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 . . . . . . . . . . . . . . . . . . . . . . . . . . . Attachment 1
This guideline was developed within the Expert Working Group (Efficacy) of the 1

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.

The time frames and definitions in this guideline differ from those in the Code of 2

Federal Regulations [21 CFR 314.80]. Until the regulations are revised, the time

frames and definitions in the CFR should be followed.

GUIDELINE FOR INDUSTRY1

CLINICAL SAFETY DATA MANAGEMENT:

DEFINITIONS AND STANDARDS FOR EXPEDITED

REPORTING2

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
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).