11284 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 93D–0203]

International Conference on

Harmonisation; Guideline on Clinical

Safety Data Management: Definitions

and Standards for Expedited

Reporting; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

final guideline entitled ‘‘Clinical Safety

Data Management: Definitions and

Standards for Expedited Reporting.’’

This guideline was prepared under the

auspices of the International Conference

on Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The guideline provides standard

definitions and terms for key aspects of

clinical safety reporting. The guideline

also discusses mechanisms for

expedited reporting. This guideline is

intended to help harmonize methods for

gathering and evaluating clinical safety

data.

DATES: Effective March 1, 1995. Submit

written comments at any time.

ADDRESSES: Submit written comments

on the guideline to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, rm. 1–23,

12420 Parklawn Dr., Rockville, MD

20857. Copies of the guideline are

available from CDER Executive

Secretariat Staff (HFD–8), Center for

Drug Evaluation and Research, Food

and Drug Administration, 7500 Standish

Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:

Regarding the guideline: Murray M.

Lumpkin, Center for Drug

Evaluation and Research (HFD–2),

Food and Drug Administration,

1451 Rockville Pike, Rockville, MD

20852, 301–594–6740.

Regarding ICH: Janet J. Showalter,

Office of Health Affairs (HFY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–443–1382.

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 Industry 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 Association (IFPMA).

The ICH Steering Committee includes

representatives from each of the ICH

sponsors and IFPMA, as well as

observers from the World Health

Organization, the Canadian Health

Protection Branch, and the European

Free Trade Area.

Harmonization of clinical safety data

management was selected as a priority

topic during the early stages of the ICH

initiative. In the Federal Register of July

9, 1993 (58 FR 37408), FDA published

a draft tripartite guideline entitled,

‘‘Clinical Safety Data Management:

Definitions and Standards for Expedited

Reporting.’’ The notice gave interested

persons an opportunity to submit

comments by August 9, 1993.

After consideration of the comments

received and revisions to the guideline,

a final draft of the guideline was

submitted to the ICH Steering

Committee and endorsed by the three

participating regulatory agencies at the

ICH meeting held in October 1994.

The guideline defines basic terms,

such as ‘‘adverse event,’’ ‘‘adverse drug

reaction,’’ and ‘‘unexpected adverse

drug reaction.’’ The guideline also

provides guidance on determining

whether an adverse drug reaction is

‘‘expected,’’ and contains standards for

expedited reporting, describing what

information should be reported,

recommending reporting timeframes

and the use of the CIOMS-I form for

reporting information or, alternatively,

suggesting that basic information or data

elements be used. The guideline also

discusses: Whether and when the blind

should be broken for a patient; reporting

reactions associated with comparison

drug or placebo treatments; products

with more than one dosage form, route

of administration, or use; and adverse

events that occur after the patient has

completed the clinical study.

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 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.

As with all of FDA’s guidelines, the

public is encouraged to submit written

comments with new data or other new

information pertinent to this guideline.

The comments in the docket will be

periodically reviewed, and, where

appropriate, the guideline will be

amended. The public will be notified of

any such amendments through a notice

in the Federal Register.

Interested persons may, at any time,

submit written comments on the

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 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 guideline follows:

Clinical Safety Data Management:

Definitions and Standards for Expedited

Reporting

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
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 11285

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

postmarketing 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 versus marketed).

There are two issues within the broad

subject of clinical safety data management

that are appropriate for harmonization at this

time:

(1) The development of standard

definitions and terminology for key aspects

of clinical safety reporting, and

(2) The appropriate mechanism for

handling expedited (rapid) reporting, in the

investigational (i.e., preapproval) 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 preapproval, 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 preapproval 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 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 postmarketing 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 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 that 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

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

ADR’s

All ADR’s that are both serious and

unexpected are subject to expedited

reporting. This applies to reports from

spontaneous sources and from any type of
11286 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

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 ADR’s. 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 lifethreatening 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

ADR’s

Certain ADR’s 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 lifethreatening, unexpected ADR’s 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 ADR’s

Serious, unexpected reactions (ADR’s) that

are not fatal or life-threatening should 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 timeframes 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.

Followup 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 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 versus chronic administration, for

example). Thus, ‘‘expectedness’’ may be
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 11287

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. Poststudy 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 posttreatment

followup) 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.

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 followup

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 Nonproprietary 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 nonprescription/OTC medicinal

products) and nonmedicinal 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 (specialty).

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 followup (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 followup reports

on the same case.)

Dated: February 23, 1995.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 95–4961 Filed 2–28–95; 8:45 am]

BILLING CODE 4160–01–F