Guidance for Industry
E2B(M): Data Elements for Transmission of Individual
CaseSafety Reports
Questions and Answers
This
guidance represents the Food and Drug Administration's (FDA's)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if that
approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of
this guidance.
This question and answer (Q&A) guidance is
intended to assist applicants who plan the electronic transmission
of individual case safety reports (ICSRs) to the Food and Drug
Administration (FDA). The guidance is a revision of the E2B(M)
Q&A guidance that was published in May 2004. The guidance
provides answers to questions that have arisen since the
finalization of the ICH E2B(M) guidance, version 4.4.1, and the M2
specification document, version 2.3. This Q&A quidance is not
meant to be all inclusive, as further questions may be addressed
in the future.
The
questions and answers provided here reflect the consensus of the
ICH parties.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
The ICH guidance E2B Data Elements for
Transmission of Individual Case Safety Reports was signed off
by the International Conference on Harmonisation (ICH) in July
1997 and issued by the FDA in January 1998. ICH subsequently
issued a revised guidance, E2B(M), to provide additional
information and clarification. The revised guidance incorporated
adjustments based on the successful pilot projects being conducted
in the three ICH regions. ICH signed off on E2B(M) in November
2001, and the FDA issued the revised guidance in April 2002.
Q1: During the period of transition, as health
authorities or pharmaceutical companies migrate from paper to
electronic ICSR submissions and exchanges using E2B(M)/M2
standards, certain ICSRs will likely be exchanged in both paper
and electronic format.
This could
occur either because the initial ICSR was on paper and the
follow-up is in electronic format or because the two parties are
in a pilot program where they are exchanging ICSRs in both paper
and electronic format. Two questions arise:
Question 1a:
How can two or more exchanges of the same ICSR be linked together
to avoid a duplicate report?
Question 1b:
How can the current paper forms accommodate the full ICH format of
the worldwide unique case identifier? (E2BM IWG0001)
A1: Answer 1a: Compliant with the definition of field
A.1.0.1, the ICH format of the worldwide unique case identifier
(country code-company or regulator name-report number) should
always be used, and copied into field A.1.10.1 or A.1.10.2. as
appropriate.
In the event that
the ICSR either has been exchanged by the two parties in the past
using a different identifier or that it is exchanged
simultaneously with a different identifier, this other identifier
should be listed in field A.1.11.2 and the organization’s name
should be captured in field A.1.11.1, consistent with the
definition of the A.1.11 field for the identification of
duplicates.
This
recommendation applies to DTD version 2.0 and DTD version 2.1.
Answer 1b: In
case the ICH conforming worldwide unique case identifier cannot be
accommodated on the paper forms, it is recommended that the report
number alone (without the country code or the company or regulator
name) be used.
Q2: For fields where only one MedDRA coding level is
accommodated, should I use PT or LLT?
Section
B.2 contains fields B.2.i.0, B.2.i.1 and B.2.i.2 to capture the
verbatim term, LLT and PT, respectively. However, sections
B.1.7.1a, B.1.8f, B.1.8g, B.1.9.2, B.1.9.4, B.1.10.7.1a,
B.1.10.8f, B.1.10.8g, B.4.k.11, B.4.k.17.2, B.4.k.18.1, B.5.3
contain only one field and do not specify whether the LLT or PT
should be used. (E2BMIWG0002)
A2: For the ICH E2B(M) fields B.1.7.1a, B.1.8f, B.1.8g,
B.1.9.2, B.1.9.4, B.1.10.7.1a, B.1.10.8f, B.1.10.8g, B.4.k.11,
B.4.k.17.2, B.4.k.18.1, B.5.3 the following should be used:
·
For EU regulators: LLTs
·
For FDA: PTs
·
For MHLW: PTs
Q3: What is the process to maintain, add, modify, or
delete entries in the code lists in attachments 1 and 2 of E2B(M)?
(E2BM IWG0003)
A3: Currently these lists cannot be
modified.
Q4: The current definition of B.4.k.7 calls for the use
of free text until a controlled vocabulary is available. Is a
harmonized vocabulary for pharmaceutical dosage forms available?
(E2BM IWG0004)
A4: There is currently no harmonized
vocabulary for pharmaceutical dosage forms.
Until an ICH
vocabulary is available, the following should be used:
·
For EU Regulators: the European Pharmacopoeia standard list
·
For FDA: Free text
·
For MHLW: The list of pharmaceutical forms as made available by
MHLW
Q5: How can I send product-specific registration or
other regulatory administrative information to multiple receivers
in a single transmission? (E2BM IWG0005)
A5: A single transmission for administrative information of
an ICSR to multiple receivers in the ICH regions is currently not
possible.
Various health
authorities have engaged in production or pilot programs to
implement E2B(M). A need to capture in more detail
registration–related information (similar to the existing paper
submission process using fax cover sheets or regulatory forms)
became evident. As a consequence, local guidance has been
introduced to transmit additional information accompanying each
ICSR:
·
For EU Regulators: see E2B section B.4.k.4.
·
For FDA: Field B.4.k.4.1. should contain the NDA, BLA or STN
number in the appropriate format.
·
For MHLW: Each ICSR should be accompanied by a corresponding
J-file, as detailed in the relevant MHLW guidance documents.
Q6: What language should I use for an ICSR
transmission? (E2BM IWG0007)
A6: For EU Regulators: ICSRs in English are generally
accepted. However, there can be local requirements for a
translation of the case narrative in the official local language.
For FDA: English
For MHLW: Japanese
Q7: How can I submit a causality or scientific
assessment in either an algorithmic or text representation in the
current E2B(M) format? (E2BM IWG0008)
A7: The current structure of E2B(M) includes fields
B.4.k.18.1-4, which allow the sender to indicate such assessments
for each drug-event combination.
In addition, field
B.5.4 can be used to further elaborate the sender’s position or
assessment. Local regulatory requirements regarding expedited and
periodic reporting determine whether inclusion of sponsor
assessments is necessary.
Q8: How can I identify the primary source and the
reporter qualification when an ICSR is forwarded by health
authorities with minimal or no information on the primary source?
(E2BM IWG0009)
A8: If no information on the primary source is available,
section A.2.1 should identify the health authority as the primary
source. Field A.2.1.4 “Qualification” should be populated with a
code of “3” (Other health professional).
In addition, field
A.1.4 “Type of report” should be populated with a code of “4” (Not
available to sender (unknown), if appropriate.
Q9: How can I identify the study name, the study
number, the patient, and the drug in clinical trials to be
reported to the EU regulators and MHLW in the E2B(M) format? (E2BM
IWG0010)
A9: The code list of “Study type” in field A.2.3.3. is very
short, so the type of study should be characterized more clearly
in the study name. For a more explicit description of the study
beyond 100 characters, the full study name should be given in the
case narrative. In addition, some regulatory authorities request
the additional submission of a regulatory study number (e.g.,
EUDRACT number). For this situation, the study name in element
A.2.3.1 should be a concatenation of the EUDRACT number and the
“Study name,” i.e., EUDRACT number-Study name.
The “Study number”
in field A.2.3.2 should be the sponsor study number.
The patient
identification in a clinical trial can be transmitted in field
B.1.1.1d “Patient investigation number.” Note that multiple
elements from the source database, like Center- Patient and random
number, should be concatenated in this element to ensure a unique
patient identification.
The trial
drug identification is possible through the usual elements for the
description of the suspected drug B.4.k.2.1 and B.4.k.2.2. For
some countries, the project-related regulatory drug identification
number can be submitted in field B.4.k.4.
The present version of E2B(M) allows for the distinction of
unblinded vs. blinded information.
Q10: There might be cases where, for one drug, and more
than one formulation/dosage, lot number and indication are
provided. How should this information be presented in the
electronic transmission? (E2BM IWG0011)
A10: The drug section B.4 is a repeatable block.
If for
one drug there is information on multiple dosages/formulations or
indications, the entire section should be repeated to capture all
the information.
For lot
numbers, the guidance allows for multiple batch/lot numbers in the
same field B.4.k.3. However, it is recommended that the drug
section B.4 be repeated.
Q11: Field B.1.2.1 “Patient birth date” provides for
population with a full date format including day, month, year. If
incomplete dates are reported, how should these be presented?
(E2BM IWG0013)
A11: If an incomplete date of birth is reported, then the field
B.1.2.2. “Age at the time of onset of reaction/event” should be
used, as indicated in the user guidance. Alternatively, field
B.1.2.3 “Patient age group (as per reporter)” can be used to
indicate the age of the patient.
Q12: Do the concepts of parent child reporting as
described in the ICH E2B(M) guideline also apply to a fetus or an
unborn child? (E2BM IWG0015)
A12: All
reports affecting a fetus or an unborn child should be recorded as
parent-child reports with the appropriate sections of E2B(M)
completed.
Q13: Where in the E2B(M) message should a patient's drug
allergy history be reported e.g., reporter has stated that the
patient has an allergy to aspirin? There is no indication in the
report as to whether the patient previously took the medication as
treatment and had an allergic reaction or whether this knowledge
came from patch testing.
In addition,
reports of drug allergy history are often subjective and can be
erroneous. MedDRA terms are available for allergies to insulin
and a few antibiotics (sulfonamide, penicillin) but few drugs are
specifically named in conjunction with the allergy. (E2BM IWG0017)
A13: It might
be advisable to obtain additional information from the primary
reporter.
If it is
the first allergic reaction for the patient and allergy testing
results are available, they can be recorded along with other ADR-related
terms. For example, the reaction itself is coded to the PT “Drug
hypersensitivity” (or a more descriptive LLT) in B.2.i.1 or
B.2.i.2. In addition, the testing results are recorded by use of
the PT “Skin test positive” or “Allergy test positive” (or their
more descriptive LLTs) in B.2.i.1 or B.2.i.2.
Relevant
past drug history, such as a history of allergy to a particular
drug, can be reported in repeatable section B.1.8, using the
suspect drug name and MedDRA terms in the indication and reactions
fields.
The information
could also be reported in section B.1.7.1, “Structured information
on relevant medical history...” by using the PT “Drug
hypersensitivity” (or a more descriptive LLT) under “Disease /
surgical procedure / etc.,” and the name of the drug under
“comments.” This latter field is not searchable in most databases
and thus this is not the preferred option.
Q14: What is the time frame for a drug to be included in
the drug history section or as a concomitant drug? (E2BM IWG0018)
A14: This is a medical judgment that should be made by the
medically trained reporter and evaluator (e.g., in the company or
health authority).
The
decision should be based on the elimination half-life of the drug
and the known pharmacodynamic effects of the drug in that
particular patient (for example, a patient with known renal or
liver impairment).
If it is
unlikely that the product is still in the body and if there are no
biologic effects known or suspected in that patient, the product
should be listed in the medical history.
If the
drug is still in the body or if there is a suggestion of biologic
activity (even if the kinetics suggest complete elimination
already) and if the reporter or the evaluator feel there is a
possibility that the product played a role in the AE, then the
product should be listed as a suspect drug. If the reporter and
evaluator both agree that it is not a suspect drug, it should be
listed as a co-medication (concomitant medication).
It is
difficult to give an absolute time interval between the ingestion
or use of the drug and the appearance of the AE. This is a
medical judgment.
Overall,
a conservative approach should be taken, and if there is any
doubt, the product should be considered a suspect drug. If there
are critical or controversial issues to be discussed in regard to
this judgment, they can be briefly mentioned in the narrative.
As a
general principal, all drugs that were completed/discontinued
before the start of the treatment with the suspect(ed) drug(s)
should be included in the “Relevant drug history” section
(B.1.8). Any drug(s) that are not suspected of causing the event
or reaction and that are administered to the patient at the time
the case is reported should be listed as concomitant medication.
Q15: Based on current experience it has become evident
that the information collected for many of the E2B(M) fields is
exceeding the current field lengths (e.g., A.1.8.2 “List of
documents held by the sender,” A.2.3.1 “Study name,” B.4.k.6
“Dosage text,” B.2.i.0 “Reaction/event as reported by primary
source,” B.5.1 “Case narrative,” B.5.2 “Reporter commen”t).
As the information can be critical to the report, there is the
possibility that the sender organization could get into legal
problems. (E2BM IWG0019)
A15: As a general principle, it is recommended that the sender
structure all available information on the case to the highest
possible extent in the currently available E2B(M) fields.
The
E2B(M) standards should be adhered to. Each sender is responsible
for managing the information in the appropriate way.
Q16: We have an issue on reporting pregnancy cases which
we would be very happy to get your opinion on:
We
have a study on pregnant women concerning diabetic patients. Up
to 60% of these deliver by caesarean section (CS) either planned
or emergency.
We suggest submitting linked serious adverse events reports
as follows:
Scenario 1: Fetal distress and CS: One case on fetus (fetal
distress), but none on the mother (CS). Follow-up on fetus: Event
can be recoded to e.g., brain hypoxia: Outcome of event on fetus:
e.g., recovered or recovered with sequelae of brain damage. If the
mother suffers a complication, e.g., an infection in the wound,
this could be another adverse event.
Scenario 2: Mother suffers from pre-eclampsia and the child is
fine. One AE of pre-eclampsia on the mother. No event on the
child.
Scenario 3: Mother suffers from pre-eclampsia and the child is
small and a complication on the child occurs. One AE of pre-eclampsia
on the mother. Just one code of Pre-eclampsia? or two codes one
of pre-eclampsia and one of CS, one or more events on the child?
(E2BM IWG0022)
A16: This answer was revised on November 18, 2004; the
revision is indicated below in bolded text.
The User Guidance, section B.1 (patient
characteristics) states that in cases where a fetus or nursing
infant sustains an adverse reaction/event, information on both the
parent and child/fetus should be provided (referred to as
parent-child/fetus report). If there has been no reaction/event
affecting the child/fetus, the parent-child fetus report does not
apply. For those cases describing fetal demise or early
spontaneous abortion, only a parent report is applicable. If both
the parent and the child/fetus sustain adverse events, two reports
should be provided, but they should be linked using sections
A.1.12 in each report. When only the child/fetus has an adverse
reaction/event (other than early spontaneous abortion/fetal
demise), the information provided in this section applies to the
child/fetus and the characteristics concerning the parent who was
the source of exposure should be provided in section B.1.10.
Scenario
1: As the author of the question suggests, only one SAE report
should be completed for the fetus mother, with the
AE of fetal distress (recoded later to brain hypoxia). The
caesarean section should not be considered an AE for the mother.
The mother’s characteristics should be captured in B.1.10.1 with
the caesarean section as relevant medical history (B.1.10.7).
Scenario
2: As the author of the question suggests, only one SAE report
should be completed for the mother, with the AE of pre-eclampsia.
No events are reported for the child; therefore, a linked SAE
report is not called for.
Scenario
3: Two linked SAE reports should be submitted: The mother’s
report should have the AE pre-eclampsia; the report for the fetus
should have a term for fetal complication. The term pre-eclampsia
would only apply to the mother’s case. Section A.1.12 (ID number
of the linked report) should be completed for both the mother and
child’s case.
Q 17: Can you provide more detailed user guidance on the
use of “Term highlighted by the reporter” (B.2.i.3)? (E2BM IWG0026
and 0037)
A17: All adverse reactions/events that occur at any point after
introduction of the suspect drug/vaccine should be reported in
E2B(M) section B.2 . Field B.2.i.0 should be used to report all
reactions/events. Each reaction/event reported in the field
B.2.i.0 should be coded in the fields B.2.i.1 (MedDRA LLT) or
B.2.i.2 (MedDRA PT) or both, depending on regional preference.
Field B.2.i.3 “Term highlighted by the reporter” is an optional
field that, if used, should be correlated with medical concept(s)
listed in field B.2.i.0. B.2.i.3 should be used to categorize the
reactions/events as to (a) whether the medical concept was the
reason the reporter contacted the company and (b) whether the
medical concept is serious according to the company. If field
B.2.i.3 is used, a single entry is selected from four listed
numeric responses (1-4). The optional entries in B.2.i.3 should
always map to entries in B.2.i.0.
This
field is intended for the identification of a specific diagnosis
as identified by the reporter, e.g., if the reporter specifies
flu-like syndrome comprising of fever, chills, sneezing, myalgia
and headache, then flu-like syndrome is the highlighted term.
If only
one event is cited in a case report, this one is by implication
considered highlighted by the reporter.
This
field is optional for completion in the European Union and the
United States but is mandatory in Japan for all complete case
report types. For details, please consult MHLW guidance.
Q18: When is it intended to introduce a
repeatable indication section within the drug section? (E2BM
IWG0027)
A18: DTD version 2.1 cannot currently be modified. Therefore,
it is not possible to introduce a repeatable “indication” section
within the “Drug(s) information” section B.4.
If for
one drug there is information on multiple indications, the entire
section B.4 should be repeated to capture all the specified
indications (please refer also to user guidance as provided in the
answer to question 10 (E2BM IWG0011)).
Q19: When is it intended to add the
time zone information in M1.7 “Message date”? (E2BM IWG0028)
A19: The fields M.1.7a “Message date format” and M.1.7b
“Message date” allow the specification of the exact message date,
including year, month, day, hour, minute, and second.
Information on the time zone cannot currently be accommodated in
DTD version 2.0 or 2.1 since the specifications cannot be
modified.
In
general, the time specified in M.1.7 should always reflect the
sender’s time and time zone.
Q20: Practical experience has shown that it is important
to capture seriousness criteria at reaction/event level.
How can this be handled within the current E2B(M) guideline?
(E2BM IWG0029)
A20: All seriousness criteria as specified in field A.1.5.2
“Seriousness criteria” apply to the case as a whole.
Field
B.2.i.3 “Term highlighted by the reporter” can be used to identify
the seriousness of each reaction/event that the primary source
indicated was a major concern or reason for reporting the case.
Q21: For some time I have been looking, unfortunately
without success, for an official message definition for a message
to exchange company profiles including certificates between the
organisations.
Is
an official standardized message for this purpose available and if
so where can I get the guideline / DTD / schema from? (E2BM
IWG0031)
A21: There is no ICH standard procedure for exchanging
certificates (or public keys) of encryption software. However, in
general, the use of safe and reliable procedures is recommended.
The
procedures for exchanging certificates and public keys between
health authorities and industry are specified in the regional
legislation or guidelines.
EU:
http://eudravigilance.emea.eu.int
Japan:
http://www.pharmasys.gr.jp/e2bm2/e2bm2_index.html (Notification
No.0630004/No.0630006 dated on 30 June 2003).
US: http://www.fda.gov/cder/aerssub
Q22: ICHE2B(M) refers to the basic elements for
developing an electronic Serious Adverse Reaction Form.
In
section B.2, Reaction(s)/Event(s) Description, it seems that more
than one reaction could be described.
Does this mean that a syndrome should be divided into the
different symptomatologies defining this syndrome (e.g., should
flu syndrome be
divided into headache, joint aches, etc.)? In that case, and as
far as I understood, there is a concept discrepancy because
requirements also say that a different form should be used for
each serious adverse event. (E2BM IWG0034)
A22: The purpose of the E2B(M) document is to standardize the
data elements for the transmission of ICSRs. For advice on
describing syndromes, please refer to the latest edition of the
ICH document “MedDRA Term Selection: Points to Consider” as
published at http://www.ich.org. At the time of this writing,
advice is provided in sections on “Diagnosis reported with signs
and symptoms” and “Provisional diagnoses.”
B.2.i.1
and B.2.i.2 are repeatable fields, and a separate block should be
used for each reaction/event term for the purpose of accommodating
multiple reactions within a single report. A separate form should
not be used for each serious adverse event occurring in the same
patient with the same suspect product.
Q23: A serious case was sent
electronically by a company to a Regulatory Authority. Meanwhile,
due to follow-up information received at the company, this case is
now determined to be non-serious.
Question 23a: Should the company
send a new message indicating that the case is now non-serious?
Question 23b: Should the company
send a new message to nullify the case in the Regulatory
Authority's database?
Question 23c: If the case becomes serious again, should the
company send a new message with the same <safetyreportid>? (E2BM
IWG0037)
A23: Answer 23a: Yes, the company
should send a new message, updating the previous report with the
new information, indicating that the case is now non-serious. The
new information should be provided and, in addition, the fields
below should be populated as follows:
A.1.0.1:
same identifier as in the initial report
A.1.10.2: same
identifier as in the initial report
A.1.5.1: value =
no
A.1.7: date of
receipt of the most recent information.
Answer 23b: The company should not send
a new message to nullify the case in the Regulatory Authority's
database.
Answer 23c: Yes, this would be new
information, and a follow-up report would be appropriate. The
same identifiers A.1.0.1 and A.1.10.2 for the link to the initial
ICSR should be used.
Q24: In case of miscarriage:
Question
24a: Should an ICSR be prepared for the parent, the fetus, or
both the parent and the fetus?
Question
24b: For the ICSR, should the seriousness criterion be “other
medically important conditio” rather than “result in death”?
Question 24c: Should the outcome of the parent’s condition be
entered in B.2.i.8 (outcome of reaction/event at the time of last
observation)? (E2BM IWG0038)
A24: Answer 24a: See the answer to
question 16 (E2BM IWG0022).
Answer 24b: Since
the ICSR should be prepared only for the parent, the seriousness
criterion is “other medically important condition.” But,
depending on the parent’s condition, the seriousness criterion
could be life-threatening and/or hospitalization.
Answer
24c: Yes, the outcome of the parent’s
condition should be entered in B.2.i.8.
Q25: How should field A.1.6 (the date report was first
received from source) be populated, taking into consideration the
recommendations of the ICH-E2D guideline:
Question
25a: Is it the date when the MAH receives a case report that
fulfills minimum criteria for reporting? Or, the date when the
sender receives the information that fulfills minimum criteria
regardless of reportability from the primary source?
Question
25b: For example, what if the initial report was obtained on 01
May for the non-serious case and was not reported to the relevant
regulatory agency; then on 10 May, what if follow-up information
became available that necessitated expedited reporting because the
case was determined to be serious and unlabeled? (E2BM IWG0040)
A25: Answer 25a: Field A.1.6 should be populated with the date
the information is received from the source. This information
should fulfill the recommendations of the current ICH
E2B(M)guideline, Section 1.5, “Minimum information” and the ICH
E2D guideline, Section 4.2, “Minimum information for reporting.”
The minimum information for the transmission of a report should
include at least one identifiable reporter (section A.2),
identifiable patient (section B.1), one reaction/event (section
B. 2), and one suspect drug (section B.4).
Answer
25b: In this example, in the field A.1.6, the initial report date
and the follow-up report date are both 01 May. In the field
A.1.7, the most recent information available date is 01 May for
the initial report and 10 May for the follow-up report. Whether
or not this case safety report should be reported to the relevant
regulatory authority will depend on the local authorities.
Q26: What is the difference between releases 1.0 and 2.0 of
the v2.1 DTD? Is either one acceptable for use? (E2BM IWG0042)
A26: Release 1.0 of v2.1 DTD had errors that
were corrected, which resulted in release 2.0 of v2.1 DTD.
Release 1.0 should not be used. Release 2.0 should be used.
Q27: Case A is linked with Case B.
When case B
is transmitted in E2B format, should A.1.12 field in the file
contain A.1.0.1 Safety Report Id or A.1.10 Company Number for case
A? (E2BM IWG0046)
A27: When a case report A is to be linked to case report B by a
company X, the field A.1.12 of both reports should be populated.
In case report A the field A.1.12 should capture the value of the
field A.1.10.1 (if the sender is a regulator) or A.1.10.2 (if the
sender is a company) as the field appears in case report B.
Similarly, in case
report B, the field A.1.12 should capture the value of the field
A.1.10.1 (if the sender is a regulator) or A.1.10.2 (if the sender
is a company) as the field appears in case report A.
Q28: A man started medications before his partner became
pregnant. But she has a miscarriage now.
Question
28a: Is the ADR a miscarriage?
Question
28b: Is the patient of the report the father or mother?
Question
28c: Is the route of administration how the father took the
medicine? (E2BM IWG0047)
A28: Answer 28a: Yes. In this case the ADR should be the
miscarriage experienced by the mother.
Answer 28b:
The patient should be the mother. Per the user guidance,
in case of fetal demise or early spontaneous abortion, only a
parent report is applicable. The sections B.1.1 to B.1.8 should
be completed.
Answer
28c: Yes. The route of administration should be how the father
was given the suspect medication. But while the characteristics
of the suspect drug should be captured in section B.4, it should
be clearly mentioned in field B.4.k.19 (additional information on
drug) that the suspect medication was taken by the father. Since
it’s a mother’s report, the route of administration (B.4.k.8.)
should be indicated as unknown.
Q29: A man started medications before his partner became
pregnant. The baby was born with ADR. Are the following
statements correct?
Question
29a: A report should be submitted as a parent-child/fetus
report.
Question
29b: B.1.10 captures the data of the father.
Question 29c: Route of administration is unknown. (E2BM
IWG0048)
A29: Answer 29a: Yes. The report should be submitted as a
parent-child/fetus report. The patient should be the baby.
Answer 29b: Yes,
B.1.10 should be populated with the father's data.
Answer 29c: Yes,
in this case, not enough information was provided to determine the
route of administration of the suspected drug to the baby. The
route of administration should be indicated as unknown.
Q30: Given the user guidance in the E2BM guideline and
the answer to question 10 (E2BM IWG0011) in the Q&A document,
please describe the preferred use of B.4.k.15a for the following
two scenarios. The reports are from spontaneous sources and exact
dates of drug administration are unknown in both instances:
Scenario 1: Identifiable patient received drug “X” p.o. in
hospital for one week and then the same drug/form/dose for two
weeks at home. There was a serious, unexpected event and an
identifiable reporter, etc.
Question 30a: For scenario 1, would it be necessary to repeat
B.4.k.15a? That is, should a single entry of <3> populate the
duration field (B.4.k.15b units entry <803> week) or should the
related field repeat with the drug listed twice with <1> and <2>
populating the corresponding B.4.k.15a field, respectively?
Question 30c: Should, for Scenario 2, the drug be listed twice
(different forms, per Q&A 10) and the duration for BOTH show as 3?
Question 30d: Should an adjustment be made in the E2B message if
there was a known missed dose/day or two in either scenario (to
cover the “intermittent” user guidance)? (E2BM IWG0050)
A30: Answer 30a: For scenario 1, if the drug treatment was
continuous, drug “X” should be listed in B.4.k.2 (B.4.k.2.1,
Proprietary medicinal product name, and B.4.k.2.2, Active drug
substance name) with <3> populating field B.4.k.15a (Duration of
drug administration) and <803> (week) populating field B.4.k.15b
(Duration of drug administration unit). Fields B.4.k.15a and
B.4.k.15b would not need to be repeated. However, if treatment was
stopped between hospital and home, it would be preferred to
repeat drug “X” in block B.4.k.2 (repeat entries in both field
B.4.k.2.1 and field B.4.k.2.2), with values of <1> and <2>
populating the corresponding duration fields (B.4.k.15a) and <803>
(week) populating the two unit fields (B.4.k.15b).
Answer 30d: An
adjustment in the structured data fields need not be made for a
known missed dose/day or two in either scenario (in accordance
with the “intermittent” user guidance); descriptive information
can be provided in the dosage text field (B.4.k.6).
Q31: ICH E2D states: For regulatory purposes, if an
event is spontaneously reported, even if the relationship is
unknown or unstated, it meets the definition of an adverse drug
reaction.
Question
31a: In the case of a spontaneous report with an unstated
relationship, does that imply that the fields B.4.k.18.1 through
B.4.k.18.4 should be populated with the causality assessment
“possible” for all the drugs?
Question 31b: Can the company have a different opinion from the
reporter and state the causality with the same drug is unrelated
or unlikely? (E2BM IWG0051)
A31: Answer 31a: If an event is spontaneously reported to a
company about the patient who took that company's drug, and the
relationship is unstated, it implies a suspected causal
relationship to the drug. However, fields B.4.k.18.1 through
B.4.k.18.4 should be left blank unless otherwise required by local
regulation.
Answer
31b: The company's causality assessment can be captured in fields
B.4.k.18.1 through B.4.k.18.4 and the sender’s comments can be
captured in field B.5.4.
Q32: A company wishes to report a fixed
combination medicinal product (e.g., ace inhibitor 20 mg and
diuretic 12.5 mg). How should we code this information in section
B.4, taking into account the need to provide the structured dosage
information for this combination?
(E2BM IWG0053)
A32: The proprietary medicinal product name of the fixed
combination product should be entered in B.4.k.2.1. The active
substance for the ace inhibitor should be entered in B.4.k.2.2.
B.4.k.2.2 should
be repeated and the active substance for the diuretic should be
repeated.
The dosage
information should be entered in B.4.k.6 as free text.
In
Japan, codes are available for approved combination drugs and can
be used in the appropriate fields: B.4.k.2.1 (proprietary
medicinal product name) and B.4.k.2.2 (active substance name).
Q33: If a report is forwarded to a company by a Health
Authority, should the company consider that:
Question
33a: the Health Authority's causality assessment is at least
“possible”?
Question 33b: the reporter’s causality assessment is also at
least “possible”? (E2BM IWG0054)
Q34: Use of Elements:
--
B.4.k.5.3 <drugseparatedosagenumb>
-- B.4.k.5.4
<drugintervaldosageunitnumb>
-- B.4.k.5.5
<drugintervaldosagedefinition>
Can you confirm that it is the case that if any one of the
above three elements is provided then all three must be provided,
as sending only some of these elements gives information that
cannot be interpreted? (E2BM IWG0055)
A34: To provide structured information in
B.4.k.5 (Structured dosage information), the information should be
provided in the relevant fields. However, if the data are
incomplete or difficult to structure, the available information
should be provided in B.4.k.6 (Dosage text).
This guidance was developed within
the E2B(M) Implementation Working Group (IWG) of the
International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
and has been subject to consultation by the regulatory parties,
in accordance with the ICH process. This document has been
endorsed by the ICH Steering Committee at Step 4 of the
ICH process, June 10 and November 18, 2004, updated in January
2005, and corrected in March 2005. At Step 4 of the
process, the final draft is recommended for adoption to the
regulatory bodies of the European Union, Japan, and the United
States.
The numbers in parentheses reflect
the numbering used by the E2B(M) Implementation Working Group.