Federal Register, Volume 63 Issue 10 (Thursday, January 15, 1998)

[Federal Register Volume 63, Number 10 (Thursday, January 15, 1998)]
[Notices]
[Pages 2396-2404]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-959]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 96D-0236]

International Conference on Harmonisation; Guidance on Data
Elements for Transmission of Individual Case Safety Reports;
Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a
guidance entitled ``E2B Data Elements for Transmission of Individual
Case Safety Reports.'' The guidance was prepared under the auspices of
the International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH). The guidance
is intended to facilitate the standardization of the data elements for
the transmission of individual case safety reports for both preapproval
and postapproval reporting periods.

DATES: Effective January 15, 1998. Submit written comments at any time.

ADDRESSES: Submit written comments on the guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guidance are
available from the Drug Information Branch (HFD-210), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-4573. Single copies of the guidance
may be obtained by mail from the Office of Communication, Training and
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and
Research (CBER), or by calling the CBER Voice Information System at 1-
800-835-4709 or 301-827-1800. Copies may be obtained from CBER's FAX
Information System at 1-888-CBER-FAX or 301-827-3844.

FOR FURTHER INFORMATION CONTACT:
Regarding the guidance: Marcel E. Salive, Center for Biologics
Evaluation and Research (HFM-220), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852, 301-827-3974.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.

SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
In the Federal Register of October 1, 1996 (61 FR 51287), FDA
published a draft tripartite guideline entitled ``Data Elements for
Transmission of Individual Case Safety Reports'' (E2B). The notice gave
interested persons an opportunity to submit comments by December 30,
1996.
After consideration of the comments received and revisions to the
guidance, a final draft of the guidance was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies on July 17, 1997.
In accordance with FDA's Good Guidance Practices (62 FR 8961,
February 27, 1997), this document has

[[Page 2397]]

been designated a guidance, rather than a guideline.
The guidance is intended to facilitate the standardization of the
data elements for the transmission of individual case safety reports by
identifying and defining the data elements for the transmission of all
types of individual case safety reports, regardless of source and
destination. This includes case safety reports for both preapproval and
postapproval reporting periods and covers both adverse drug reaction
and adverse event reports. It is not intended that this format should
be used for cases in the integrated safety summary of a marketing
license application dossier. For adverse reactions encountered in
clinical trials, this format should be used only for those subject to
expedited reporting.
This guidance represents the agency's current thinking on data
elements for the transmission of individual case safety reports. It
does not create or confer any rights for, or on, any person and does
not operate to bind FDA or the public. An alternative approach may be
used if such approach satisfies the requirements of the applicable
statute, regulations, or both.
As with all of FDA's guidances, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guidance. The comments in the docket will be periodically
reviewed, and, where appropriate, the guidance will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
guidance to the Dockets Management Branch (address above). Two copies
of any comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. The guidance and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. An electronic version of this guidance is
available on the Internet at ``http://www.fda.gov/cder/guidance/
index.htm'' or at CBER's World Wide Web site at ``http://www.fda.gov/
cber/publications.htm''. Information on the electronic transmission of
individual case safety reports is available on the Internet at IFPMA's
ICH site home page at ``http://www.ifpma.org/ich1.html'' (see ``http://
www.ifpma.org/m2-site/manicsr.htm'').
The text of the guidance follows:

E2B Data Elements for Transmission of Individual Case Safety
Reports\1\
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\1\ This guidance represents the agency's current thinking on
data elements for the transmission of individual case safety
reports. It does not create or confer any rights for or on any
person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirements of the applicable statute, regulations, or both.
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1. Introduction

1.1 Scope of this guidance

The objectives of the working group are to facilitate the
standardization of the data elements for transmission of individual
case safety reports by identifying and, where necessary or
advisable, by defining the data elements for the transmission of all
types of individual case safety reports, regardless of source and
destination. This includes case safety reports for both pre- and
postapproval periods and covers both adverse drug reaction and
adverse event reports. It is not intended that this format should be
used for cases in the integrated safety summary of a marketing
license application dossier. For adverse reactions encountered in
clinical trials, this format should be used only for those subject
to expedited reporting. The scope of this topic does not encompass
the definition of database structures, nor the design of a paper
report form, quality control/quality assurance aspects, or technical
security issues.

1.2 Background

Because of national and international laws, rules, and
regulations, individual case safety reports of adverse drug
reactions and adverse events need to be transmitted:
- From identified reporting sources to regulatory authorities
and pharmaceutical companies;
- Between regulatory authorities;
- Between pharmaceutical companies and regulatory authorities;
- Within authorities or pharmaceutical companies;
- From clinical investigators, via the sponsor, to ethics
committees;
- From authorities to the World Health Organization (WHO)
Collaborating Center for International Drug Monitoring.
The transmission of such individual case safety reports
currently relies on paper-based formats (e.g., yellow cards, Council
for International Organizations of Medical Sciences (CIOMS) forms,
MedWatch) or electronic media (e.g., within pharmaceutical
companies, or with WHO), usually by online access, tape, or file
transfer.
Considering the large number of potential participants in a
world-wide exchange of information, there is a need for an
electronic format capable of accommodating direct database to
database transmission using message transfers.
Successful electronic transmission of information relies on the
definition of common data elements, provided in this document, and
standard transmission procedures to be specified by the ICH
Electronic Standards for the Transfer of Regulatory Information
(ESTRI) Expert Working Group (M2).
This document has taken into account the documents provided by
ICH sponsors, the ENS-CARE Single Case Format, EuroSCaPE format, and
the CIOMS IA proposal, and comments received following the
circulation of these papers.

1.3 Notes on format of this document

Section 2 and its subsections designated A and B contain notes
that are directed toward clarifying the nature of the data that
should be provided. In addition, there are notes to assist in
defining the format that should be used to transmit the data.

1.4 Definition of Data Elements

The format for individual case safety reports includes
provisions for transmitting all the relevant data elements useful to
assess an individual adverse drug reaction or adverse event report.
The data elements are sufficiently comprehensive to cover complex
reports from most sources, different data sets, and transmission
situations or requirements; therefore, not every data element will
be available for every transmission. In many, if not most,
instances, a substantial number of the data elements will not be
known and therefore will not be included in the transmission. Where
it was deemed necessary, provisions for unknown/not applicable were
included (e.g., outcome, route of administration). However, since
the transmission is intended to be electronic, it was thought to be
unnecessary to include provisions to assign values of unknown for
all data elements. Different ways of including the same data have
been provided to cope with differing information contents: e.g., age
information can be sent as date of birth and date of reaction/event,
age at the time of reaction/event, or patient age group according to
the available information (see section B.1.2 and the respective user
guidance). In this example, age would be provided by the most
precise available data element rather than including multiple
elements of redundant data.
Structured data are strongly recommended in electronic
transmission and provisions for including information in this way
have been made. However, structuring of the data also implies the
use of controlled vocabularies, which are not yet available for some
data elements. It is anticipated that electronic transmission of
individual case safety reports will be implemented without
controlled vocabularies until they become available. In certain
instances, there are provisions for the transmission of some free
text items, including a full text case summary narrative. The
transmission of other unstructured data, such as full clinical
records or images, is outside the scope of this guidance.

1.5 Minimum information

The minimum information for the transmission of a report should
include at least one identifiable patient (section B.1), one
identifiable reporter (section A.2), one reaction/event (section
B.2), and one suspect drug (section B.4). Because it is often
difficult to obtain all the information, any one of several data
elements is considered sufficient to define an identifiable patient
(e.g., initials, age, sex) or an identifiable reporter (e.g.,
initials, address, qualification). It is also

[[Page 2398]]

recognized that the patient and the reporter may be the same
individual and still fulfill the minimum reporting criteria.
In addition, in order to properly process the report, the
following administrative information is needed: The sender
identifier (A.3.1.2), the report identification number(s) (A.1.10),
and the date of receipt of the most recent information (A.1.7) (see
user guidance for A.1.7).

2. Guidance: Content of the Data Elements

The data elements are divided into sections pertaining to:
A: Administrative and Identification Information
A.1 - Identification of the case safety report
A.2 - Primary source(s) of information
A.3 - Information on sender and receiver of case safety report
B: Information on the Case:
B.1 - Patient characteristics
B.2 - Reaction(s)/event(s)
B.3 - Results of tests and procedures relevant to the
investigation of the patient
B.4 - Drug(s) information
B.5 - Narrative case summary and further information
A. Administrative and Identification Information
A.1 Identification of the case safety report
A.1.1 Identification of the country of the primary source
User Guidance:
Generally, this item would be the only country provided.
Provisions are made to include other countries for unusual cases
concerning foreign travel and sources of manufactured material
(A.1.2 and B.4.k.2.3).
Note concerning transmission:
The codes for countries are defined by the transmission
standard.
A.1.2 Identification of the country where the reaction/event occurred
User Guidance:
For example, if the reaction was detected while the patient was
traveling, but the report was made by a health professional on the
patient's return.
A.1.3 Date of this transmission
Note concerning transmission:
Full precision date, i.e., day, month, and year.
A.1.4 Type of report
- Spontaneous report
- Report from study
- Other
- Not available to sender (unknown)
User Guidance:
A separate category for the designation of a literature source
is covered in item A.2.2 and is not duplicated in this section which
is intended to capture the type of report. If the case in the
literature arises from spontaneous observations, type should be
Spontaneous report; if the case arises from a study, type should be
Report from study. If it is unclear from the literature report
whether the case(s) cited are spontaneous observations or arise from
a study, then this item should be Other.
Differentiation between types of studies, e.g., clinical trials or
others, is given in section A.2.3.3.
The Not available to sender option allows for the transmission
of information by a secondary sender (e.g., regulatory authority)
where the initial sender did not specify the type of report; it
differs from Other which indicates the sender knows the type of
report but cannot fit it into the categories provided.
A.1.5 Seriousness
A.1.5.1. Serious
- Yes/no
A.1.5.2. Seriousness criteria (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 terms life-threatening and other medically important
condition are defined in the ICH E2A guidance. All the criteria
apply to the case as a whole and should not be confused with the
outcome(s) of individual reactions(s)/event(s) that are provided in
section B.2.i.9.
A.1.6 Date report was first received from source
User Guidance:
For senders dealing with initial information, this should always
be the date received from the primary source. When retransmitting
information received from another regulatory agency or another
company or any other secondary source, receivers should use the date
they first received the information.
Note concerning transmission:
Full precision date, i.e., day, month, and year.
A.1.7 Date of receipt of the most recent information for this report
User Guidance:
Because reports are required to be sent at different times to
multiple receivers, the initial/follow up status is dependent upon
the receiver. For this reason, an item to capture followup status is
not included. However, the date of receipt of the most recent
information taken together with the ``sender identifier'' (A.3.1.2)
and sender's ``report identification number'' (A.1.10) provide a
mechanism for each receiver to identify whether the report being
transmitted is an initial or followup report. For this reason, these
items are considered necessary for each transmission.
Note concerning transmission:
Full precision date, i.e., day, month, and year.
A.1.8 Additional available documents held by sender
A.1.8.1 Are additional documents available?
- Yes/no
A.1.8.2 List of documents held by sender
User Guidance:
List the documents received from the primary source (e.g.,
clinical records, hospital records, autopsy reports). It is
recognized that these documents may not be obtainable in many
instances.
Note concerning transmission:
Free text.
A.1.9 Does this case fulfill the local criteria for an expedited
report?
- Yes/no
User Guidance:
This item is used to provide the sender's local reporting
requirements, and the definition of expedited is dependent on the
local regulatory requirements. When the countries of origin and
destination of the transmission differ, the receiver should be aware
that the information may not be applicable to their regulatory
requirements.
A.1.10 Report identification number(s)
A.1.10.1 National regulatory authority's case report number
A.1.10.2 Company's case report number
A.1.10.3 Other sender's case report number
User Guidance:
A.1.10.1 and A.1.10.2 are the identifiers given by a national
regulatory authority and by a company, respectively. Both
identifiers may be transmitted if known. Companies should ensure a
single international report number to facilitate the unique
identification of a report that may have been sent to many places
and subject to multiple retransmissions. A.1.10.3 would be used by
senders who are not representing either a pharmaceutical company or
a national regulatory authority.
Note concerning transmission:
Alpha/numeric data.
A.1.11 Suspected duplicate
- Yes
User Guidance:
This item is used when the sender suspects or knows that the
report has already been transmitted to the receiver. Only an
affirmative answer is needed, otherwise the item is left empty. If
known, the suspect duplicate case report number(s) and the other
sender(s), where applicable, can be provided.
A.1.11.1 Source(s) of the duplicate (e.g., name of the company, name of
regulatory agency)
A.1.11.2 Case report number of the suspected duplicate(s)
Note concerning transmission:
Alpha/numeric data for the number and source.
A.1.12 Identification number of the report which is linked to this
report (repeat as necessary)
User Guidance:
This section is used in the case of, e.g., a mother-child pair
where both had reactions/events or siblings with common exposure, or
several reports involving the same patient, or several similar
reports from same reporter (cluster). These links do not refer to
duplicates, but to links of clinical relevance (the reactions/events
are shared among patients or in the same patient and appear
pertinent to each other).
Note concerning transmission:
Alpha/numeric data.
A.1.13 Report nullification
- Yes
User Guidance:
This item is used to indicate that a previously transmitted
report should be considered completely void (nullified), for example
when the whole case was found to be erroneous. It is essential to
use the same case report number previously submitted.

[[Page 2399]]

A.1.13.1 Reason for nullification
Note concerning transmission:
Free text.
A.1.14 Was the case medically confirmed, if not initially from a health
professional?
- Yes/no
User Guidance:
This section is completed if the primary source of information
was a lawyer, consumer, or other nonhealth professional and it is
needed because of differences in postmarketing surveillance
regulations concerning lay reports.
A.2 Primary source(s) of information
The primary source(s) of the information is a person who reports
the facts. This should be distinguished from senders (secondary
sources) who are transmitting the information, e.g., industry to
regulatory authority.
Any or all of the three subsections (A.2.1, A.2.2, A.2.3) can be
used. In the case of a published study or published individual case,
the reporter would be the investigator or first author, and details
on publication and trial type should also be provided.
A.2.1 Primary source(s) (repeat as necessary)
A.2.1.1 Reporter identifier (name or initials)
User Guidance:
The identification of the reporter may be prohibited by certain
national confidentiality laws or directives. The information is only
provided when it is in conformance with the confidentiality
requirements and this guidance applies to all the subsections of
A.2.1. Notwithstanding the above, at least one subsection should be
completed to fulfill the general need of having an identifiable
reporter. If only the name of the reporter is known and it is
prohibited to provide it because of confidentiality requirements,
initials can be used.
A.2.1.2 Reporter's address
Note concerning transmission:
The format for addresses are defined in the transmission
standard.
A.2.1.3 Country
Note concerning transmission:
The codes for countries are defined by the transmission
standard.
A.2.1.4 Qualification
- Physician
- Pharmacist
- Other health professional
- Lawyer
- Consumer or other nonhealth professional
User Guidance:
In some regions, consumer and lawyer reports are transmitted
only when there is medical confirmation.
A.2.2 Literature reference(s)
User Guidance:
References are provided in the Vancouver Convention (known as
``Vancouver style'') as developed by the International Committee of
Medical Journal Editors. The standard format, as well as those for
special situations, can be found in the following reference, which
is in the Vancouver style. International Committee of Medical
Journal Editors, Uniform requirements for manuscripts submitted to
biomedical journals, New England Journal of Medicine, 1997; 336:309-
15.
Note concerning transmission:
Alpha/numeric data.
A.2.3 Study identification
A.2.3.1 Study name
A.2.3.2 Sponsor study number
User Guidance:
This section would be completed only if the sender is the study
sponsor or has been informed of the study number by the sponsor.
A.2.3.3 Study type in which the reaction(s)/event(s) were observed
- Clinical trials
- Individual patient use, e.g., ``compassionate use'' or named
patient basis
- Other studies
User Guidance:
Other studies include pharmacoepidemiology, pharmacoeconomics,
intensive monitoring, PMS, etc.
A.3 Information on sender and receiver of case safety report
A.3.1 Sender
A.3.1.1 Type
- Pharmaceutical company
- Regulatory authority
- Health professional
- Regional pharmacovigilance center
- WHO collaborating center for international drug monitoring
- Other (e.g., distributor, study sponsor, or contract research
organization)
User Guidance:
In this context, a pharmaceutical company includes biotechnology
companies and other manufacturers required to submit individual case
safety reports.
A.3.1.2 Sender identifier
User Guidance:
Identifies the sender, e.g., company name or regulatory
authority name. This item should always be completed.
A.3.1.3 Person responsible for sending the report
User Guidance:
Name of person in the company or agency who is responsible for
the authorization of report dissemination. This would usually be the
same person who signs the covering memo for paper submissions. The
inclusion of the name of this person in the transmission may be
subject to national or international regulations.
A.3.1.4 Sender's address, fax, telephone and e-mail address
A.3.2 Receiver
User Guidance:
See the user guidance concerning the sender (A.3.1).
A.3.2.1 Type
- Pharmaceutical company
- Regulatory authority
- Regional pharmacovigilance center
- WHO collaborating center for international drug monitoring
- Other (e.g., a company affiliate or a partner)
A.3.2.2 Receiver identifier (see glossary)
A.3.2.3 Receiver's address, fax, telephone and e-mail address
B. Information on the Case
B.1 Patient characteristics
User Guidance:
In cases where a fetus or suckling infant sustains an adverse
reaction/event, information on both the parent and the child/fetus
should be provided. Reports of these cases are referred to as
parent-child/fetus report. Several general principles are used for
filing these reports. 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 are provided, but
they are linked by using sections A.1.12 in each of the reports.
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 characteristics
concerning the parent who was the source of exposure to the drug are
provided in section B.1.10.
B.1.1 Patient (name or initials)
User Guidance:
The identification of the patient may be prohibited by certain
national confidentiality laws or directives. The information is only
provided when it is in conformance with the confidentiality
requirements. This also applies to medical record number(s)
(B.1.1.1).
B.1.1.1 Patient medical record number(s) and source(s) (if allowable)
User Guidance:
Record numbers may include the general practitioner and/or
specialist record(s) number(s), hospital record(s) numbers, or
patient/subject identification number in a study.
Note concerning transmission:
Alpha/numeric data.
B.1.2 Age information
User Guidance:
To be used according to the most precise information available.
B.1.2.1 Date of birth
User Guidance:
If the full date of birth is not known, use section B.1.2.2
Note concerning transmission:
Full precision date, i.e., day, month, and year.
B.1.2.2 Age at time of onset of reaction/event
User Guidance:
If several reactions/events are in the report, use the Age at
the time of the first reaction/event. For fetal reaction(s)/
event(s), use the next item Gestation period when reaction/event was
observed (B.1.2.2.1).
When providing the age in decades, please note that, for
example, the 7th decade refers to a person in their 60's.
Note concerning transmission:
The codes to be used are defined in the transmission standard
but should include various age units (days, weeks, months, years,
decades).
B.1.2.2.1 Gestation period when reaction/event was observed in the
fetus
User Guidance:
The gestation period at the time of exposure is captured in
section B.4.k.10.
Note concerning transmission:
Number and units (days, weeks, months or trimester).

[[Page 2400]]

B.1.2.3 Patient age group (as per reporter)
- Neonate
- Infant
- Child
- Adolescent
- Adult
- Elderly
User Guidance:
The terms are not defined in this document and are intended to
be used as they were reported by the primary source. This section
should be completed only when the age is not provided more
specifically in sections B.1.2.2 or B.1.2.3.
B.1.3 Weight (kg)
User Guidance:
The weight at the time of the event/reaction.
Note concerning transmission:
The codes for items B.1.3-B.1.5 are defined in the transmission
standard.
B.1.4 Height (cm)
B.1.5 Sex
B.1.6 Last menstrual period date
Note concerning transmission:
Imprecise dates are acceptable, i.e., month and year, or year
only.
B.1.7 Relevant medical history and concurrent conditions (not including
reaction/event)
B.1.7.1 Structured information (repeat as necessary)

------------------------------------------------------------------------
Disease/
surgical Continuing Y/
procedure/ Start date N/U End date Comments
etc.
------------------------------------------------------------------------
...........
------------------------------------------------------------------------

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. Each of the items in the table can be repeated
as necessary. 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.
Note concerning transmission:
Imprecise dates may be used for both start and end dates. The
continuing column should accept values for yes, no, and unknown; and
the main descriptive column should have alpha data in concordance
with the controlled vocabulary being developed.
B.1.7.2 Text for relevant medical history and concurrent conditions
(not including reaction/event)
User Guidance:
To be used if structured information is not available in the
sender's database. Otherwise, it is preferable to send structured
data in segment B.1.7.1.
Note concerning transmission:
Free text.
B.1.8 Relevant past drug history (repeat the line as necessary)

------------------------------------------------------------------------
Name of drug
as reported Start date End date Indication Reactions
------------------------------------------------------------------------
...........
------------------------------------------------------------------------

User Guidance:
This segment concerns previously taken drugs, but not those
taken concomitantly or drugs that may have potentially been involved
in the current reaction(s)/event(s). Information concerning
concomitant and other suspect drugs is included in section B.4. The
information provided here may 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. The
term ``none'' should be used when appropriate, e.g., when there is
no previous exposure to the drug or vaccine, or no previous reaction
following exposure.
Note concerning transmission:
The data element for name of drug should accept alpha/numeric
data and include provisions for accepting the word none. The data
elements for reactions and indications should conform to the
controlled vocabulary when fully implemented. Both dates may be
imprecise.
B.1.9. In case of death
B.1.9.1 Date of death
Note concerning transmission:
Imprecise date format.
B.1.9.2 Reported cause(s) of death (repeat as necessary)
Note concerning transmission:
Controlled vocabulary should be used when fully implemented.
B.1.9.3 Was autopsy done?
- Yes/no/unknown
B.1.9.4 Autopsy-determined cause(s) of death (repeat as necessary)
Note concerning transmission:
Controlled vocabulary should be used when fully implemented.
B.1.10 For a parent-child/fetus report, information concerning the
parent
User Guidance:
This section is used only in the case of a parent-child/fetus
report where the parent had no reaction/event. See user guidance for
section B.1. Guidance regarding confidentiality is provided in B.1.1
and should be considered before providing the parent identification.
For the subsections B.1.10.4 through B.1.10.8, review the guidances
provided for B.1.3 through B.1.5 and B.1.7 through B.1.8.
B.1.10.1 Parent identification
B.1.10.2 Parent age information
User Guidance:
Use the date of birth if the precise birthday is known,
otherwise use age.
B.1.10.2.1 Date of birth of parent
Note concerning transmission:
Full precision date.
B.1.10.2.2 Age of parent
B.1.10.3 Last menstrual period date
User Guidance:
If a precise date is not available, complete the gestation
period at time of exposure in B.4.k.10.
Note concerning transmission:
Full precision date.
B.1.10.4 Weight (kg) of parent
B.1.10.5 Height (cm) of parent
B.1.10.6 Sex of parent
B.1.10.7 Relevant medical history and concurrent conditions of parent
(not including reaction/event)
B.1.10.7.1 Structured information (parent)

[[Page 2401]]

------------------------------------------------------------------------
Disease/
surgical Continuing Y/
procedure/ Start date N/U End Date Comments
etc.
------------------------------------------------------------------------
...........
------------------------------------------------------------------------

B.1.10.7.2 Text for relevant medical history and concurrent conditions
of parent (not including reaction/event)
B.1.10.8 Relevant past drug history of parent

------------------------------------------------------------------------
Reactions
Name of drug Start date End date Indication (if any and
as reported known)
------------------------------------------------------------------------
...........
------------------------------------------------------------------------

B.2 Reaction(s)/event(s)
User Guidance:
The designation of ``i'' in this section indicates that each
item is repeatable and that it carries an appropriate correspondence
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.2.1.1
through B.2.1.9, and the other reaction would be described in items
B.2.2.1 through B.2.2.9.
B.2.i.1 Reaction/event as reported by the primary source
User Guidance:
The original reporter's words and/or short phrases are used to
describe the reaction/event. This should be provided in a language
agreed upon by sender and receiver. For international transmissions,
English is the generally accepted language.
Note concerning transmission:
Alpha/numeric data.
B.2.i.2 Reaction/event term
User Guidance:
The term can be a sign, symptom, or diagnosis. A controlled
vocabulary should be used when available. This also applies to the
other items of structured data, such as indication, diseases in past
medical history.
Note concerning transmission:
Alpha/numeric data.
B.2.i.3 Term highlighted by the reporter
- Yes
User Guidance:
To be used when the primary source indicated that the reaction/
event was a major concern or reason for reporting the case. If the
information is not explicitly provided by the initial reporter, the
item should be left blank. Only affirmative answers are needed.
B.2.i.4 Date of start of reaction/event
B.2.i.5 Date of end of reaction/event
B.2.i.6 Duration of reaction/event
User Guidance:
This section can usually be computed from start/end of reaction/
event. However, sometimes, both dates and duration are useful, e.g.,
for a reaction/event of short duration such as anaphylaxis or
arrhythmia.
Note concerning transmission:
Imprecise dates may be used and the duration is defined by the
transmission standard.
B.2.i.7 Time intervals between suspect drug administration and start of
reaction/event
User Guidance:
The major uses of intervals are to cover circumstances where
both the dates are known but the interval is very short (e.g.,
minutes, such as in anaphylaxis), and when only imprecise dates are
known but more information concerning the interval is known. Dates,
if available, should always be transmitted in the appropriate fields
rather than intervals.
When there is more than one reaction/event and more than one
suspect drug, there is a matrix of intervals between the exposures
and reactions/events. B.2.i.7 captures the interval between each
reaction/event and one suspect drug. B.4.k.13 captures the interval
between each suspect drug and one reaction/event. The sender should
choose the drug and reaction/event considered based on information
available and/or the reporter's judgment. The complexity of the
intervals highlights the desirability of providing dates.
Note concerning transmission:
Codes are defined in the transmission standard.
B.2.i.7.1 Time interval between beginning of suspect drug
administration and start of reaction/event
B.2.i.7.2 Time interval between last dose and start of reaction/event
B.2.i.8 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, according to both the reporter
and the sender, the death is unrelated to the reaction/event,
``death'' should not be selected here, but is 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 captures the tests and procedures performed to
diagnose or confirm the reaction/event, including those tests done
to investigate (exclude) a nondrug 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 are made to transmit the
information as free text in B.3.2.
B.3.1 Structured information (repeat as necessary)

----------------------------------------------------------------------------------------------------------------
More
Normal low Normal high information
Date Test Result Unit range range available (Y/
N)
----------------------------------------------------------------------------------------------------------------
.............
----------------------------------------------------------------------------------------------------------------

[[Page 2402]]

Note concerning transmission:
Imprecise dates may be used. The description of the tests,
results, units, and normal ranges will be in free text unless
covered by a controlled vocabulary. The column entitled ``more
information available'' accepts only yes or no.
B.3.2 Results of tests and procedures relevant to the investigation
Note concerning transmission:
Free text.
B.4 Drug(s) information
User Guidance:
This section covers both suspect drugs and concomitant
medications, including biologicals. 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. The designation of ``k'' in this section indicates that
each item is repeatable and that it carries an appropriate
correspondence 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
User Guidance:
Characterization of the drug as provided by primary reporter. By
convention, all spontaneous reports have at least one suspect drug.
B.4.k.2 Drug identification
User Guidance:
Drug substance name and/or proprietary medicinal product name is
provided as it was reported.
B.4.k.2.1 Proprietary medicinal product name
User Guidance:
The name should be that used by the reporter. It is recognized
that a single product may have different proprietary names in
different countries, even when produced by a single manufacturer.
Note concerning transmission:
Alpha/numeric data.
B.4.k.2.2 Active substance name(s)
User Guidance:
Provide the international nonpropriety name(s) (INN(s)) or drug
substance name(s) or drug identification code(s) if no name exists.
For combination products, each active ingredient should be
specified. This information, as well as that requested for
Proprietary medicinal product name (B.4.k.2.1), may not be known for
concomitant or interacting drugs when the sender is a pharmaceutical
company. In the case of blinded trials, in the exceptional
circumstance when the blind has not been broken, the word
``blinded'' should precede the names of the drugs included in the
study. Placebo can be included as a drug.
B.4.k.2.3 Identification of the country where the drug was obtained
Note concerning transmission:
The codes for countries are defined by the transmission
standard.
B.4.k.3 Batch/lot number
User Guidance:
This information is particularly important for vaccines and
biologicals. The section allows for multiple batch/lot numbers, each
separated by a delimiter defined by the transmission standard
chosen. Provide the most specific information available. For
expiration date and other related information, see additional
information on drug (B.4.k.19).
Note concerning transmission:
Alpha/numeric data, the delimiter to separate batch and lot
numbers to be defined by the transmission standard.
B.4.k.4 Holder and authorization/application number of drug
User Guidance:
If relevant and known, provide the name of the holder and 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 provide
this information for their own suspect drug(s).
B.4.k.4.1 Authorization/application number
Note concerning transmission:
Alpha/numeric data.
B.4.k.4.2 Country of authorization/application
Note concerning transmission:
The codes for countries are defined by the transmission
standard.
B.4.k.4.3 Name of holder/applicant
Note concerning transmission:
Alpha/numeric data.
B.4.k.5 Structured dosage information
E.g., 2 milligrams (mg) three times a day for 5 days
B.4.k.5.1 dose (number): 2
B.4.k.5.2 dose (unit): mg
B.4.k.5.3 number of separate dosages: 3
B.4.k.5.4 number of units in the interval: 1
B.4.k.5.5 definition of the interval unit: day
B.4.k.5.6 cumulative dose to first reaction (number): 30
B.4.k.5.7 cumulative dose to first reaction (unit): mg
User Guidance:
Please note the side-by-side illustration of how the structured
dosage is provided. For the more complex example of 5 mg (in one
dose) every other day for 30 days, subsections B.4.k.5.1 through
B.4.k.5.7 would be 5, mg, 1, 2, day, 75, mg, respectively. In the
same way, 50 mg daily for 2 days would be 50, mg, 1, 1, day, 100,
mg. For prolonged chronic therapy, the sender should consider the
need to complete the cumulative dose sections.
In the case of a parent-child/fetus report, the dosage section
applies to the parental dose.
For dosage regimen that involve more than one dosage form and/or
changes in dosage, the information is provided in section B.4.k.6 as
text. Alternatively, the sender can provide more than one iteration
(k) for the same drug. Categories for ``dose unit'' and for
``definition of the interval'' are described in Attachment 1.
B.4.k.6 Dosage text
User Guidance:
To be used in cases where provision of structured dosage
information is not possible.
Note concerning transmission:
Free text.
B.4.k.7 Pharmaceutical form (Dosage form)
User Guidance:
E.g., tablets, capsules, syrup.
Note concerning transmission:
Free text until a controlled vocabulary is available.
B.4.k.8 Route of administration
User Guidance:
See suggested vocabulary in the route of administration list in
Attachment 2. 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 route of administration is provided in B.4.k.9.
B.4.k.9 Parent route of administration (in case of a parent child/fetus
report)
User Guidance:
This section is used only in a parent-child/fetus report and
linked parent reports to indicate the route of administration to the
parent.
B.4.k.10 Gestation period at time of exposure
User Guidance:
Use the gestational age at the time of the earliest exposure
Note concerning transmission:
Gestation period at time of exposure is expressed by providing
both a number and designation of units of days, weeks, months, or
trimester.
B.4.k.11 Indication for use in the case
User Guidance:
The indication as reported.
Note concerning transmission:
Controlled vocabulary to be used when fully implemented.
B.4.k.12 Date of start of drug
Note concerning transmission:
Imprecise date formats in this section as well as in B.4.k.14.
B.4.k.13 Time intervals between drug administration and start of
reaction/event
User Guidance:
The major uses of intervals are to cover circumstances where
both the dates are known but the interval is very short (e.g.,
minutes, such as in anaphylaxis), and when only imprecise dates are
known but more information concerning the interval is known. Dates,
if available, should always be transmitted in the appropriate items
rather than intervals.
When there is more than one reaction/event and more than one
suspect drug, there is a matrix of intervals between the exposures
and reactions/events. B.2.i.7 captures the interval between each
reaction/event and one suspect drug. B.4.k.13 captures the interval
between each suspect drug and one reaction/event. The sender should
select the drug and reaction/event based on information available
and/or the reporter's judgment.
Note concerning transmission:
The format for intervals is defined in the transmission
standard.

[[Page 2403]]

B.4.k.13.1 Time interval between beginning of drug administration and
start of reaction/event
B.4.k.13.2 Time interval between last dose of drug and start of
reaction/event
B.4.k.14 Date of last administration
User guidance:
For ongoing drug administration after the onset of the reaction/
event, leave this item blank and use Action(s) taken with drug
(B.4.k.16).
B.4.k.15 Duration of drug administration
User Guidance:
This item is 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.
Note concerning transmission:
The format is defined in the transmission standard.
B.4.k.16 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.8), provide the information concerning dechallenge. Not
applicable is used in circumstances such as if the patient died or
the treatment had been completed prior to reaction/event.
B.4.k.17 Effect of rechallenge (or re-exposure), for suspect drug(s)
only
B.4.k.17.1 Did reaction recur on readministration?
- Yes/no/unknown
User Guidance:
Unknown indicates that a rechallenge was done, but it is not
known if the event recurred. This segment is not to be completed if
it is unknown whether a rechallenge was done.
B.4.k.17.2 If yes to item B.4.k.17.1, which reaction(s)/event(s)
recurred?
Note concerning transmission:
Controlled vocabulary to be used when fully implemented.
B.4.k.18 Relatedness of drug to reaction(s)/event(s) (repeat B.4.k.18.1
through B.4.k.18.4 as necessary)
User Guidance:
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 a conventional implied suspected
causality for spontaneous reports. It is recognized that information
concerning the relatedness, especially for spontaneous reports, is
often subjective and may not be available.
Note concerning transmission:
For subsection B.4.k.18.1, the controlled vocabulary, when fully
implemented, should be used. For subsections B.4.k.18.2 through
B.4.k.18.4, alpha/numeric data with uncontrolled vocabulary should
be used.
B.4.k.18.1 Reaction assessed
User Guidance:
Generally the reaction assessed is the most important or the
most serious.
B.4.k.18.2 Source of assessment
User Guidance:
E.g., initial reporter, investigator, regulatory agency,
company.
B.4.k.18.3 Method of assessment
User Guidance:
E.g., global introspection, algorithm, Bayesian calculation.
B.4.k.18.4 Result
B.4.k.19 Additional information on drug
User Guidance:
Use 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).
B.5 Narrative case summary and further information
B.5.1 Case narrative including clinical course, therapeutic measures,
outcome, and additional relevant information.
User guidance:
Focused, factual, and clear description of the case.
Note concerning transmission:
Free text.
B.5.2 Reporter's comments
User Guidance:
Use for including 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
User Guidance:
This section provides the sender with an opportunity to combine
signs and symptoms that were reported into a succinct diagnosis and
the reasoning would be included in section B.5.4.
Note concerning transmission:
Uncontrolled vocabulary until the controlled vocabulary is fully
implemented.
B.5.4 Sender's comments
User Guidance:
This section provides information concerning the sender's
assessment of the case and may be used to describe disagreement with
and/or alternatives to the diagnoses given by the initial reporter.
Note concerning transmission:
Free text.

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 primary source of the information, i.e., a
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 may be the same
person, the function of the sender should not be confused with that
of the reporter.

Attachment 1

Unit List
Mass
kg kilogram(s)
g gram(s)
mg milligram(s)
g microgram(s)
ng nanogram(s)
pg picogram(s)
mg/kg milligram(s)/kilogram
g/kg microgram(s)/kilogram
mg/m² milligram(s)/sq. meter
g/m² microgram(s)/sq. meter
Radioactivity
Bq becquerel(s)
GBq gigabecquerel(s)
MBq megabecquerel(s)
Kbq kilobecquerel(s)
Ci curie(s)
mCi millicurie(s)
Ci microcurie(s)
nCi nanocurie(s)
Volume
l litre(s)
ml millilitre(s)
l microlitre(s)
Other
mol mole(s)
mmol millimole(s)
mol micromole(s)
iu international unit(s)
kiu iu(1000s)
Miu iu(1,000,000s)
iu/kg iu/kilogram
mEq milliequivalent(s)
% percent
gtt drop(s)
DF dosage form
User Guidance:
This is the suggested list of units. When having other measure
units, transformation is recommended if possible. Otherwise use the
free text field.
Definition of Interval List
Minutes
Hours
Days
Weeks
Months
Years
Cyclical
As necessary
Total

Attachment 2

Route of Administration List
Auricular (otic)
Buccal
Cutaneous
Dental
Endocervical
Endosinusial
Endotracheal
Epidural
Extra-amniotic
Hemodialysis
Intra corpus cavernosum
Intra-amniotic
Intra-arterial
Intra-articular
Intra-uterine
Intracardiac
Intracavernous
Intracerebral
Intracervical
Intracisternal

[[Page 2404]]

Intracorneal
Intracoronary
Intradermal
Intradiscal (intraspinal)
Intrahepatic
Intralesional
Intralymphatic
Intramedullar (bone marrow)
Intrameningeal
Intramuscular
Intraocular
Intrapericardial
Intraperitoneal
Intrapleural
Intrasynovial
Intratumor
Intrathecal
Intrathoracic
Intratracheal
Intravenous bolus
Intravenous drip
Intravenous (not otherwise specified)
Intravesical
Iontophoresis
Nasal
Occlusive dressing technique
Ophthalmic
Oral
Oropharyngeal
Other
Parenteral
Periarticular
Perineural
Rectal
Respiratory (inhalation)
Retrobulbar
Subconjunctival
Subcutaneous
Subdermal
Sublingual
Topical
Transdermal
Transmammary
Transplacental
Unknown
Urethral
Vaginal

Dated: January 6, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-959 Filed 1-14-98; 8:45 am]
BILLING CODE 4160-01-F