Guideline for Industry
Clinical Safety Data
Management:  Definitions
and Standards for
Expedited Reporting
ICH-E2A
March 1995 TABLE OF CONTENTS
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. DEFINITIONS AND TERMINOLOGY ASSOCIATED WITH CLINICAL
SAFETY EXPERIENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
A. Basic Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1. Adverse Event (or Adverse Experience) . . . . . . . . . . . . . . . . . . . 3
2. Adverse Drug Reaction (ADR) . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. Unexpected Adverse Drug Reaction . . . . . . . . . . . . . . . . . . . . . . 4
B. Serious Adverse Event or Adverse Drug Reaction . . . . . . . . . . . . . . . . 4
C. Expectedness of an Adverse Drug Reaction . . . . . . . . . . . . . . . . . . . . . 5
III. STANDARDS FOR EXPEDITED REPORTING . . . . . . . . . . . . . . . . . . . . . . 6
A. What Should be Reported . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1. Single Cases of Serious, Unexpected ADRs . . . . . . . . . . . . . . . . 6
2. Other Observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
B. Reporting Time Frames . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1. Fatal or Life-Threatening Unexpected ADRs . . . . . . . . . . . . . . . . 8
2. All Other Serious, Unexpected ADRs . . . . . . . . . . . . . . . . . . . . . 8
3. Minimum Criteria for Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . 8
C. How to Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
D. Managing Blinded Therapy Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
E. Miscellaneous Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1. Reactions Associated with Active Comparator or Placebo
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 2. Products with More Than One Presentation or Use . . . . . . . . . 10
3. Post-study Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
F. Informing Investigators and Ethics Committees/Institutional Review
Boards of New Safety Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
IV. REFERENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED REPORTS OF
SERIOUS ADVERSE DRUG REACTIONS  . . . . . . . . . . . . . . . . . . . . . . . .A .t t.a .c hment 1 GUIDELINE FOR INDUSTRY 1
CLINICAL SAFETY DATA MANAGEMENT:
DEFINITIONS AND STANDARDS FOR EXPEDITED
REPORTING 2
I. INTRODUCTION
It is important to harmonize the way to gather and, if necessary, to take action
on important clinical safety information arising during clinical development. Thus,
agreed definitions and terminology, as well as procedures, will ensure uniform
Good Clinical Practice standards in this area. The initiatives already undertaken
for marketed medicines through the CIOMS-1 and CIOMS-2 Working Groups on
expedited (alert) reports and periodic safety update reporting, respectively, are
important precedents and models.  However, there are special circumstances
1This guideline was developed within the Expert Working Group (Efficacy) of the
International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH) and has been subject to consultation by the
regulatory parties, in accordance with the ICH process.  This document has been
endorsed by the ICH Steering Committee at  Step 4 of the ICH process, October 27,
1994.  At Step 4 of the process, the final draft is recommended for adoption to the
regulatory bodies of the European Union, Japan and the USA.  This guidance was
published in the Federal Register on March 1, 1995 (60 FR 11284) and is applicable to
both drug and biological products.  In the past, guidelines have generally been issued
under  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 that
are acceptable to FDA.  The agency is now in the process of revising 10.90(b). 
Therefore, this guideline is not being issued under the authority of 10.90(b), and it
does not create or confer any rights, privileges or benefits for or on any person, nor
does it operate to bind FDA in any way.  For additional copies of this guideline contact
the Executive Secretariat Staff, HFD-8, Center for Drug Evaluation and Research,
7500 Standish Place, Rockville, MD  20855, 301-594-1012.  An electronic version of
this guideline is also available via Internet by connecting to the CDER FTP server
(CDVS2.CDER.FDA.GOV) using the FTP protocol.
2The time frames and definitions in this guideline differ from those in the Code of
Federal Regulations [21 CFR 314.80].  Until the regulations are revised, the time
frames and definitions in the CFR should be followed. involving medicinal products under development, especially in the early stages
and before any marketing experience is available.  Conversely, it must be
recognized that a medicinal product will be under various stages of development
and/or marketing in different countries, and safety data from marketing
experience will ordinarily be of interest to regulators in countries where the
medicinal product is still under investigational only (Phase 1, 2, or 3) status.  For
this reason, it is both practical and well-advised to regard premarketing and
post-marketing clinical safety reporting concepts and practices as
interdependent, while recognizing that responsibility for clinical safety within
regulatory bodies and companies may reside with different departments,
depending on the status of the product (investigational vs. marketed).
There are two issues within the broad subject of clinical safety data
management that are appropriate for harmonization at this time:
the development of standard definitions and terminology for key aspects
of clinical safety reporting, and
the appropriate mechanism for handling expedited (rapid) reporting, in the
investigational (i.e., pre-approval) phase.
The provisions of this guideline should be used in conjunction with other ICH
Good Clinical Practice guidelines.
II. DEFINITIONS AND TERMINOLOGY ASSOCIATED WITH CLINICAL
SAFETY EXPERIENCE
A. Basic Terms
Definitions for the terms adverse event (or experience), adverse reaction,
and unexpected adverse reaction have previously been agreed to by
consensus of the more than 30 Collaborating Centers of the WHO
International Drug Monitoring Centre (Uppsala, Sweden). [Edwards, I.R.,
et al, "Harmonisation in Pharmacovigilance,"  Drug Safety 10(2): 93-102,
1994.] Although those definitions can pertain to situations involving
clinical investigations, some minor modifications are necessary,
especially to accommodate the pre-approval, development environment.
The following definitions, with input from the WHO Collaborative Centre,
have been agreed:
1. Adverse Event (or Adverse Experience)
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and
which does not necessarily have to have a causal relationship with
this treatment.
An adverse event (AE) can therefore be any unfavorable and
unintended sign (including an abnormal laboratory finding, for
example), symptom, or disease temporally associated with the use
of a medicinal product, whether or not considered related to the
medicinal product.
2. Adverse Drug Reaction (ADR)
In the pre-approval clinical experience  with a new medicinal
product or its new usages, particularly as the therapeutic dose(s)
may not be established:
all noxious and unintended responses to a medicinal
product related to any dose should be considered adverse
drug reactions.
The phrase "responses to a medicinal products" means that a
causal relationship between a medicinal product and an adverse
event is at least a reasonable possibility, i.e., the relationship
cannot be ruled out.
Regarding marketed medicinal products , a well-accepted definition
of an adverse drug reaction in the post-marketing setting is found
in WHO Technical Report 498 [1972] and reads as follows:
A response to a drug which is noxious and unintended and
which occurs at doses normally used in man for
prophylaxis, diagnosis, or therapy of disease or for
modification of physiological function.
The old term "side effect" has been used in various ways in the
past, usually to describe negative (unfavorable) effects, but also
positive (favorable) effects.  It is recommended that this term no
longer be used and particularly should not be regarded as
synonymous with adverse event or adverse reaction.
3. Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not
consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational
medicinal product).  See section III.C.
B. Serious Adverse Event or Adverse Drug Reaction
During clinical investigations, adverse events may occur which, if
suspected to be medicinal product-related (adverse drug reactions),
might be significant enough to lead to important changes in the way the
medicinal product is developed (e.g., change in dose, population, needed
monitoring, consent forms).  This is particularly true for reactions which,
in their most severe forms, threaten life or function.  Such reactions
should be reported promptly to regulators.
Therefore, special medical or administrative criteria are needed to define
reactions that, either due to their nature ("serious") or due to the
significant, unexpected information they provide, justify expedited
reporting.
To ensure no confusion or misunderstanding exist of the difference
between the terms "serious" and "severe," which are not synonymous,
the following note of clarification is provided:
The term "severe" is often used to describe the intensity (severity)
of a specific event (as in mild, moderate, or severe myocardial
infarction); the event itself, however, may be of relatively minor
medical significance (such as severe headache).  This is  not the
same as "serious," which is based on patient/event  outcome or
action criteria usually associated with events that pose a threat to
a patient's life or functioning.  Seriousness (not severity) serves as
a guide for defining regulatory reporting obligations.
After reviewing the various regulatory and other definitions in use or
under discussion elsewhere, the following definition is believed to
encompass the spirit and meaning of them all:
A serious adverse event (experience) or reaction is any untoward
medical occurrence that at any dose:
Results in death, 
Is life-threatening,
NOTE: The term "life-threatening" in the definition of
"serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an
event which hypothetically might have caused death if it
were more severe.
Requires inpatient hospitalization or prolongation of existing
hospitalization, 
Results in persistent or significant disability/incapacity, or 
Is a congenital anomaly/birth defect.
Medical and scientific judgment should be exercised in deciding whether
expedited reporting is appropriate in other situations, such as important
medical events that may not be immediately life-threatening or result in
death or hospitalization but may jeopardize the patient or may require
intervention to prevent one of the other outcomes listed in the definition
above.  These should also usually be considered serious.
Examples of such events are intensive treatment in an emergency room
or at home for allergic bronchospasm; blood dyscrasias or convulsions
that do not result in hospitalization; or development of drug dependency
or drug abuse.
C. Expectedness of an Adverse Drug Reaction
The purpose of expedited reporting is to make regulators, investigators,
and other appropriate people aware of new, important information on
serious reactions.  Therefore, such reporting will generally involve events
previously unobserved or undocumented, and a guideline is needed on
how to define an event as "unexpected" or "expected"
(expected/unexpected from the perspective of previously observed,  not
on the basis of what might be anticipated from the pharmacological
properties of a medicinal product).
As stated in the definition (II.A.3.), an "unexpected" adverse reaction is
one, the nature or severity of which is not consistent with information in
the relevant source document(s).  Until source documents are amended,
expedited reporting is required for additional occurrences of the reaction.
The following documents or circumstances will be used to determine
whether an adverse event/reaction is expected:
1. For a medicinal product not yet approved for marketing in a
country, a company's Investigator's Brochure will serve as the source document in that country.  See section III.F. and ICH
Guideline for the Investigator's Brochure.
2. Reports which add significant information on specificity or severity
of a known, already documented serious ADR constitute
unexpected events. For example, an event more specific or more
severe than described in the Investigator's Brochure would be
considered "unexpected."  Specific examples would be (a) acute
renal failure as a labeled ADR with a subsequent new report of
interstitial nephritis and (b) hepatitis with a first report of fulminant
hepatitis.
III. STANDARDS FOR EXPEDITED REPORTING
A. What Should be Reported?
1. Single Cases of Serious, Unexpected ADRs
All ADRs that are both serious and unexpected are subject to
expedited reporting.  This applies to reports from spontaneous
sources and from any type of clinical or epidemiological
investigation, independent of design or purpose.  It also applies to
cases not reported directly to a sponsor or manufacturer (for
example, those found in regulatory authority generated ADR
registries or in publications).  The source of a report (investigation,
spontaneous, other) should always be specified.
Expedited reporting of reactions that are serious but  expected will
ordinarily be inappropriate.  Expedited reporting is also
inappropriate for serious events from clinical investigations that are
considered not related to study product, whether the event is
expected or not. Similarly, nonserious adverse reactions, whether
expected or not, will ordinarily not be subject to  expedited
reporting.
Information obtained by a sponsor or manufacturer on serious,
unexpected reports from any source should be submitted on an
expedited basis to appropriate regulatory authorities if the
minimum criteria for expedited reporting can be met.  See section
III.B.
Causality assessment is required for clinical investigation cases. 
All cases judged by either the reporting health care professional or
the sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as ADRs.  For purposes of
reporting, adverse event reports associated with marketed drugs
(spontaneous reports) usually imply causality.
Many terms and scales are in use to describe the degree of
causality (attributability) between a medicinal product and an
event, such as certainly, definitely, probably, possibly or likely
related or not related. Phrases such as "plausible relationship,"
"suspected causality," or "causal relationship cannot be ruled out"
are also invoked to describe cause and effect.  However, there is
currently no standard international nomenclature.  The expression
"reasonable causal relationship" is meant to convey in general that
there are facts (evidence) or arguments to suggest a causal
relationship.
2. Other Observations
There are situations in addition to single case reports of "serious"
adverse events or reactions that may necessitate rapid
communication to regulatory authorities; appropriate medical and
scientific judgment should be applied for each situation.  In
general, information that might materially influence the benefit-risk
assessment of a medicinal product or that would be sufficient to
consider changes in medicinal product administration or in the
overall conduct of a clinical investigation represents such
situations.  Examples include:
a. For an "expected," serious ADR, an increase in the rate of
occurrence which is judged to be clinically important.
b. A significant hazard to the patient population, such as lack
of efficacy with a medicinal product used in treating
life-threatening disease.
c. A major safety finding from a newly completed animal study
(such as carcinogenicity) .
B. Reporting Time Frames
1. Fatal or Life-Threatening Unexpected ADRs
Certain ADRs may be sufficiently alarming so as to require very
rapid notification to regulators in countries where the medicinal
product or indication, formulation, or population for the medicinal product are still not approved for marketing, because such reports
may lead to consideration of suspension of, or other limitations to,
a clinical investigation program.  Fatal or life-threatening,
unexpected ADRs occurring in clinical investigations qualify for
very rapid reporting. Regulatory agencies should be notified (e.g.,
by telephone, facsimile transmission, or in writing) as soon as
possible but no later than 7 calendar days after first knowledge by
the sponsor that a case qualifies, followed by as complete a report
as possible within 8 additional calendar days.  This report should
include an assessment of the importance and implication of the
findings, including relevant previous experience with the same or
similar medicinal products.
2. All Other Serious, Unexpected ADRs
Serious, unexpected reactions (ADRs) that are not fatal or
life-threatening must be filed as soon as possible but no later than
15 calendar days after first knowledge by the sponsor that the
case meets the minimum criteria for expedited reporting.
3. Minimum Criteria for Reporting
Information for final description and evaluation of a case report
may not be available within the required time frames for reporting
outlined above.  Nevertheless, for regulatory purposes, initial
reports should be submitted within the prescribed time as long as
the following minimum criteria are met:  an identifiable patient; a
suspect medicinal product; an identifiable reporting source; and an
event or outcome that can be identified as serious and
unexpected, and for which, in clinical investigation cases, there is
a reasonable suspected causal relationship. Follow-up information
should be actively sought and submitted as it becomes available.
C. How to Report
The CIOMS-I form has been a widely accepted standard for expedited
adverse event reporting.  However, no matter what the form or format
used, it is important that certain basic information/data elements, when
available, be included with any expedited report, whether in a tabular or
narrative presentation.  The listing in Attachment 1 addresses those data
elements regarded as desirable; if all are not available at the time of
expedited reporting, efforts should be made to obtain them.  See section
III.B. All reports must be sent to those regulators or other official parties
requiring them (as appropriate for the local situation) in countries where
the drug is under development.
D. Managing Blinded Therapy Cases
When the sponsor and investigator are blinded to individual patient
treatment (as in a double-blind study), the occurrence of a serious event
requires a decision on whether to open (break) the code for the specific
patient.  If the investigator breaks the blind, then it is assumed the
sponsor will also know the assigned treatment for that patient.  Although it
is advantageous to retain the blind for all patients prior to final study
analysis, when a serious adverse reaction is judged reportable on an
expedited basis, it is recommended that the blind be broken only for that
specific patient by the sponsor even if the investigator has not broken the
blind.  It is also recommended that, when possible and appropriate, the
blind be maintained for those persons, such as biometrics personnel,
responsible for analysis and interpretation of results at the study's
conclusion.
There are several disadvantages to maintaining the blind under the
circumstances described which outweigh the advantages.  By retaining
the blind, placebo and comparator (usually a marketed product) cases
are filed unnecessarily.  When the blind is eventually opened, which may
be many weeks or months after reporting to regulators, it must be
ensured that company and regulatory data bases are revised.  If the
event is serious, new, and possibly related to the medicinal product, then
if the Investigator's Brochure is updated, notifying relevant parties of the
new information in a blinded fashion is inappropriate and possibly
misleading.  Moreover, breaking the blind for a single patient usually has
little or no significant implications for the conduct of the 
clinical investigation or on the analysis of the final clinical investigation
data.
However, when a fatal or other "serious" outcome is the primary efficacy
endpoint in a clinical investigation, the integrity of the clinical investigation
may be compromised if the blind is broken.  Under these and similar
circumstances, it may be appropriate to reach agreement with regulatory
authorities in advance concerning serious events that would be treated as
disease-related and not subject to routine expedited reporting.
E. Miscellaneous Issues 1. Reactions Associated with Active Comparator or Placebo
Treatment
It is the sponsor's responsibility to decide whether active
comparator drug reactions should be reported to the other
manufacturer and/or directly to appropriate regulatory agencies. 
Sponsors should report such events to either the manufacturer of
the active control or to appropriate regulatory agencies.  Events
associated with placebo will usually not satisfy the criteria for an
ADR and, therefore, for expedited reporting.
2. Products with More Than One Presentation or Use
To avoid ambiguities and uncertainties, an ADR that qualifies for
expedited reporting with one presentation of a product (e.g., a
dosage form, formulation, delivery system) or product use (e.g., for
an indication or population), should be reported or referenced to
regulatory filings across other product presentations and uses.
It is not uncommon that more than one dosage form, formulation,
or delivery system (oral, IM, IV, topical, etc.) of the
pharmacologically active compound(s) is under study or marketed;
for these different presentations there may be some marked
differences in the clinical safety profile.  The same may apply for a
given product used in different indications or populations (single
dose vs. chronic administration, for example).  Thus,
"expectedness" may be product or product use specific, and
separate Investigator's Brochures may be used accordingly. 
However, such documents are expected to cover ADR information
that applies to all affected product presentations and uses. When
relevant, separate discussions of pertinent product-specific or
use-specific safety information will also be included.
It is recommended that any adverse drug reactions that qualify for
expedited reporting observed with one product dosage form or use
be cross referenced to regulatory records for all other dosage
forms and uses for that product.  This may result in a certain
amount of overreporting or unnecessary reporting in obvious
situations (for example, a report of phlebitis on IV injection sent to
authorities in a country where only an oral dosage form is studied
or marketed).  However, underreporting is completely avoided.
3. Post-study Events Although such information is not routinely sought or collected by
the sponsor, serious adverse events that occurred after the patient
had completed a clinical study (including any protocol required
post-treatment follow-up) will possibly be reported by an
investigator to the sponsor.  Such cases should be regarded for
expedited reporting purposes as though they were study reports. 
Therefore, a causality assessment and determination of
expectedness are needed for a decision on whether or not
expedited reporting is required.
F. Informing Investigators and Ethics Committees/Institutional Review
Boards of New Safety Information 
International standards regarding such communication are discussed
within the ICH GCP Guidelines, including the addendum on "Guideline for
the Investigator's Brochure." In general, the sponsor of a study should
amend the Investigator's Brochure as needed, and in accord with any
local regulatory requirements, so as to keep the description of safety
information updated.
IV. REFERENCE
Federal Register. Vol.60, No. 40, Wednesday, March 1, 1995, pages 11284-
11287. Attachment 1
KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED REPORTS OF
SERIOUS ADVERSE DRUG REACTIONS
The following list of items has its foundation in several established precedents,
including those of CIOMS-I, the WHO International Drug Monitoring Centre, and
various regulatory authority forms and guidelines.  Some items may not be relevant
depending on the circumstances.  The minimum information required for expedited
reporting purposes is: an identifiable patient, the name of a suspect medicinal product,
an identifiable reporting source, and an event or outcome that can be identified as
serious and unexpected and for which, in clinical investigation cases, there is a
reasonable suspected causal relationship. Attempts should be made to obtain
follow-up information on as many other listed items pertinent to the case.
1. Patient Details:
Initials,
Other relevant identifier (clinical investigation number, for example),
Gender,
Age and/or date of birth,
Weight,
Height,
2. Suspected Medicinal Product(s) :
Brand name as reported,
International Non-Proprietary Name (INN),
Batch number,
Indication(s) for which suspect medicinal product was prescribed or
tested,
Dosage form and strength, Daily dose and regimen (specify units - e.g., mg, mL, mg/kg),
Route of administration,
Starting date and time of day,
Stopping date and time, or duration of treatment.
3. Other Treatment(s):
For concomitant medicinal products (including non-prescription/OTC
medicinal products) and non-medicinal product therapies, provide the
same information as for the suspected product.
4. Details of Suspected Adverse Drug Reaction(s) :
Full description of reaction(s) including body site and severity, as well as
the criterion (or criteria) for regarding the report as serious should be
given.  In addition to a description of the reported signs and symptoms,
whenever possible, attempts should be made to establish a specific
diagnosis for the reaction.
Start date (and time) of onset of reaction,
Stop date (and time) or duration of reaction,
Dechallenge and rechallenge information,
Setting (e.g., hospital, out-patient clinic, home, nursing home),
Outcome:  Information on recovery and any sequelae; what specific tests
and/or treatment may have been required and their results; for a fatal
outcome, cause of death and a comment on its possible relationship to
the suspected reaction should be provided.  Any autopsy or other
post-mortem findings (including a coroner's report) should also be
provided when available.  Other information: anything relevant to facilitate
assessment of the case, such as medical history including allergy, drug
or alcohol abuse; family history; findings from special investigations.
5. Details on Reporter of Event (Suspected ADR): Name,
Address,
Telephone number,
Profession (speciality).
6. Administrative and Sponsor/Company Details :
Source of report:  Was it spontaneous, from a clinical investigation
(provide details), from the literature (provide copy), other?
Date event report was first received by sponsor/manufacturer,
Country in which event occurred,
Type of report filed to authorities:  initial or follow-up (first, second, etc.),
Name and address of sponsor/manufacturer/company,
Name, address, telephone number, and FAX number of contact person in
reporting company or institution,
Identifying regulatory code or number for marketing authorization dossier
or clinical investigation process for the suspected product (for example
IND or CTX number, NDA number),
Sponsor/manufacturer's identification number for the case (This number
should be the same for the initial and follow-up reports on the same
case).