-2012. The decision was made
to change his therapy to xxxxx.
OUTCOME: The patient recovered from the events. RELATEDNESS
ASSESSMENT: The reporter suspected that the adverse events
were related to the suspect drug. No additional information was
available at the time of this report. </narrativeincludeclinical>
Example 2:

The following is an example of a case narrative with preferred addition of Follow-up
information:
<narrativeincludeclinical>Case received on 15-Aug-2014: A
physician reported via Danish health and medicines authority
that a female patient was hospitalized with hypoglycemia while
on therapy with XXX. On 06-Feb-2013, the patient initiated oral
XXX daily for the treatment of diabetes mellitus type II. On 29Jul-2013, the patient was hospitalized due to hypoglycemia. At
the time of this report, the event was resolving. The patient had
difficulty concentrating, heart palpitations and dizziness. XXX
was interrupted during admission in response to the event and
reintroduced at discharge.
FOLLOW-UP received by MAH 10-Sep-2014: A physician reported
that the patient recovered from the hypoglycemia 2-Aug-2014.
Outcome for the adverse reaction hypoglycemia was changed to
recovered.</narrativeincludeclinical>
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12
TEST RESULTS
All tests relevant to the ADR should be captured in the structured test fields.
For ICSRs containing large amounts of laboratory data, e.g. literature articles, judgment
should be used to determine the level of test information entered into the structured fields.
This can include limiting the test data entered to only tests related to the reaction
experienced, only tests with abnormal results or limiting the test data to a 3-month period
before and after the reaction was experienced. However, where possible it is preferable for
all test data to be entered into the structured fields. DHMA cannot receive more than 999
Individually coded test results.
<test>

<testdateformat>102</testdateformat>
<testdate>20090503</testdate>
<testname>White blood cell count</testname>
<testresult>4.2</testresult>
<testunit>mmol/L</testunit>
<lowtestrange>4</lowtestrange>
<hightestrange>10</hightestrange>
<moreinformation>2</moreinformation>
</test>
DHMA only accepts MedDRA LLTs in the <testname> field. Any cases, which have nonMedDRA terms in this field, will be rejected.
Any additional test information, which uses more than 50 characters (e.g. scan or X-ray
results) and therefore cannot be captured in the structured test fields, should be captured
in the free text <testresultsprocedures> tag.
If the dates of the test are unknown but their chronology is known, this information should
be captured in the <testresult> field as shown below:
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
<test>

<testname>White blood cell count</testname>
<testresult>On admission: 4.2</testresult>
<testunit>mmol/L</testunit>
<lowtestrange>4</lowtestrange>
<hightestrange>10</hightestrange>
<moreinformation>2</moreinformation>
</test>
<test>
<testname>White blood cell count</testname>
<testresult>On Day 2: 6.3</testresult>
<testunit>mmol/L</testunit>
<lowtestrange>4</lowtestrange>
<hightestrange>10</hightestrange>
<moreinformation>2</moreinformation>
</test>
A test result without an applicable unit should be coded in the testname, testresult and
testunit fields, e.g. Creatine kinase increased should be coded as
<testname>Creatine kinase</testname>

<testresult>increased</testresult>
<testunit>NA</testunit>
Testunit must be populated with a value if there is a testresult. The testunit could be
populated with ’NA’ or other suitable word. Failure to do so will result in case rejection.
<test>
<testdateformat></testdateformat>
<testdate></testdate>
<testname>APGAR Score</testname>
<testresult>10</testresult>
<testunit>NA</testunit>
<lowtestrange>4</lowtestrange>
<hightestrange>10</hightestrange>
<moreinformation>2</moreinformation>
</test>
DHMA only accepts MedDRA LLTs in the <testname> field.
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
13
FATAL REACTIONS
13.1 REPORTS OF DEATH
If a reaction is fatal, then the following practices should be followed:
•
For ‘Death unexplained’ cases, the date of death can be used as the start and
stop date (with the same being applied for completed suicides).
•
Reports of death, e.g. ‘Death unexplained’, ‘Sudden death’, ‘Sudden death
unexplained’, ‘Sudden unexplained death in epilepsy’ and ‘Completed suicide’
can only have a reaction outcome of fatal. Under no circumstances should
these reaction terms be classified with any other outcome.
•
If a reaction term has been coded with a fatal outcome, then it is not correct to
include ‘Death unexplained’ as a reaction term as well.
If more than one reaction outcome is reported as fatal, it should be stated in the narrative
which reaction is assessed as the primary ADR leading to the cause of death. Only the
primary fatal reaction will appear on the DAPs published on the DHMA website.
If the only information reported is death, then the most specific term available should be
selected and the report followed up for further information.
Reports of disease progression should only be coded as a reaction if the reporter suspects
a causal relationship with the suspect drug. If the patient experiences a non-fatal ADR, and
later dies of an unrelated cause, then the cause of death should be coded in the
<patientdeathreport> or <patientdetermineautopsy> fields only.
Example 1:

A patient with a history of bowel cancer received drug X for the treatment of nausea.
Following the administration of drug X, the patient experienced a rash. The patient
recovered from the rash the next day, however, the patient died 4 weeks later from
progression of the underlying bowel cancer. The reporter did not consider the death to be
related to the treatment with drug X.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
In this example, the report should be coded as:
•
•
•
LLT coded: ‘Rash’ with a reaction outcome of 'recovered'
Seriousness flags: 'Patient died' should be flagged as 'no' as the patient did not
die as a result of the reaction
Reported cause of death field: Populated with ‘Bowel cancer’
All information in <patientdeath> tags should be completed when available. Also, ‘Bowel
cancer’ should be coded as medical history.
13.2 PATIENT DEATH DETAILS
The patient death fields should be used to capture information regarding the patient’s
cause of death.
If a patient death date is provided then the corresponding date format also needs to be
populated.
The patient’s cause of death should be recorded in the reported cause of death and
autopsy-determined cause of death as appropriate.
Reported cause of death (<patientdeathreport>): If Post-Mortem or Death Certificate
details are not available, but information on the report suggests a likely cause(s) of death,
this should be entered in the reported cause of death field.
Autopsy-determined cause of death (<patientdetermineautopsy>): The cause(s) of
death identified in an autopsy should be entered here. For each MedDRA term provided,
the corresponding MedDRA version must also be populated.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
14
REPORTS OF DRUG EXPOSURE DURING
PREGNANCY
14.1 REPORTS OF DRUG EXPOSURE DURING PREGNANCY
Module VI states that the MAH should follow up on all reports at the expected due date
relating to pregnancies where the foetus may have been exposed to one of its medicinal
products. This may include, but is not limited to, maternal exposure or transmission of a
medical product via semen following paternal exposure. The MAH should gather
information on both normal and abnormal outcomes. Individual cases with an abnormal
outcome related to a suspect medicinal product should be reported.
Cases, e.g. reports of termination of pregnancy without information on congenital
malformation (including reports of elective termination) and reports of pregnancy exposure
without outcome data, should not normally be reported.
In certain circumstances, the MAH may be requested to treat any reports of pregnancy
exposure as cases requiring expedited reporting, e.g. pregnancy exposure to products
contraindicated in pregnancy because a high teratogenic potential should be expedited
even without a known outcome. This may be a requirement of either a Pregnancy
Prevention Program or Risk Management Plan. A note of this should be written in the case
narrative. DHMA will follow up on pregnancy outcome in cases initiated by DHMA.
All reports on outcome of exposure during pregnancy should be included in the PSUR
together with aggregated data on the overall exposure and details of normal/abnormal
outcomes. Reports from prospective registries should also be included and evaluated in
the PSUR.
If the MAH identifies, or becomes aware of, a signal of a possible teratogenic effect (e.g.
through a cluster of similar abnormal outcomes) all Competent Authorities where a
marketing authorisation is held, and also the EMA in the case of centrally authorised
medicinal products, should be informed on an expedited basis. This also applies to
possible signals arising from consumer reports for which medical confirmation has not
been obtained.
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14.2 PARENT-CHILD REPORTS
Reports where a foetus/neonate/child suffers an ADR as a result of a medication that was
taken by the parent should be classified as parent-child reports.
In these cases, the patient is classified as the foetus/neonate/child and the parent details
captured in the parent fields. A separate case for the parent should only be generated if the
parent also suffered adverse events (e.g. the foetus developed tachycardia and a heart
defect and the mother suffered heavy bleeding and high blood pressure). These reports
should then be linked using the linked reports option. The ICH E2B(M) field A.1.12
‘Identification number of the report which is linked to this report’ can be used to link these
reports.
The guideline EMEA/CHMP/313666/2005, ‘Guideline on the exposure to medicinal
products during pregnancy: need for post-authorisation data’ states that foetal death
without information on malformation should be entered as one case for the mother. This
guideline defines early foetal death (i.e. death before 22 completed weeks of gestation) as
miscarriage/Spontaneous abortion and ectopic pregnancies. Late foetal death (i.e. death
after 22 completed weeks of gestation) is known as stillbirth.
‘Drug exposure during pregnancy’ should be recorded in the MAH’s pharmacovigilance
system; however, these reports should not be reported if there is no ADR. Other events
relating to pregnancy, such as ‘Elective termination’ should not be reported in a parentchild report either.
A case of miscarriage/spontaneous abortion, foetal death, stillbirth or caesarian section
without information of an ADR in the foetus should only be generated as a mother/parent
case.
Example 1:

This report should not have been reported, because pregnancy is not normally considered
an ADR; however, MAHs may wish to record this information in their databases, e.g. to
facilitate discussion of pregnancy in PSURs.
<reaction>
<primarysourcereaction>Normal baby</primarysourcereaction>
<Reactionmeddraversionllt>18.0</reactionmeddraversionllt>
<reactionmeddrallt>10029757</reactionmeddrallt>
<reactionmeddraversionpt>18.0</reactionmeddraversionpt>
<reactionmeddrapt>10029769</reactionmeddrapt>
<reactionoutcome>6</reactionoutcome>
</reaction>
<narrativeincludeclinical>This prospective pregnancy case was
reported by a pharmacist and described the occurrence of drug
exposure during pregnancy in a female patient who received
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
xxxxxxxx. The patient became pregnant. On an unknown date,
approximately in her 12th week of pregnancy the patient started
xxxxxxxx. At an unknown time after starting xxxxxxxx, the
patient experienced drug exposure during pregnancy. At the time
of reporting, the outcome of the event was unknown. Last
Menstrual Period and Expected Due Date were not reported.
Verbatim text: Medicines Information Pharmacist has reported
that a female patient who is currently estimated to be 26 weeks
pregnant has been receiving xxxxxxxxx since her 12 week
pregnancy. Patient has been using xxxxxx at home. No adverse
events have been observed at time of reporting. Follow up
information received 19 June 2014 from patient's physician: The
physician reported that the 35 year old pregnant patient's waters
broke on 13 June 2014 at a gestational age of 31 weeks. Her
estimated date of delivery was 14 August 2014. At an unknown
time later the patient gave birth to a healthy baby via caesarean
section. </narrativeincludeclinical>
Information regarding the route of administration of the drug to the foetus should be
captured in the <drugadministrationroute> field and the parent route in the
corresponding <drugparadministration> field.
The most common routes of administration include ‘transplacental’, ‘transmammary’ and
‘other’ (for father-child cases).
For father-child cases, an appropriate term such as ‘Paternal drug exposure’ may be coded
to aid identification of these cases on an MAH’s pharmacovigilance system. For cases
where a patient experienced an ADR as a result of a medicine taken by their male partner,
the reaction term ‘Transmission via semen’ may be coded.
The indication of the suspect and concomitant drugs should be classified as that of the
parent and not as ‘Drug exposure during pregnancy’.
14.3 PREGNANCY WITH CONTRACEPTIVE MEDICINES
Regarding ineffective contraceptive medicines resulting in unintended pregnancies, the
most appropriate and accurate MedDRA terms should be coded rather than ‘Drug
ineffective’ or ‘Lack of efficacy’, whenever possible. The following reaction terms should be
considered:
•
•
•
•
43
Contraceptive failure with injectable contraceptive
Pregnancy on contraceptive
Pregnancy on oral contraceptive
Pregnancy with injectable contraceptive
GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
•
•
•
•
44
Pregnancy with contraceptive device
Pregnancy with contraceptive patch
Pregnancy with implant contraceptive
Pregnancy with vaginal contraceptive device.
GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
15
LITERATURE REPORTS
Adverse reactions, which appear in the published literature, should be reported in line with
the reporting requirements. Further guidance is provided in Module VI.
When reports from the worldwide literature are submitted as ICSRs, the literature
references should be provided in the Vancouver Convention (known as “Vancouver style”)
as developed by the International Committee of Medical Journal Editors in the field ICH
E2B(M) A.2.2 ‘Literature reference(s)’. Literature reference should be added to all reporters
related to the literature article.
All literature references should be provided in Vancouver style.
Author. Title of journal article. Title of journal (this should be in italics); Year of publication:
Volume number (Issue number); Page numbers of the article (use ‘p.’ before a single page
number and ‘pp.’ where there are multiple pages).

<literaturereference>Al-Aloul M, Miller H, Stockton P, Ledson M,
Walshaw M. Acute renal failure in cystic fibrosis patients
chronically infected by the Liverpool epidemic Pseudomonas
aeruginosa strain (LES). Journal of cystic fibrosis 2005; 4:
pp197-201.</literaturereference>
Literature articles on which the ICSRs are based should not be sent to DHMA.
Each patient included in a multiple patient report should be identified by at least one of the
usual criteria (age, sex, etc.) and a report must be submitted for each patient separately.
The details of these should not be amalgamated, i.e. with an average age and unknown
sex and the same report submitted for each patient – this does not meet the requirements
of individual patient identifiers required for expedited reporting.
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Cases, which do not contain individual patient identifiers, do not meet the criteria for the
reporting of ICSRs. Literature articles, such as these when identified during routine
literature searches, should be assessed and included in the PSURs for relevant products
and not submitted as ICSRs.
When reporting ICSRs from literature, the MAH should avoid using report type “Other”, and
use report type “Spontaneous” or “Study/other study” whenever possible (section 17.2
“Report type”).
Cases originating from literature articles based on data from clinical trials should not be
sent to DHMA, since these cases have already been handled by sponsor or investigator.
However, if only non-IMP is suspected, the case should be reported as a spontaneous
case.
Cases described in “Nyt om bivirkninger”/”Danish Pharmacovigilance Update” or other
publications originating from DHMA should not be reported to DHMA, since the cases
originate from the DHMA pharmacovigilance database. These cases have been forwarded
to the relevant MAHs.
Cases described in publications from other EU competent authorities’ databases, incl.
Eudravigilance and Vigibase, should not be reported to DHMA either.
DHMA strives not to send out cases based on literature articles. However, if this happens,
the MAH should not submit the same case to DHMA using a different WWRN. If significant
information relating to the suspect drug and reaction is missing, the case should be
returned using the original WWRN to avoid duplicates.
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16
REPORTER DETAILS
For a report to be considered valid for reporting, it must contain an identifiable reporter.
Contact details for a reporter should be available for the reporter to be considered as
identifiable. As many details on the reporter(s) as possible should be provided to facilitate
duplicate identification.
Healthcare professionals are defined as medically qualified persons, such as physicians,
dentists, pharmacists, nurses and coroners.
E2B qualifications include physician, pharmacist, other health professional (e.g. nurses,
midwives and dentists), lawyer and consumer or other non-health professional.
DHMA requires at least one reporter qualification per case. Cases with no
reporter qualification will be rejected.
<reportertitle>Dr</reportertitle>
<reportergivename>Jens</reportergivename>
<reporterfamilyname>Jensen</reporterfamilyname>
<reporterorganization>Rigshospitalet</reporterorganization>
<reporterdepartment>Onkologisk afdeling</reporterdepartment>
<reporterstreet>Blegdamsvej 9</reporterstreet>
<reportercity>København Ø</reportercity>
<reporterstate>Region Hovedstaden</reporterstate>
<reporterpostcode>2100</reporterpostcode>
<reportercountry>DK</reportercountry>
<qualification>1</qualification>
Special characters (e.g. %$£*#@) in these fields should be avoided. If there are any
special characters in these fields, the case will be rejected.
The reporter needs to be contactable for acknowledgement and follow-up. A case from the
internet with a user name/ screen name would be considered valid for processing and
entering on a safety database if an email address is available to gain validating
information.
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
17
ADMINISTRATIVE INFORMATION
17.1 WORLDWIDE UNIQUE CASE IDENTIFICATION NUMBER AND
SENDERS SAFETY REPORT UNIQUE IDENTIFIER
The Worldwide unique case identification number (<companynumb> (A.1.10.2) or
<authoritynumb> (A.1.10.1)) and the Sender’s (case) Safety Report Unique Identifier
(<safetyreportid> (A.1.0.1)) are numbers that are used to identify a case. The
Worldwide unique case identification number is determined by the originator of the case
and must be maintained through all future transmissions (including maintaining upper/lower
case). The Sender’s (case) Safety Report Unique Identifier is used by any organisation
transmitting the case to record their reference number. If the originator and transmitter are
the same organisation, then these values can be the same. The Sender’s (case) Safety
Report Unique Identifier should remain constant in subsequent transmissions of the case
by the same sender.
The Sender’s (case) Safety Report Unique Identifier should be unique to a single ICSR.
The prefix of the number should represent the country from which the report originated.
The rest of the number should contain reference to the originating MAH followed by a
series of digits unique to the case. For example, an initial report transmitted by a company
to a regulatory authority concerning a case from Denmark would populate
<companynumb> with “DK-companyname-12345” where 12345 is a company’s unique
case report number.
Reference numbers should not exceed the field length of 100 characters. Reference
numbers greater than 100AN will result in the case being rejected.
If the report has been received from another MAH or Regulatory Authority, the
<companynumb> or <authoritynumb> must be maintained.
Reports received from DHMA should generally not be reported back to DHMA.
If necessary, the original Worldwide unique case identification number must be
maintained to avoid duplicates.
Submission of cases received from license partners may result in duplication of reports. It
should be noted that the ICSR should only be reported to DHMA from the MAH who has
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GUIDE TO INDIVIDUAL CASE SAFETY REPORTING
the responsibility for reporting based upon the licensing agreement. If follow-up is received
by a MAH that was not the original sender, the follow-up information should be submitted
using the WWRN assigned by the originating MAH.
Reports originating from DHMA can have one of the following prefix-structures in the
Worldwide unique case identification number (<authoritynumb>):




DK-DKMA-EFO
DK-DKMA-ESU
DK-DKMA-WBS
DK-DKMA-ADR
17.2 REPORT TYPE
All cases require a report type to be populated.
The report type Spontaneous should be selected for any ADR reported spontaneously to
an MAH from healthcare professionals and consumers.
<reporttype>1</reporttype>
The report type Study should be selected for any ADRs experienced in a clinical trial or
post-marketing study.
<reporttype>2</reporttype>
In order to further clarify the type of study, the <observestudytype> field must be
completed.
Clinical trial
<observestudytype>1</observestudytype>
This should be selected for studies carried out with investigational drugs (e.g. in phases I
to III of clinical trials) and interventional Phase IV clinical trials.
Other studies
<observestudytype>3</observestudytype>
Study/Other Studies reports should be selected for post-marketing studies and clinical
trials carried out with marketed drugs (e.g. non-interventional phase IV clinical trials).
These reports may also have a EudraCT number in addition to the study/clinical trial
numbers or names.
In addition to the <observestudytype> field for all study cases, the <studyname> and
<sponsorstudynumb> are also mandatory. In clinical trial cases, the<studyname>
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tag should be populated with the EudraCT number followed by # and the short name of the
study. The <sponsorstudynumb> tag should be populated using the protocol number.
<studyname>2015-123456-01#Short name of study</studyname>
<sponsorstudynumb>123456789</sponsorstudynumb>
If the study name exceeds 100 characters, the name should be truncated and entered in
this field.
Any study cases that do not have the <observestudytype>, <studyname> and
<sponsorstudynumb> will be rejected.
The field length for the <studyname> tag is 100 characters. If this field
exceeds the character limit, the file will be rejected.
It should be noted that DHMA does not accept clinical trial cases that have not been
unblinded. Any SUSARs received that contain blinded study medications will be nullified
and a notification sent. This includes instances where there is a known comparator listed
as a co-suspect medication. These cases should not be reported until the study medication
has been unblinded so that a thorough causality assessment can be made.
Other
<reporttype>3</reporttype>
On rare occasions where the source of spontaneous or study cannot be determined
(usually as a result of a literature article), then the report type 'other' can be selected. This
report type should only be used in exceptional circumstances.
For the purpose of safety reporting, reports from registries are classified as solicited
reports and, where possible, should have an appropriate causality assessment by a
Healthcare Professional or the MAH. Reports from registries should be coded as:
<reporttype>2</reporttype>
and
<observestudytype>3</observestudytype>
According to the E2B guideline, a literature report arising from spontaneous observations,
should have report type ‘Spontaneous’. If the report arises from a study, the report type
should be ‘Study’.
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A number of literature articles have been reported with a report type of ‘Other’
when it is clear that the source is spontaneous or from a study. Ensure that the
most appropriate report type is selected at all times.
17.3 SERIOUSNESS CRITERIA AND MEDICALLY CONFIRMED SELECTION
The seriousness criteria are (more than one can be selected):
•
•
•
•
•
•
Results in death
Is life-threatening
Requires hospitalisation or prolongation or existing hospitalisation
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Other medically important condition.
One or more criteria can be selected as appropriate.
<serious>1</serious>
<seriousnessdeath>2</seriousnessdeath>
<seriousnesslifethreatening>2</seriousnesslifethreatening>
<seriousnesshospitalization>2</seriousnesshospitalization>
<seriousnessdisabling>2</seriousnessdisabling>
<seriousnesscongenitalanomali>2</seriousnesscongenitalanomali>
<seriousnessother>1</seriousnessother>
The terms life-threatening and other medically important conditions are defined in the ICH
E2A guideline:
The term "life-threatening" in the definition of "serious" refers to an event in which the
patient was at risk of death at the time of the event; it does not refer to an event which
hypothetically might have caused death if it were more severe.
Medical and scientific judgment should be exercised in deciding whether expedited
reporting is appropriate in other situations, such as important medical events that may not
be immediately life-threatening or result in death or hospitalisation but may jeopardise the
patient or may require intervention to prevent one of the other outcomes listed in the
definition above. These should also usually be considered serious.
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm; blood dyscrasias, convulsions that do not result in hospitalisation
or development of drug dependency or drug abuse.
All serious and non-serious cases, incl. non-medically confirmed reports from nonhealthcare professionals, should be submitted.
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If an MAH wants to upgrade a non-serious case originating from DHMA to serious, an
email with clarification should be sent to [email protected]. DHMA will update the case if
appropriate.
17.4 DUPLICATES AND NULLIFICATIONS
The nullification of an ICSR indicates that the report should be considered void (nullified),
for example, when the case is found to be erroneous or in the case of duplicate reports.
Individual cases that have been nullified should not be used for scientific evaluation;
however, they should remain in the database for audit purposes.
All identified duplicates should be captured in the duplicate fields.
<reportduplicate>
<duplicatesource>Other MAH</duplicatesource>
<duplicatenumb>123456789</duplicatenumb>
</reportduplicate>
Both the <duplicatesource> and <duplicatenumb> fields need to be
completed for each duplicate entry. Failure to do so will result in case failure.
An individual case can only be requested to be nullified by the sending organisation or
DHMA. It should be noted that an update cannot be submitted for a nullified case.
The nullification reason should be clear and concise to explain why the report is no longer
considered to be a valid report. For example, a nullification reason stating, ‘the report no
longer meets the reporting criteria’ or ‘report sent previously in error’ are not considered
sufficiently detailed to qualify as an explanation.
<casenullification>Other MAH</casenullification>
<nullificationreason>Valid reason to be entered
here</nullificationreason>
All nullification requests are checked before the nullification is complete.
Cases, which have been requested to be nullified with no reason given or with
an incorrect reason, will not be nullified.
If an MAH receives a case coded on a substance where the MAH, based on formulation,
strength etc., can rule out the possibility of being the MAH for the suspect product, the
case can be rejected. The negative ACK should contain a reason for rejection. DHMA does
not require further notification.
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If an MAH receives a nullification to a case because it is a duplicate and the MAH has not
received the master case from DHMA, the MAH can nullify or disregard the duplicate case
in their system. The MAH should not submit a nullification back to DHMA. The MAH will
only receive the master case if it is associated with one of their products. This does not
apply to literature cases.
If the MAH receives a nullification to a literature case because it is a duplicate, the MAH
should only nullify it if they have the master case.
On submission of a nullification request, the ‘master’ companynumb>/<authoritynumb>
and the DHMA reference number <safetyreportid> should be entered in the
<nullificationreason> field.
Cases can be nullified if receipt of follow-up reveals that the case is no longer valid. Tables
11 and 12 from Module VI outline the scenarios of when cases can be nullified:
Scenario
An individual case has been identified as a
duplicate of another individual case
previously submitted.
A wrong ‘Worldwide unique case
identification number’ (ICH-E2B(R2)
A.1.10) was accidentally used and does
not refer to an existing case.
On receipt of further information, it is
confirmed that the adverse reaction
occurred before the suspect drug(s) was
taken.
On receipt of further information on an
individual case, it is confirmed that the
patient did not receive the suspect drug.
Minimum reporting criteria for an ICSR as
outlined in VI.B.2 are no longer met.
On receipt of further information, it is
confirmed by the same reporter that the
reported adverse reaction(s) did not occur
to the patient. Minimum reporting criteria
for an ICSR as outlined in VI.B.2 are no
longer met.
On receipt of further information, it is
confirmed that there was no valid patient
for the individual case. Minimum reporting
criteria for an ICSR as outlined in VI.B.2
are no longer met.
Action to be taken
One of the individual cases should be
nullified. The remaining valid case should
be updated with any additional information
and from the nullified case.
The case with the wrong ‘Worldwide
unique case identification number’ (ICHE2B(R2) A.1.10) should be nullified.
A new case should be created with a
correct ‘Worldwide unique case
identification number’.
The case should be nullified.
The case should be nullified.
The case should be nullified.
The case should be nullified.
The table below outlines scenarios for which ICSRs should not be nullified:
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Scenario
A wrong ‘Worldwide unique case
identification number’ (ICH E2B(R2)
A.1.10) was accidentally used. This wrong
‘Worldwide unique case identification
number’ referred to an existing case.
On receipt of further information on an
individual case, it is confirmed that the
patient did not receive the marketing
authorisation holder’s suspect drug.
However, the patient received other
suspect drugs and the minimum reporting
criteria for an ICSR are still met.
On receipt of further information, the
reporter has confirmed that the reported
adverse reaction is no longer considered
to be related to the suspect medicinal
product(s).
Change of the individual case from serious
to non-serious (downgrading).
The primary source country has changed,
which has an impact on the ICH-E2B(R2)
convention regarding the creation of the
‘Worldwide unique case identification
number’ (ICH-E2B(R2) A.1.10).
Action to be taken
The report with the wrong ‘Worldwide
unique case identification number’ (ICH
E2B(R2) A.1.10) should not be nullified.
A follow-up report should be submitted to
correct the information previously
submitted.
A new ICSR should be created and
submitted with the correct ‘Worldwide
unique case identification number’.
The case should not be nullified.
The case should not be nullified.
A follow-up report should be submitted
within the appropriate time frame with the
updated information on the case.
The case should not be nullified.
A follow-up report should be submitted
with the data element ‘Seriousness’ (ICHE2B(R2) A.1.5.1) populated with the value
‘No’ without selection of a value for the
data element ‘Seriousness criteria’ (ICHE2B(R2) A.1.5.2).
The data element ‘Does this case fulfil the
local criteria for an expedited report?’
(ICH-E2B(R2) field A.1.9) should remain
populated with the value ‘Yes’.
The case should not be nullified.
The ‘Sender’s (case) safety report unique
identifier’ (ICH-E2B(R2) A.1.0.1) can be
updated on the basis of the new primary
source country code. However, the
‘Worldwide unique case identification
number’ (ICH-E2B(R2) A.1.10) should
remain unchanged.
If, for some technical reason, the sender’s
local system is not fully ICH-E2B(R2)
compliant and cannot follow this policy,
then the sender should nullify the original
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Scenario
The suspected medicinal product belongs
to another marketing authorisation holder
(e.g. a product with the same active
substance but marketed under a different
invented name).
The suspected medicinal product taken
does not belong to the marketing
authorisation holder (same active
substance, the invented name is unknown
and the report originates from a country,
where the marketing authorisation holder
has no marketing authorisation for the
medicinal product in question).
The case is mistakenly reported by the
marketing authorisation holder A although
the marketing authorisation holder B as
co-marketer is responsible for reporting
the case.
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Action to be taken
case. A new case should be created with
a new ‘Worldwide unique case
identification number’ (ICH-E2B(R2)
A.1.10) reflecting the changed primary
source country code. The ‘Worldwide
unique case identification number’ (ICHE2B(R2) A.1.10) of the case that was
nullified should be reflected in the data
elements ‘Other case identifiers in
previous transmissions’ (ICH-E2B(R2)
A.1.11).
The case should not be nullified.
It is recommended that the initial sender
informs the other marketing authorisation
holder about this case (including the
‘Worldwide unique case identification
number’ (ICH-E2B(R2) A.1.10) used). The
original organisation should also submit a
follow-up report to provide this new
information.
The other concerned marketing
authorisation holder should create a new
case and specify the reference case
number and the name of the initial sending
marketing authorisation holder in the data
elements ‘Source(s) of the case identifier
(e.g. name of the company name of
regulatory agency)’ (ICH-E2B(R2)
A.1.11.1) and ‘Case identifier(s)’ (ICHE2B(R2) A.1.11.2). This will allow
grouping the cases in the EudraVigilance
database.
The case should not be nullified.
The marketing authorisation holder should
submit a follow-up report with this
information within the appropriate time
frame.
The case should not be nullified.
An explanation should be sent by the
marketing authorisation holder A to the comarketer marketing authorisation holder B
that the case has already been reported.
Scenario
Action to be taken
The marketing authorisation holder B
should provide any additional information
on the case as a follow-up report with the
same ‘Worldwide unique case
identification number’ (ICH-E2B(R2)
A.1.10).
17.5 DATES
The ‘receive date’ is the date on which the report was first received from the primary
source fulfilling the four minimum criteria for expedited reporting as described in section 3.
The ‘receipt date’ is the date of receipt of the most recent information for the report. Both of
these fields are mandatory. The ‘receive’ and ‘receipt’ dates should be the same in all initial
cases.
<receivedateformat>102</receivedateformat>
<receivedate>20150430</receivedate>
<receiptdateformat>102</receiptdateformat>
<receiptdate>20150430</receiptdate>
<fulfillexpeditecriteria>1</fulfillexpeditecriteria>
<authoritynumb>DK-DKMA-12345678</authoritynumb>
For any dates provided throughout the file, a corresponding date format must
be provided. Failure to do so will result in case rejection.
It is important to ensure that the ‘receipt date’ is correctly entered as DHMA uses this date
to measure MAH compliance.
17.6 FOLLOW-UP REPORTS
When submitting follow-up information, the Worldwide unique case identification number
must be the same as that in the initial case.
In addition, the receive date in follow-up cases should refer to the date where the initial
information was received. The receipt date should then be updated to the date on which
the most recent information was received.
<receivedateformat>102</receivedateformat>
<receivedate>20150430</receivedate>
<receiptdateformat>102</receiptdateformat>
<receiptdate>20150829</receiptdate>
<fulfillexpeditecriteria>1</fulfillexpeditecriteria>
<authoritynumb>DK-DKMA- 12345678</authoritynumb>
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Updates to DHMA cases should only be submitted when further significant new information
has been received. This includes additional patient identifiers, new ADRs or new drugs.
Reports received from DHMA where the suspect drug is coded as specific,
product/brand names should not be changed to be coded on active substance.
If the MAH disagrees significantly in the coding of a case originating from DHMA, send an
email to [email protected]. DHMA does not need to be informed before internal additions of
minor changes, such as ‘Wrong administration route’ and the cases should not be reported
back to DHMA.
17.7 SENDER AND RECEIVER DETAILS
The sender’s information should be completed with at least sendertype,
senderorganization and senderemailaddress. Senderemailaddress should not be a
personal email address; a general emailaddress to the PV or safetydepartment should be
included. The emailaddress is used for correspondence regarding the case. The sender
type must always be populated with ‘pharmaceutical company’.
<sender>
<sendertype>1</sendertype>
<senderorganization>MAH</senderorganization>
<senderdepartment>Pharmacovigilance/Regulatory Affairs
</senderdepartment>
<sendertitle>Dr.</sendertitle>
<sendergivename>ABC</sendergivename>
<senderfamilyname>Andersen</senderfamilyname>
<senderstreetaddress>Vestergade 1</senderstreetaddress>
<sendercity>København</sendercity>
<senderpostcode>2100</senderpostcode>
<sendercountrycode>DK</sendercountrycode>
<sendertel>12345678</sendertel>
<sendertelextension></sendertelextension>
<sendertelcountrycode>+45</sendertelcountrycode>
<senderfax>87654321</senderfax>
<senderfaxextension></senderfaxextension>
<senderfaxcountrycode>+45</senderfaxcountrycode>
<senderemailaddress>[email protected]</senderemailaddres
s>
</sender>
The information provided in the senderemailaddress is used for requests for
further information. It is therefore essential that this information is valid at all
times.
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DHMA receiver details are as follows:
<receiver>
<receivertype>2</receivertype>
<receiverorganization>DHMA</receiverorganization>
<receiverdepartment>Pharmacovigilance and Medical
Devices</receiverdepartment>
<receivergivename></receivergivename>
<receiverfamilyname></receiverfamilyname>
<receiverstreetaddress>Axel Heides Gade 1</receiverstreetaddress>
<receivercity>København S</receivercity>
<receiverpostcode>DK-2300</receiverpostcode>
<receivercountrycode>DK</receivercountrycode>
<receivertel>44889757</receivertel>
<receivertelcountrycode>45</receivertelcountrycode>
<receiveremailaddress>[email protected]</receiveremailaddress>
</receiver>
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18
APPENDIX 1 – ABBREVIATIONS
ADR
AE
ASPR
CHMP
CIOMS
DAP
DHMA
E2B
EMA
EU
EV
EVCTM
ICH
ICSR
LLT
MAH
MedDRA
MTS:PTC
Module VI
MSSO
PT
PV
PSUR
SUSAR
WHO
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Adverse drug reaction
Adverse event
Anonymised Single Patient Report
Committee for Medicinal Products for
Human Use
Council for International Organizations of
Medical Sciences
Drug Analysis Print
Danish Health and Medicines Authority
The current international standard for ADR
reporting developed by ICH
European Medicines Agency
European Union
EudraVigilance
EudraVigilance Clinical Trial Module
International Conference on
Harmonisation
Individual Case Safety Report
Lowest Level Term (MedDRA)
Marketing Authorisation Holder
Medical Dictionary for Regulatory Activities
MedDRA Term Selection: Points to
Consider
Guideline on Good Pharmacovigilance
practices. Module VI covers Management
and reporting of adverse reactions to
medicinal products
Maintenance and Support Services
Organization
Preferred Term (MedDRA)
Pharmacovigilance
Periodic Safety Update Report
Suspected Unexpected Serious Adverse
Reaction
World Health Organization
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APPENDIX 2 – USEFUL WEBPAGES
EU Commission
http://ec.europa.eu/
Official website of the EU Commission.
European Medicines Agency (EMA)
http://www.ema.europa.eu/
The European Medicines Agency is a decentralised agency of the European Union,
responsible for the scientific evaluation of medicines developed by pharmaceutical
companies for use in the European Union.
EudraVigilance General Guidance related to electronic reporting of ICSRs
https://eudravigilance.ema.europa.eu/human/euPoliciesAndDocs03.asp
List of relevant Guidance documents related to electronic reporting of ICSRs.
Guideline on Good Pharmacovigilance practices
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/docume
nt_listing_000345.jsp
List of relevant Guidance documents on good pharmacovigilance practices.
EudraVigilance Important Medical Event Terms List (IME list)
https://eudravigilance.ema.europa.eu/human/textforIME.asp
The EudraVigilance Expert Working Group (EV-EWG) has co-ordinated the development
of an Important Medical Event Terms (IME) list. This IME list aims to facilitate the
classification of suspected adverse reactions as well as aggregated data analysis and case
assessment in the frame of the day-to-day pharmacovigilance activities of stakeholders in
the EU.
International Conference on Harmonisation (ICH)
http://www.ich.org/home.html
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The International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory
authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific
and technical aspects of drug registration.
The Electronic Transmission of Individual Case Safety Reports Message
Specification
http://estri.ich.org/e2br22/ICH_ICSR_Specification_V2-3.pdf
The specification (ICH ICSR DTD version 2.1) provides information on the E2B fields.
MedDRA Maintenance and Support Services Organization (MSSO)
http://www.meddra.org/
The MSSO serves as the repository, maintainer, and distributor of MedDRA as well as the
source for the most up-to-date information regarding MedDRA and its application within the
biopharmaceutical industry and regulators.
MedDRA versions and MedDRA Term Selection: Points to Consider (MTS:PTC)
http://www.meddra.org/how-to-use/support-documentation
General documentation on MedDRA versions and corresponding MedDRA points to
consider. Grouped by MedDRA version number.
European Pharmacopoeia
https://www.edqm.eu/en/european-pharmacopoeia-8th-edition-1563.html
The European Pharmacopoeia (Ph. Eur.) defines requirements for the qualitative and
quantitative composition of medicines.
Pharmaceutical drug dosage forms
https://eudravigilance.ema.europa.eu/human/PharmaceuticalDoseFormsUpdate.asp
Council for International Organizations of Medical Sciences
http://www.cioms.ch/index.php/publications/printablepublications?task=showCategory&catid=58
The Council for International Organizations of Medical Sciences (CIOMS) is an
international, non-governmental, non-profit organization established jointly by WHO and
UNESCO.
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20
APPENDIX 3 – GLOSSARY
Further information can be found in Eudralex Module VI.
Abuse of a medicinal product, synonym: Drug abuse
Persistent or sporadic, intentional excessive use of medicinal products which is
accompanied by harmful physical or psychological effects.
Adverse event
Any untoward medical occurrence in a patient or clinical-trial subject administered a
medicinal product and which does not necessarily have to have a causal relationship
with this treatment. An adverse event can therefore be any unfavourable and unintended
sign (e.g. an abnormal laboratory finding), symptom, or disease temporarily associated
with the use of a medicinal product, whether or not considered related to the medicinal
product.
Adverse reaction, synonym: Adverse drug reaction (ADR), suspected adverse
(drug) reaction
A response to a medicinal product which is noxious and unintended and which occurs at
doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for
the restoration, correction or modification of physiological function. Response in this
context means that a causal relationship between a medicinal product and an adverse
event is at least a reasonable possibility. Adverse reaction also includes adverse clinical
consequences associated with use of the product outside the terms of the Summary of
Product Characteristics or other conditions laid down for the marketing and use of the
product (including prescribed doses higher than those recommended, overdoses or
abuse).
Anonymised Single Patient Report (ASPR)
Anonymised report of an ADR reported to the DHMA and sent to MAHs who hold the
marketing authorisation for the suspected medicinal product (or substance where the
product has not been specified) for reports meeting expedited reporting requirements.
Reports are sent to companies as E2B files or as paper printouts.
Clinical trial
Any investigation in human subjects intended to discover or verify the clinical,
pharmacological and/or other pharmacodynamic effects of one or more investigational
medicinal product(s), and/or to identify any adverse reactions to one or more
investigational medicinal product(s) and/or to study absorption, distribution, metabolism
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and excretion of one or more investigational medicinal product(s) with the objective of
ascertaining its (their) safety and/or efficacy.
Coding/Classification
Transposition of ADR data from source documents into an XML file for submission as an
ICSR.
Consumer
A person who is not a healthcare professional, such as a patient, lawyer, friend or
relative/parents/children of a patient.
Drug Analysis Print (DAP)
A DAP contains a complete listing of all DK spontaneous ADRs reported by health
professionals, MAHs and patients to the DHMA. Each DAP lists all of the reactions
reported for a particular medicine, which are listed by the name of the active ingredient.
DAPs are available from the DHMA website and regularly updated. The website also
includes an interpretation note explaining the limitations of the data.
Healthcare Professional
For the purposes of reporting suspected adverse reactions, Healthcare Professionals are
defined as medically qualified persons, such as physicians, dentists, pharmacists,
nurses, midwives and coroners.
Individual Case Safety Report (ICSR), synonym: Safety report
A document providing the most complete information related to an individual case at a
certain point of time. An individual case is the information provided by a primary source
to describe suspected adverse reaction(s) related to the administration of one or more
medicinal products to an individual patient at a particular point of time.
Medicinal product
Any substance or combination of substances presented as having properties for
treating or preventing disease in human beings; or
• Any substance or combination of substances which may be used in or administered
to human beings either with a view to restoring, correcting or modifying physiological
functions by exerting a pharmacological, immunological or metabolic action, or to
making a medical diagnosis.
•
Non-interventional trial
A study where the medicinal product(s) is (are) prescribed in the usual manner in
accordance with the terms of the marketing authorisation. The assignment of the patient
to a particular therapeutic strategy is not decided in advance by a trial protocol but falls
within the current practice and the prescription of the medicine is clearly separated from
the decision to include the patient in the study. No additional diagnostic or monitoring
procedures shall be applied to the patients and epidemiological methods shall be used
for the analysis of the collected data.
Post-authorisation study
Any study conducted within the conditions laid down in the Summary of Product
Characteristics and other conditions laid down for the marketing of the product or under
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normal conditions of use. A post-authorisation study falls either within the definitions of a
clinical trial or a non-interventional study and may also fall within the definition of a postauthorisation safety study.
Post-authorisation safety study (PASS)
A pharmacoepidemiological study or a clinical trial carried out in accordance with the
terms of the marketing authorisation, conducted with the aim of identifying or quantifying
a safety hazard relating to an authorised medicinal product.
Risk-benefit balance
An evaluation of the positive therapeutic effects of the medicinal product in relation to the
risks (any risk relating to the quality, safety or efficacy of the medicinal product as
regards patients’ health or public health).
Serious adverse reaction
Serious adverse reaction means an adverse reaction, which results in death, is lifethreatening, requires in-patient hospitalisation or prolongation of existing hospitalisation,
results in persistent or significant disability or incapacity, or is a congenital anomaly/birth
defect.
Life-threatening in this context refers to a reaction in which the patient was at risk of
death at the time of the reaction; it does not refer to a reaction that hypothetically might
have caused death if more severe.
Medical and scientific judgement should be exercised in deciding whether other
situations should be considered serious reactions, such as important medical events that
might not be immediately life-threatening or result in death or hospitalisation but might
jeopardise the patient or might require intervention to prevent one of the other outcomes
listed above. Examples of such events are intensive treatment in an emergency room or
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in
hospitalisation or development of dependency or abuse.
Any suspected transmission via a medicinal product of an infectious agent is also
considered a serious adverse reaction.
Solicited sources of Individual Case Safety Reports
Organised data collection schemes which include clinical trials, registries, namedpatients use programmes, other patient support and disease management programmes,
surveys of patients or healthcare providers or information gathering on efficacy or patient
compliance.
For the purpose of safety reporting, solicited reports should be classified as Individual
Case Safety Reports from studies and therefore should have an appropriate causality
assessment by a Healthcare Professional or the Marketing Authorisation Holder.
Spontaneous report, synonym: Spontaneous notification
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An unsolicited communication by a Healthcare Professional or consumer to a company,
regulatory authority or other organisation (e.g. WHO, a regional centre, a poison control
centre) which fulfils the following three conditions:
•
•
•
It describes one or more suspected adverse reactions in a patient
The patient was given one or more medicinal products
It does not derive from a study or any organised data collection scheme.
Healthcare Professionals or consumers may be stimulated to report a suspected
adverse reaction by several situations including:
•
•
•
•
A Direct Healthcare Professional Communication
Early Post-Marketing Phase Vigilance (EPPV), e.g. in Japan
A report in the press
Direct questioning of Healthcare Professionals by company representatives.
In these circumstances, provided the report meets the three conditions above, it should
be considered a spontaneous report.
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