[Federal Register Volume 60, Number 40 (Wednesday, March 1, 1995)]
[Notices]
[Pages 11284-11287]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4961]




[[Page 11283]]

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Part XIII





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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International Conference on Harmonisation; Guideline on Clinical Safety 
Data Management; Notice

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

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 
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). Therefore, this 
guideline is not being issued under the authority of Sec. 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 [[Page 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:
    <bullet> Results in death,
    <bullet> 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.)
    <bullet> Requires inpatient hospitalization or prolongation of 
existing hospitalization,
    <bullet> Results in persistent or significant disability/
incapacity, or
    <bullet> 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 [[Page 11286]] 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 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 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 life-threatening, 
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 [[Page 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:

    <bullet> Initials,
    <bullet> Other relevant identifier (clinical investigation 
number, for example),
     <bullet> Gender,
     <bullet> Age and/or date of birth,
     <bullet> Weight,
     <bullet> Height.

 2. Suspected Medicinal Product(s):

    <bullet> Brand name as reported,
     <bullet> International Nonproprietary Name (INN),
     <bullet> Batch number,
    <bullet> Indication(s) for which suspect medicinal product was 
prescribed or tested,
     <bullet> Dosage form and strength,
     <bullet> Daily dose and regimen (specify units--e.g., mg, mL, 
mg/kg)
     <bullet> Route of administration,
     <bullet> Starting date and time of day,
     <bullet> Stopping date and time, or duration of treatment.

 3. Other Treatment(s):

    <bullet> 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)

    <bullet> 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.
    <bullet> Start date (and time) of onset of reaction,
    <bullet> Stop date (and time) or duration of reaction,
    <bullet> Dechallenge and rechallenge information,
    <bullet> Setting (e.g., hospital, out-patient clinic, home, 
nursing home),
    <bullet> 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):

    <bullet> Name,
    <bullet> Address,
    <bullet> Telephone number,
    <bullet> Profession (specialty).

 6. Administrative and Sponsor/Company Details:

    <bullet> Source of report: was it spontaneous, from a clinical 
investigation (provide details), from the literature (provide copy), 
other?
    <bullet> Date event report was first received by sponsor/
manufacturer,
    <bullet> Country in which event occurred,
    <bullet> Type of report filed to authorities: initial or 
followup (first, second, etc.).
    <bullet> Name and address of sponsor/manufacturer/company,
    <bullet> Name, address, telephone number, and FAX number of 
contact person in reporting company or institution,
    <bullet> 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).
    <bullet> 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