User Guidance:
Medical judgment should be exercised in completing this section.
Information pertinent to understanding the case is desired (such as
diseases, conditions such as pregnancy, surgical procedures,
psychological trauma, risk factors, etc.). In case of prematurity,
the birth weight should be recorded in the comments. Each of the
items in the table can be repeated as appropriate. If precise dates
are not known and a text description aids in understanding the
medical history, or if concise additional information is helpful in
showing the relevance of the past medical history, this information
can be included in the Comments column. In order to identify
relevant medical information of the family (e.g., hereditary
diseases) a flag should be added to the appropriate disease(s).
B.1.7.2 Text for relevant medical history and concurrent conditions
(not
including reaction/event) If structured information is not available in the sender’s database, this field should be used. Otherwise, it is preferable to send structured data in segment B.1.7.1. B.1.8 Relevant past drug history (repeat as necessary)
User Guidance:
This
segment concerns drugs previously taken. It does not concern drugs
taken concomitantly or drugs which might have potentially been
involved in the current reaction(s)/event(s). Information concerning
concomitant and other suspect drugs should be included in section
B4. The information provided here can also include previous
experience with similar drugs. Medical judgment should be exercised
in completing this section. When completing the item concerning the
name of the drug, it is important to use the words provided by the
primary source. Trade name, generic name or class of drug can be
used. B.1.9 In case of death B.1.9.1 Date of death
|
Disease / surgical procedure/ etc. |
Start date |
Continuing Y/N/U |
End date |
Comments |
|
|
|
|
|
User Guidance:
MedDRA LLT code should be used in the main descriptive column for disease/surgical procedure/etc.
B.1.10.7.2 Text for relevant medical history and concurrent conditions of
parent (not including reaction/event)
Name of drug |
MedID |
PhPID |
Start date |
End date |
Indication |
Reactions (if any and known) |
|
|
|
|
|
|
|
User Guidance:
To standardise this information, the ICH M5 guideline should be used. Based on the medicinal product name as reported by the primary source, the most specific identifier, being either the Medicinal Product Identifier (MedID) or the Pharmaceutical Product Identifier (PhPID) should be provided. If a MedID and a PhPID for the reported medicinal product are not available, this field should be left blank. MedDRA LLT code should be used in the Indication and Reaction columns.
B.2 Reaction(s)/event(s)
User Guidance:
The designation of “i” in this section indicates that each item is repeatable and that it corresponds to the same “i” in all subsections. A separate block (i) should be used for each reaction/event term. For example, if two reactions are observed, the first reaction would be described in items B.2.1.0 through B.2.1.6, and the other reaction would be described in items B.2.2.0 through B.2.2.6.
The original reporter's words and/or short phrases used to describe the reaction/event should be provided. These can also be included in the narrative B.5.1.
B.2.i.1 Reaction/event in MedDRA terminology
User Guidance:
Only the MedDRA Lowest Level Term (LLT) most closely corresponding to the reaction/event as reported by the primary source should be provided. In the exceptional circumstance when a MedDRA term cannot be found the sender should use good clinical judgment to complete this item with the best MedDRA approximation (see MedDRA™ TERM SELECTION:POINTS TO CONSIDER). MedDRA terms should be provided as code.
B.2.i.2 Term highlighted by the reporter and seriousness at event level
B.2.i.2.1 Term highlighted by the reporter
- yes, highlighted by the reporter
User Guidance:
A highlighted term is a reaction/event that the primary source indicated was a major concern or reason for reporting the case. If the information is not explicitly provided by the initial reporter the term should not be considered a highlighted term.
B.2.i.2.2 Seriousness criteria at event level (more than one can be
chosen)
- Results in death
-
Is life-threatening
-
Requires inpatient hospitalization or prolongation of existing
hospitalization
-
Results in persistent or significant disability/incapacity (as per
reporter's opinion)
-
Is a congenital anomaly/birth defect
-
Other medically important condition
User Guidance:
The seriousness criteria of the reaction/event should be based on the definitions provided in the ICH E2A and E2D guidelines.
B.2.i.3 Date of start of reaction/event
User Guidance:
See the companion document for format specifications.
B.2.i.4 Date of end of reaction/event
User Guidance:
This field should include the date corresponding to the date the reaction/event is assessed as resolved/recovered or resolved/recovered with sequelae (B.2.i.6).
B.2.i.5 Duration of reaction/event
User Guidance:
This
section can usually be computed from start/end of reaction/event.
Both dates and duration can be useful (e.g., for a reaction/event of
short duration such as anaphylaxis or arrhythmia).
Imprecise dates can be used. See the companion document for format
specifications.
B.2.i.6 Outcome of reaction/event at the time of last observation
− recovered/resolved
− recovering/resolving
− not recovered/not resolved
− recovered/resolved with sequelae
− fatal
− unknown
User Guidance:
In
case of irreversible congenital anomalies the choice
not recovered/not resolved
should be used.
“Fatal” should be used when death is possibly related to the
reaction/event. Considering the difficulty of deciding between
"reaction/event caused death" and "reaction/event contributed
significantly to death", both were grouped in a single category.
Where the death is unrelated, according to both the reporter and the
sender, to the reaction/event, death should not be selected here,
but should be reported only under section B.1.9.
B.3 Results of tests and procedures relevant to the
investigation of the patient
User Guidance:
This section should capture the tests and procedures performed to diagnose or confirm the reaction/event, including those tests done to investigate (exclude) a non-drug cause (e.g., serologic tests for infectious hepatitis in suspected drug-induced hepatitis). Both positive and negative results should be reported. While structured information is preferable, provisions have been made to transmit the information as free text in B.3.2.
B.3.1 Structured information (repeat as necessary)
Date |
Test |
Result |
Unit |
Normal low range |
Normal high range |
More information |
|
|
|
|
|
|
|
User Guidance:
Imprecise dates can be used; units and normal ranges should be in
free text unless covered by a controlled vocabulary. The column
entitled "more information available" accepts only yes or no (see
the companion document for the appropriate format). “Yes” means
that more documentation is available upon request e.g., ECG strips,
chest Xray. “No” means that no more documentation is available.
MedDRA LLT codes should be used to code test names.
If results and units cannot be split, B.3.2 should be used. More
than one test can be included in B.3.2.
B.3.2 Results of tests and procedures relevant to the investigation
B.4 Drug(s) information
User Guidance:
This section covers both suspect drugs and concomitant medications (including biologics). In addition, the section can be used to identify drugs thought to have an interaction. For each drug, the characterization of the drug role (B.4.k.1) is that indicated by the primary reporter, (i.e., the original source of the information) and the sender. The designation of ”k” in this section indicates that each item is repeatable and that it corresponds to the same “k” in all subsections. A separate block (k) should be used for each drug. Drugs used to treat the reaction/event should not be included here.
B.4.k.1 Characterization of drug role
Suspect / Concomitant / Interacting / Drug Not Administered /
Blinded
User Guidance:
This field contains the characterization of the drug as provided by primary reporter or if this information is missing, by the sender. All spontaneous reports should have at least one suspect drug (see Section 1.5). If the reporter indicates a suspected interaction, “interacting” should be selected. All interacting drugs are considered to be suspect drugs.
“Drug
not administered” can be used for example in two
circumstances:
-
in
clinical trial: if the adverse event occurred after the informed
consent was signed but prior to the administration of the study drug
e.g., during the screening period or the washout procedure. In
general the adverse event should be reported as due to the trial
procedure. In that case, the rest of the section B.4 should be left
blank and the information on the suspect cause of the event should
be provided in the section B.5.
-
medication error: if the patient did not receive the actual
prescribed drug but another one, repeatable section B.4 should be
completed with the information about the prescribed drug (including
the fact that it was not administered), as well as the information
on the dispensed drug as the “suspect” drug.
“Blinded”:
The ICH E2A guideline recommends that the case safety reports with blinded therapy should not be reported. However, if it is important to exchange a case safety report during a clinical trial, this value should be used. In that case the fields of the section B.4.k.2 Drug identification should be populated with the characteristics of all the blinded study drug(s).
B.4.k.2 Drug identification
User Guidance:
Medicinal product names and active ingredient names should be provided as they were reported. To standardise this information, the ICH M5 guideline should be used. In case of investigational drugs, only a code might be known and provided. If more than one active ingredient is specified, each should be included in item B.4.k.2.2,and can be repeated as necessary.
Based on the medicinal product name as reported by the primary source, the most specific identifier either the Medicinal Product Identifier (MedID) or the Pharmaceutical Product Identifier (PhPID) should be provided. If a MedID and a PhPID for the reported medicinal product are not available, this field should be left blank.
B.4.k.2.0.1 MedID and MedID operation date
B.4.k.2.0.2 PhPID and PhPID operation date
The name should be that used by the reporter. It is recognized that a single product can have different proprietary names in different countries, even when produced by a single manufacturer.
B.4.k.2.2 Active ingredient identifier (repeat as necessary)
User Guidance:
Each active ingredient should be specified individually by repeating this section. For each active ingredient, the ICH M5 active ingredient TermID should be provided if available. If the active ingredient TermID is not available, the INN or the active ingredient name or the drug identification code should be provided.
B.4.k.2.2.1 Active ingredient name
B.4.k.2.2.2 Active ingredient TermID and TermID operation date
B.4.k.2.3 Identification of the country where the drug was
obtained.
User Guidance:
See the companion document for the appropriate codes and format.
B.4.k.3 Holder and authorization/application number of drug
User Guidance:
If the ICH M5 MedID is not available for the reported medicinal product, the name of the holder should be provided with the authorization number in the country where the drug was obtained when the case report is sent to that country. These items apply to both applications and authorizations. Pharmaceutical companies should provide this information for their own suspect drug(s).
B.4.k.3.1 Authorization/Application Number
B.4.k.3.2 Country of authorization/application
User Guidance:
See the companion document for the appropriate codes and format.
B.4.k.4 Structured Dosage Information
(repeat as necessary)
(e.g., 2 mg three times a day)
B.4.k.4.1 dose (number) 2
B.4.k.4.2 dose (unit) mg
B.4.k.4.3 number of separate dosages 3
B.4.k.4.4 number of units in the interval 1
B.4.k.4.5 definition of the
interval unit day
User Guidance:
For B.4.k.4.2 the dose unit should be provided in accordance with the ICH M5 units and measurements controlled vocabulary if available. For each unit, the respective TermID and the TermID operation date should be specified. Please note the above side-by-side illustration of how the structured dosage should be provided. For the more complex example of 5mg (in one dose) every other day, subsections B.4.k.4.1 through B.4.k.4.5 would be 5, mg, 1, 2, day, respectively. In the same way, 50mg daily would be 50, mg, 1, 1, day.
In
the case of a parent-child/fetus report, the dosage section applies
to the parental dose.
If any of these pieces of information is unknown, the field should
be left blank.
For a dosage regimen that involves more than one dosage form and/or
changes in dosage, the information should be provided in section
B.4.k.4.10 as text. Categories for "definition of the interval unit"
are described in attachment 1
B.4.k.4.6 Date of start of drug
B.4.k.4.7 Date of last administration
User Guidance:
For ongoing drug administration after the onset of the
reaction/event, this item should be blank and Action(s) taken with
drug (B.4.k.11) should be used.
B.4.k.4.8 Duration of drug administration
User Guidance:
This item should be used if exact dates of drug administration are not available at the time of the report, but there is information concerning the duration of drug administration. The information requested is the overall duration of drug administration and covers intermittent administration. See the companion document for the appropriate format.
B.4.k.4.9 Batch/lot number
User Guidance:
This information is particularly important for vaccines and biologics. The most specific information available should be provided. For expiration date and other related information, see additional information on drug (B.4.k.13).
B.4.k.4.10 Dosage text
User Guidance:
This item should be used in cases where provision of structured dosage information is not possible.
B.4.k.5 Cumulative dose to the reaction/event
User
Guidance:
The cumulative dose provided should be the total dose administered until the first sign, symptom or reaction. Where possible, cumulative dose to the reaction/event should be structured as follows: (For standardised units see the user guidance of B.4.k.4.2.)
B.4.k.5.1 cumulative dose to first reaction (number)
B.4.k.5.2 cumulative dose to first reaction (unit)
B.4.k.6 Pharmaceutical Dose form
User Guidance:
Pharmaceutical dose form should be provided as TermID using the ICH M5 pharmaceutical dose form controlled vocabulary. If the pharmaceutical dose form TermID is not available, free text in B.4.k.6.1 should be used.
B.4.k.6.1 Pharmaceutical dose form
B.4.k.6.2 Pharmaceutical dose form TermID and TermID operation date
B.4.k.7 Route of administration
User Guidance:
Route of administration should be provided as TermID using the ICH M5 Route of administration controlled vocabulary. If the route of administration TermID is not available, free text in B.4.k.7.1 should be used. For a parent-child/fetus report, this indicates the route of administration of a drug given to the child/fetus. This is usually an indirect exposure, such as transmammary, but can include more usual routes of administration for other drugs given to the child. The parent’s route of administration should be provided in B.4.k.8.
B.4.k.7.1
Route of administration
B.4.k.7.2
Route of administration TermID and TermID operation date
B.4.k.8 Parent route of administration (in case of a parent
child/fetus report)
User Guidance:
This section should be used in a parent-child/fetus report and linked parent reports to indicate the route of administration to the parent. The parent route of administration should be provided as TermID using the ICH M5 Route of administration controlled vocabulary. If the Route of administration TermID is not available, free text in B.4.k.8.1 should be used.
B.4.k.8.1 Parent
Route of administration
B.4.k.8.2
Route of administration TermID and TermID operation date
B.4.k.9 Gestation period at time of exposure
User Guidance:
The gestational age at the time of the earliest exposure should be used. Gestation period at time of exposure should be expressed by providing both a number and designation of units of days, weeks, months or trimester. See the companion document for format specifications.
B.4.k.10 Indication for use in the case
(repeat as necessary)
User Guidance:
The indication as reported by the primary source should be provided in B.4.k.10.1. The MedDRA LLT code should be used in B.4.k.10.2.
B.4.k.11 Action(s) taken with drug
- Drug withdrawn
- Dose reduced
- Dose increased
- Dose not changed
- Unknown
- Not applicable
User Guidance:
These data, taken together with the outcome of the reaction (B.2.i.6), provide the information concerning dechallenge. “Not applicable” should be used in circumstances such as when the patient has died or the treatment had been completed prior to reaction/event.
B.4.k.12 Drug-reaction(s)/event(s) matrix
(repeat B.4.k.12.1 through B.4.k.12.4 as necessary)
B.4.k.12.1 Reaction(s)/event(s) assessed
User Guidance:
Generally the reaction(s)/event(s) assessed are ordered from the most important or the most serious to the least important. MedDRA LLT code should be used.
This
section provides the means to transmit the degree of suspected
relatedness of each drug to the reaction(s)/event(s). The repeating
items could also be used to provide the assessment of relatedness by
different sources or methods of assessment. For the purpose of
reporting, there is an implied suspicion of causality for
spontaneous reports. It is recognized that information
concerning the relatedness, especially for spontaneous reports, is
often subjective and might not be available.
• The following example illustrates the extensive functionality
contained in this section.
• Assume a patient being treated with two medications: Drug A and
Drug B.
• Assume the patient has had three adverse events: Event 1, Event 2,
and Event 3
• The reporter provided assessment of causality for events 1 and 2
for both Drug A and Drug B, but not for either drug concerning event
3. The reporter’s assessment of causality is based on overall
impression, which the sender codes as “global introspection”.
• The sender applies two methods of causality assessment, one with
an algorithm (coded algorithm) and the other a bayesian analysis
that provides a decimal probability (coded Bardi) but the sender
does so only for the drug the sender manufactures (in this case Drug
A).
• From the above there are 4 sets of data for the reporter
(2drugsX2eventsX1method of assessment) and 6 sets for the sender
(1drugX3eventsX2methods of assessment) for a total 10 sets of data.
• The appropriate item with the information is B.4.k.12 2(and its 3
subfields 1-3). In this example, k is replaced by Drug A and Drug B
respectively. Please note the subfields 1-3 are repeatable. Thus:
B.4.k.12.1 |
B.4.k.12.2.1 |
B.4.k.12.2.2 |
B.4.k.12.2.3 |
k(1) = DRUG A |
|||
event1
|
reporter |
global introspection |
related |
company |
algorithm |
possibly related |
|
company |
Bardi |
0.76 |
|
event2
|
reporter |
global introspection |
not related |
company |
algorithm |
possibly related |
|
company |
Bardi |
0.48 |
|
event3
|
company |
algorithm |
unlikely related |
company |
Bardi |
0.22 |
|
k(2) = DRUG B |
|||
event1 |
reporter |
global introspection |
not related |
event2 |
reporter |
global introspection |
not related |
The
order of the rows is not important since each one represents a
complete set, however, the E2B message and M2 specifications state
that all assessments for Drug A (k=1) should appear before Drug B
(k=2).
For subsection B.4.k.12.1 MedDRA LLT codes should be used.
Subsections B.4.k.12.2.1 through B.4.k.12.2.3 do not call for a
standardised methodology.
B.4.k.12.2.1 Source of assessment
(e.g., initial reporter, investigator, regulatory agency, company)
B.4.k.12.2.2 Method of assessment
(e.g., global introspection, algorithm, Bayesian calculation).
B.4.k.12.2.3 Result
The major uses of intervals are to cover circumstances both in which the dates are known but the interval is very short (e.g., minutes, such as in anaphylaxis), and in which only imprecise dates are known but more information concerning the interval is known. Dates if available, should be transmitted in the appropriate items, rather than intervals. If the sender wants to provide time intervals as well then the first day of administration should be counted as “1”.
The complexity of using intervals highlights the desirability of providing dates. See the companion document for format specifications.
B.4.k.12.3.1 Time interval between beginning of drug administration
and start of reaction/event
B.4.k.12.3.2 Time interval between last dose of drug and start of
reaction/event
B.4.k.12.4 Did reaction recur on readministration?
- yes/no/unknown
User Guidance:
Unknown indicates that a rechallenge was done but it is not known whether the reaction recurred. This field should not be completed if it is unknown whether a rechallenge was done.
B.4.k.13 Additional information on drug
User Guidance:
This should be used to specify any additional information pertinent to the case that is not covered by above sections (e.g., beyond expiration date, batch and lot tested and found to be within specifications). This item can also be used to provide additional information concerning the indication for the drug. For cases where the suspect drug was taken by the father, this should be indicated in this field as e.g., Drug taken by the father.
B.5 Narrative case summary and further information (repeat as necessary)
B.5.1 Case narrative including clinical course, therapeutic
measures, outcome and additional relevant information
User Guidance:
A focused, factual and clear description of the case should be given, including the words or short phrases used by the reporter.
B.5.2 Reporter's comments
User Guidance:
This item should be used to include the reporter's comments on the diagnosis, causality assessment or other issues considered relevant.
B.5.3 Sender's diagnosis/syndrome and/or reclassification of
reaction/event
(repeat as necessary)
User Guidance:
This section provides the sender with an opportunity to combine signs and symptoms that were reported into a succinct diagnosis. The reasoning would be included in section B.5.4. MedDRA LLT code should be used.
B.5.4 Sender's comments
User Guidance:
This section provides information concerning the sender's assessment of the case and can be used to describe disagreement with, and/or alternatives to the diagnoses given by the initial reporter. In case of linkage of multiple ICSRs using A.1.12, the reason should be provided in these comments.
3.
GLOSSARY
Parent-child/fetus report:
Report in which the administration of medicines to a parent results
in a suspected reaction/event in a child/fetus.
Receiver: The intended recipient of the transmission.
Reporter: Reporter is the primary source of the information, i.e., the person who initially reports the facts. This should be distinguished from the sender of the message, though the reporter could also be a sender.
Sender: The person or entity creating the message for transmission. Although the reporter and sender can be the same person, the function of the sender should not be confused with that of the reporter.
Definition of Interval List
Minutes
Hours
Days
Weeks
Months
Years
Cyclical
As necessary
Total
Example of a simple single report from a company to a regulator
Hospital X reports AE1 to Company K who then in turn sends ICSR1 to
Regulator. Population of relevant fields for this case is
illustrated in the first row of the table. Company K populates
A.1.0.1 with Company K’s (case) safety report unique identifier
“JP-K-001”.
Company K populates A.1.10.2 with “JP-K-001” because company K is
the initial sender of the report. Because there has not been a
previous E2B/M2 electronic report, the identifiers in A.1.0.1 and
A.1.10.2 are the same.
Example of company to company to company to regulator transmission
Hospital X reports AE1 to Company B who then in turn sends ICSR2 to
Company C.
Population of relevant fields for this case
is illustrated in the second row of the table. Company B populates
A.1.0.1 with Company B’s (case)
safety report unique identifier
“JP-B-001”.
Company B populates A.1.10.2 with “JP-B-001” because company B
considers itself the initial sender of the report because it is
unaware that Company K also sent an ICSR for this case.
Company C sends ICSR3 to Company D. The third row of the table
indicates how Company C populates the relevant fields. Company C
populates A.1.0.1 with “JP-C-001”.
Company C populates A.1.10.2 with “JP-B-001”, leaving the field
unchanged from the way Company B
populated it. In addition, Company C populates A.1.11.1 (Source of
the case identifier) with the name of company B, “B”. A.1.11.2 is
populated with Case Identifier in the Previous Transmission by
Company B “JP-B-001”.
Company D sends ICSR4 to Regulator. The fourth row of the table
indicates how Company D populates the relevant fields. Company D
populates A.1.0.1 with “JP-D-001”. Company D retains in fields
A.1.10.2, A.1.11.1, and A.1.11.2 the information populated by
Company C, and Company D adds to the retained information in
repeatable field A.1.11.1 “C” to represent that Company C is another
source of the case identifier, and Company D adds in field A.1.11.2
“JPC-001” to represent Company C’s case identifier from the previous
transmission.
Example of Linking Two Separate Adverse Events Affecting the Same
Patient
Patient XX later suffers a separate adverse event, AE2. Hospital X
reports AE2 to Company K who then in turn sends ICSR7 to Regulator.
Population of relevant fields for this new case is illustrated in
the seventh row of the table. Company K populates A.1.0.1 with
Company K’s (case) safety report unique identifier “JP-K-002”.
Company K assigns a new (case) safety report unique identifier
“JP-K-002” because “JP-K-001”, as described above, represent a
separate adverse event. Company K populates A.1.10.2 with “JP-K-002”
because company K is the initial sender of the report. Because there
has not been a previous E2B/M2 electronic report, the identifiers in
A.1.0.1 and A.1.10.2 are the same. The previous report from Company
K, “JP-K-001”, for patient XX should be represented in A.1.12,
Identification Number of the Report which is Linked to this Report.
In a
contrasting example, Hospital X also reports AE2 to Company F.
Company F had not previously received an AE concerning Patient XX,
and therefore there is no linked report and A.1.12 is not populated.
As in the first example concerning ICSR1, ICSR8 is a simple single
report from a company to a regulator.
Example of Linking Three Separate Adverse Events Affecting the Same
Patient
Patient XX later suffers a third, separate and distinct adverse
event, AE3. Hospital Y reports AE3 to Company K who then in turn
sends ICSR9 to Regulator. Population of relevant fields for this new
case is illustrated in the ninth row of the table. Company K
populates A.1.0.1 with Company K’s (case) safety report unique
identifier “JP-K-003”. Company K assigns a new (case) safety report
unique identifier “JP-K-003” because “JP-K-001” and “JP-K-002”, as
described above, represent separate, adverse events. Company K
populates A.1.10.2 with “JPK-003” because company K is the initial
sender of the report. The previous reports from Company K,
“JP-K-001” and “JP-K-002”, for patient XX should be represented in
the repeatable field A.1.12, Identification Number of the Report
which is Linked to this Report.
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Date created: September 30, 2005