[Federal Register Volume 61, Number 191 (Tuesday, October 1, 1996)]
[Notices]
[Pages 51287-51294]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-25034]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 96D-0236]


International Conference on Harmonisation; Draft Guideline on 
Data Elements for Transmission of Individual Case Safety Reports

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

DATES: Written comments by December 30, 1996.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft 
guideline are available from the Drug Information Branch (HFD-210), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
7500 Standish Pl., Rockville, MD 20855, 301-594-1012, or written 
requests for single copies of the ICH documents can be submitted to the 
Manufacturers Assistance and Communication Staff (HFM-42), Center for 
Biologics Evaluation and Research, Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed 
adhesive label to assist that office in processing your requests. The 
document may also be obtained by mail or FAX by calling the Center for 
Biologics Evaluation and Research Voice Information System at 1-800-
835-4709.
    Persons with access to the INTERNET may obtain the document in 
several ways.
    Users of ``Web Browser'' software, such as Mosaic, Netscape, or 
Microsoft Internet Explorer may obtain this document via the World Wide 
Web by using the following Uniform Resource Locators (URL's):
    http://www.fda.gov/cber/cberftp.html
    ftp://ftp.fda.gov/CBER/
 The document may also be obtained via File Transfer Protocol (FTP). 
Requesters should connect to the FDA FTP Server, FTP.FDA.GOV 
(192.73.61.21). The Center for Biologics Evaluation and Research (CBER) 
documents are maintained in a subdirectory called ``CBER'' on the 
server. Logins with the user name of anonymous are permitted, and the 
user's e-mail address should be sent as the password.
    The ``READ.ME'' file in that subdirectory describes the available 
documents which may be available as an ASCII text file (*.TXT), or a 
WordPerfect 5.1 or 6.x document (*.w51,wp6), or both.
    The document can be obtained by ``bounce-back e-mail''. A message 
should be sent to: [email protected]
    Finally, an electronic version of this draft guideline is available 
via the U.S. Government Printing Office's ``GPO Access.'' Internet 
users can access the database through the World Wide Web; the 
Superintendent of Documents home page address is http://
www.access.gpo.gov/su__docs/
FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Richard M. Kapit, Center for Biologics 
Evaluation and Research (HFM-225), 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.
    At a meeting held on April 30, 1996, the ICH Steering Committee 
agreed that a draft guideline entitled ``Data Elements for Transmission 
of Individual Case Safety Reports'' should be made available for public 
comment. The draft guideline is the product of the Efficacy Expert 
Working Group of the ICH. Comments about this draft will be considered 
by FDA and the Efficacy Expert Working Group. Ultimately, FDA intends 
to adopt the ICH Steering Committee's guideline.

[[Page 51288]]

    The draft guideline is intended to standardize the data elements 
for the electronic 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. The electronic format is not intended to be 
used for cases in the integrated safety summary of a marketing license 
application dossier. The draft guideline applies only to those adverse 
events that are subject to expedited reporting.
    In the past, guidelines have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidelines to state procedures or standards of general applicability 
that are not legal requirements but are acceptable to FDA. The agency 
is now in the process of revising Sec. 10.90(b). Although this 
guideline does not create or confer any rights for or on any person and 
does not operate to bind FDA, it does represent the agency's current 
thinking on data elements for the electronic transmission of individual 
case safety reports.
    Interested persons may, on or before December 30, 1996, submit 
written comments on the draft guideline 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 draft guideline and received comments may be seen in 
the office above between 9 a.m. and 4 p.m., Monday through Friday.
    The text of the draft guideline follows:

Draft Guideline on Data Elements for Transmission of Individual Case 
Safety Reports

1. Introduction

1.1 Scope of this guideline

    The objectives of the working group are, as defined in the 
concept paper, to standardize 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 
preapproval 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 or that this guideline apply 
to every adverse event encountered in clinical trials, but only to 
those subjected 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 authorities to the World Health Organization (WHO) 
Collaborating Center for International Drug Monitoring.
    The transmission of such individual case safety reports 
presently 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 M2 
Expert Working Group.

1.3 Notes on format of this document

    Sections 2.2.A and 2.2.B and their respective subsections (which 
for convenience do not carry through the 2.2 designation) 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.

2. Guidelines

    This document has taken into account the concept paper; 
documents provided to date 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.

2.1 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 all the data elements 
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. 
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 only one set of data elements 
rather than including multiple elements of redundant data.
    For electronic transmission between databases, the use of 
structured data is recommended. 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 guideline.
    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 event/suspected reaction 
(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., age, sex, initials) or an identifiable reporter 
(e.g., initials, address, qualification). It is also recognized that 
the patient and the reporter may be the same individual and still 
fulfill the minimum reporting criteria.
    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.

2.2 Content of the data

    The data elements are divided into sections pertaining to:
    A: Administrative information and identification
    A.1 - Identification of the case safety report
    A.2 - Primary source of information
    A.3 - Information on sender and intended recipient of case 
safety report (receiver)
    B: Information on 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
User Guidance:
    This section contains all the relevant data to identify the 
report, the reporter, and the different persons or institutions 
involved in the processing of the report, as well as indicators of 
specific report management.

[[Page 51289]]

A.1 Identification of the case safety report
A.1.1 Identification of the country where the reaction/event was 
reported
A.1.2 Identification of the country where the reaction/event occurred
A.1.3 Identification of the country where the drug was obtained
User Guidance:
    Generally, item A.1.1 would be the only one completed. 
Provisions are made to include other countries for unusual cases 
concerning foreign travel and sources of manufactured material 
(A.1.2 and A.1.3).
Note concerning transmission:
    The codes to be used to complete the country data will be 
defined in the transmission standard.
A.1.4 Type of report
    - Spontaneous report (see glossary)
    - 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 it is unclear 
from the literature report whether or not the case(s) cited are 
spontaneous observations or arise from a study, then item A.1.4 
``Type of report'' should be ``other'' and only item A.2.2 
completed.
    Differentiation between types of studies, e.g., randomized 
controlled 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 reporter 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)
    - Death
    - Life-threatening
    - Caused/prolonged hospitalization
    - Disabling/incapacitating (as per reporter's opinion)
    - 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 guideline. These 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.8.
A.1.6 Date report was first received from primary source
Note concerning Transmission:
    This date and the following one (A.1.7) should be full precision 
dates, i.e., day, month, and year.
A.1.7 Date of receipt of the most recent information for this report
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 (e.g., clinical records, 
hospital records, autopsy reports)
User Guidance:
    It is recognized that these documents may not be obtainable in 
many instances.
Note concerning transmission:
    This is free text limited to about 100 characters.
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 the recipient.
A.1.10 Report identification number(s)
A.1.10.1 National Regulatory Authority case report number
A.1.10.2 Company case report number
A.1.10.3 Other sender's case report number
User Guidance:
    A.1.10.1 is an identifier given by a National Regulatory 
Authority when it is transmitting the case, and item A.1.10.2 would 
be provided by a pharmaceutical company when it is sending the 
report. Both identifiers can be transmitted if known. Companies 
should endeavor to have a single international report number to 
facilitate the 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 the recipient may 
have already received the case from another sender or through other 
channels. Only an affirmative answer is needed, otherwise the field 
is left empty. If known, the suspected duplicate case report 
number(s) and the identification of the other sender(s) can be 
provided.
A.1.11.1 Source of the duplicate (e.g., name of the company, name of 
regulatory agency)
A.1.11.2 Case report number of the duplicate
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
User Guidance:
    This section is used in the case of a mother-child pair where 
both had reactions/events, or of siblings with common exposure, or 
several reports involving the same patient, or several similar 
reports from same reporter (cluster). This link does 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 limited to about 50 characters.
A.1.13 Case nullification
    - Yes
User Guidance:
    This field 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.
A.1.13.1 Reason for nullification
Note concerning transmission:
    This is a free text field limited to about 200 characters.
A.2 Primary source of information
    The primary source of the information is a person who initially 
reports the facts. This should be distinguished from secondary 
sources (senders) who are only retransmitting the information, e.g., 
industry to regulatory authority.
    Any or all of the three subsections can be used. In the case of 
a published trial or published individual case, the reporter would 
be the investigator or author, and details on publication and trial 
type should also be provided.
A.2.1 Primary source(s) of this report is (are) (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 recommendations, 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 address
Note concerning transmission:
    The format for addresses will be defined in the transmission 
standard.
A.2.1.3 Country
Note concerning transmission:
    The codes to be used to complete the country data will be 
defined in the transmission standard.
A.2.1.4 Qualification
    - Physician
    - Pharmacist
    - Other health professional
    - Lawyer
    - Consumer or other nonhealth professional
User Guidance:
    Within Europe, consumer and lawyer's reports are transmitted 
only when there is medical confirmation.
A.2.1.5 Was report medically confirmed if not initially from health 
professional?
    - Yes/no
User Guidance:
    This section is completed if the initial report was not provided 
by a health professional and it is needed because of differences in 
postmarketing surveillance regulations concerning lay reports.
A.2.2 Literature reference
User Guidance:

[[Page 51290]]

    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: 
International Committee of Medical Journal Editors. Uniform 
requirements for manuscripts submitted to biomedical journals. New 
England Journal of Medicine, 1991, 324:424-428.
Note on transmission:
    Alpha/numeric data approximately 250 characters.
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 event/reaction was observed
    - Randomized controlled clinical trials
    - Other controlled clinical trials
    - Compassionate use/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)
A.3.1.2 Sender identifier
User Guidance:
    Identifies the sender, e.g., drug company name or regulatory 
authority name.
A.3.1.3 Name of 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 Address, fax, telephone, and E-mail address
A.3.2 Receiver
User Guidance:
    See all the sections 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
A.3.2.3 Address, fax, telephone, and E-mail address
B. Information on 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 is 
provided in Section B.1.10.
    Also see the user guidance on confidentiality in Section 
A.2.1.1, which should be applied to preserve patient 
confidentiality. The patient's full name and medical record number 
might be provided in special circumstances, and where permissible.
B.1.1 Patient initials
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 identification number in a study.
Note concerning transmission:
    Alpha/numeric data. The data element should be long enough to 
contain more than one kind of medical record and number.
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:
    Include a precise 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.
Note concerning transmission:
    The codes to be used will be defined in the transmission 
standard but should include various age units (days, months, years).
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 Section B.1.2.2.
B.1.3 Weight (kg)
User Guidance:
    Should be the weight at the time of the event/reaction.
B.1.4 Height (cm)
B.1.5 Sex
Note concerning transmission:
    The codes to be used for items B.1.3-B.1.5 will be defined in 
the transmission standard chosen.
B.1.6 Last menstrual period date
Note concerning transmission:
    Imprecise dates are acceptable, i.e., month and year, or year 
only is acceptable.
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, and 
psychological trauma. Each of the fields in the table can be 
repeated as necessary. If precise dates are not known and a text 
description aids in understanding the timing of the case, or if 
concise additional information is helpful in showing the relevance 
of the past medical history, this information can be included in the 
comment column.
Note concerning transmission:
    Imprecise dates are acceptable for both start and end dates. The 
continuing block should accept values for yes, no, and unknown, and 
the main descriptive block

[[Page 51291]]

should have alpha data in concordance with the controlled vocabulary 
being developed. The comment should be limited to about 100 
characters.
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:
    This is a free text area of about 500 characters.
B.1.8 Relevant past drug history (repeat as necessary)

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

User Guidance:
    This segment concerns previously taken drugs, but not those 
taken concomitantly or drugs which 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 field 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, and 
the term ``none'' should be used when appropriate.
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 will be text initially and 
then by a controlled vocabulary when fully developed. Both dates can 
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 of death (repeat as necessary)
Note concerning transmission:
    This should be a repeatable element. 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:
    These are repeatable text fields of approximately 100 
characters. 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 above 
and should be considered before providing the parent identification. 
For the subsections B.1.10.5 through B.1.10.9, 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
Note concerning transmission:
    Date of birth should accept only a precise date.
B.1.10.2.2 Age
B.1.10.3 Gestation period at time of 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.1.10.4 Last menstrual period date
Note concerning transmission:
    Date of last menstrual period should accept only a complete 
date.
B.1.10.5 Weight (kg) of parent
B.1.10.6 Height (cm) of parent
B.1.10.7 Sex of parent
B.1.10.8 Relevant medical history and concurrent conditions of parent
B.1.10.8.1 Structured information

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

B.1.10.8.2 Text for relevant medical history and concurrent conditions 
(not including reaction/event) of parent
B.1.10.9 Relevant past drug history

                                                                        
------------------------------------------------------------------------
                                                              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.
B.2.i.1 Reaction/event description
User Guidance:
    Provided in a language agreed upon by sender and receiver. For 
international transmissions, English is the general accepted 
language. The original reporter's words and/or phrases or their 
translation are used to describe the reaction.
Note concerning transmission:
    Alpha data-free text 250 characters.
B.2.i.2 Reaction/event term(s)
User Guidance:

[[Page 51292]]

    The terms can be signs, symptoms, or diagnoses. Until terms from 
an internationally agreed terminology are available the term 
provided will be from an uncontrolled vocabulary at the choice of 
the sender, and where possible should be those of the original 
reporter. This also applies to the other items of structured data 
such as indication, and diseases in past medical history, that are 
expected to be controlled with an international terminology.
Note concerning transmission:
    Alpha data - uncontrolled vocabulary at present.
B.2.i.3 Date of start of reaction/event
B.2.i.4 Date of end of reaction/event
B.2.i.5 Duration of reaction/event
User Guidance:
    This section can usually be computed from start/end of reaction. 
However, sometimes, both dates and duration are useful, e.g., for 
reactions/events of short duration such as anaphylaxis or 
arrhythmia.
Note concerning transmission:
    The format for the dates will allow imprecise dates and the 
duration will be defined by the transmission standard.
B.2.i.6 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.
    This section is to be used if there is only one suspect drug and 
one or more reactions/events. If there is more than one suspect 
drug, then the information should be captured under ``drug'' 
(Section B.4) and not here.
Note concerning transmission:
    The codes to be used will be defined in the transmission 
standard.
B.2.i.6.1 Time interval between beginning of suspect drug 
administration and start of reaction/event
B.2.i.6.2 Time interval between last dose and start of reaction/event
B.2.i.7 Gestation period when reaction/event was observed
User Guidance:
    For the parent report, when both parent and child/fetus reports 
are submitted as linked reports, the gestation period refers to when 
reaction/event occurred in the parent. For the child report, when 
both parent and child reports are submitted as linked reports, the 
gestation period refers to when reaction/event in the child/fetus 
was observed. The gestation period at the time of exposure is 
captured in Section B.1.10.3
Note concerning transmission:
    Gestation period when reaction/event was observed is expressed 
by providing both a number and designation of days, weeks, months, 
or trimester.
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 the death is unrelated to the reaction/event being reported, 
``death'' should not be selected here, but should be reported 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.
    B.3.1 Structured information (repeat as necessary)

                                                                                                                
----------------------------------------------------------------------------------------------------------------
                                                                                                More information
       Date               Test              Result              Unit          Normal ranges     available (Y/N) 
----------------------------------------------------------------------------------------------------------------
  ...............                                                                                               
----------------------------------------------------------------------------------------------------------------

Note concerning transmission:
    Imprecise dates are acceptable. 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 the yes/no dichotomy.
B.3.2 Description of results of test and procedures relevant to the 
investigation of the patient
Note concerning transmission:
    Free text of about 1,000 characters.
B.4 Drug Information
User Guidance:
    This section covers both suspect drugs and concomitant 
medications. In addition, the section can be used to identify drugs 
thought to have an interaction. For each drug, the status indicator 
clarifies the role of the medication and its status is that 
indicated by the primary reporter, i.e., the original source of the 
information. One segment is used for each drug (k) mentioned in the 
report and which was taken within a relevant time period before the 
reaction, whether suspect or not. The designation ``k'' in this and 
the following subsections indicates that each item is repeatable and 
that each subsection carries an appropriate correspondence to the 
``k'' in other subsections.
    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 Drug substance name
User Guidance:
    Provide the INN or drug substance name or drug identification 
code if no name exists. This information, as well as that requested 
in Section B.4.k.2.2, may not be known for concomitant or 
interacting drugs when the sender is a pharmaceutical company. In 
the case of blinded trials, the word ``blinded'' should precede the 
name of the drug. Placebos can be included as a drug.
B.4.k.2.2 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 for each of drug identification, substance 
name, and proprietary name.
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.
Note concerning transmission:
    Alpha/numeric data, delimiter defined by the transmission 
standard.
B.4.k.4 Premarketing authorization or marketing identification holder 
and number
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. Pharmaceutical companies 
provide this information for their own suspect drug(s).
B.4.k.4.1 Number
Note concerning transmission:
    Alpha/numeric data.

[[Page 51293]]

B.4.k.4.2 Country
Note concerning transmission:
    Format determined by standard chosen.
B.4.k.4.3 Name of authorization holder
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: day
B.4.k.5.6 cumulative total dose number: 30
B.4.k.5.7 cumulative total dose 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 
case of a parent-child report (either a single child report, or a 
linked report with both parent and child affected) 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. 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:
    This is a free text field limited to about 100 characters.
B.4.k.7 Pharmaceutical form (Dosage form)
User Guidance:
    E.g., tablets, capsules, vials, syrup.
Note concerning transmission:
    This is a free text field until a controlled vocabulary is 
available.
B.4.k.8 Route of administration
User Guidance:
    In the case of a parent-child report (a single report with only 
the child affected through indirect (parenteral) exposure, or a 
linked report where both parent and child are affected), this 
indicates the route of administration of a drug given to the child/
fetus.
Note concerning transmission:
    See controlled vocabulary in the route of administration list in 
Attachment 2.
B.4.k.9 Parent route of administration (in case of a parent child/fetus 
report)
User Guidance:
    This section is used only in parent-child reports and indicates 
the route of administration to the parent.
B.4.k.10 Indication for use in the case
Note concerning transmission:
    This field is about 100 characters. Controlled vocabulary to be 
used when fully implemented.
B.4.k.11 Date of start of drug
Note concerning transmission:
    Imprecise date formats are used in this section as well as in 
B.4.k.13.
B.4.k.12 Time intervals between drug treatment and start of earliest 
reaction/event
B.4.k.12.1 Time interval between beginning of drug administration and 
start of earliest reaction/event
B.4.k.12.2 Time interval between last dose of drug and start of 
earliest reaction/event
Note concerning transmission:
    The format to be used for intervals will be defined in the 
transmission standard.
B.4.k.13 Date of end of drug
B.4.k.14 Duration of treatment
User Guidance:
    This field 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 treatment. The information requested is 
the overall duration of drug treatment.
Note concerning transmission:
    The format to be used for intervals will be defined in the 
transmission standard.
B.4.k.15 Action(s) taken with drug
    - Drug withdrawn
    - Dose reduced
    - Dose increased
    - Dose not changed
    - Unknown
    - Not applicable
User Guidance:
    This data, taken together with the outcome of the reaction 
(B.2.i.8), provides the information concerning dechallenge. ``Not 
applicable'' is used in circumstances such as when the patient died 
or the treatment had been completed prior to reaction/event.
B.4.k.16 Effect of rechallenge (or re-exposure), for suspect drugs only
B.4.k.16.1 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.16.2 If yes to item B.4.k.16.1, which reaction(s)/event(s) 
recurred?
Note concerning transmission:
    Controlled vocabulary to be used when fully implemented.
B.4.k.17 Relatedness of drug to reaction(s)/event(s) (repeat 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). 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.17.1, the controlled vocabulary, when fully 
implemented, should be used. For subsections B.4.k.17.2 through 
B.4.k.17.4, alpha/numeric data with uncontrolled vocabulary should 
be used.
B.4.k.17.1 Reaction assessed
User Guidance:
    Generally the reaction assessed will be the most important or 
most serious reaction.
B.4.k.17.2 Source of assessment
User Guidance:
    E.g., initial reporter, investigator, agency, company.
B.4.k.17.3 Method of assessment
User Guidance:
    E.g., global introspection, algorithm, Bayesian calculation.
B.4.k.17.4 Result
B.4.k.18 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., passed 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:
    10,000 characters.
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; 
e.g., a reporter indicates that a patient with known heart failure 
developed edema, proteinuria, hypoalbuminemia, and 
hypercholesterolemia but is uncertain whether the diagnosis is 
nephrotic syndrome or heart failure. The sender, however, knows that 
there have been other cases of nephrotic syndrome reported with the 
medications. The term ``nephrotic syndrome'' could be used in this 
section, and the explanation 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:
    1,000 characters.

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.

[[Page 51294]]

    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.
    Spontaneous adverse drug reaction report: An unsolicited 
communication to a company, regulatory authority, or other 
organization that describes an adverse medical reaction in a patient 
given one or more medical products and which does not derive from a 
study or any organized data collection scheme.

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)
mmmol  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 list of accepted 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
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
Intracorneal
Intracoronary
Intradermal
Intradiscal (intraspinal)
Intralesional
Intralymphatic
Intramedullar (bone marrow)
Intrameningeal
Intramuscular
Intraocular
Intrapericardial
Intraperitoneal
Intrapleural
Intrasynovial
Intrathecal
Intrathoracic
Intratracheal
Intravenous
Intravesical
Iontophoresis
Nasal
Occlusive dressing technique
Ophthalmic
Oral
Oropharyngeal
Other
Parenteral
Periarticular
Perineural
Rectal
Respiratory (inhalation)
Retrobulbar
Subconjunctival
Subcutaneous
Subdermal
Sublingual
Transdermal
Transmammary
Transplacental
Unknown
Urethral
Vaginal

    Dated: September 24, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-25034 Filed 9-30-96; 8:45 am]
BILLING CODE 4160-01-F