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NOTE: The TEXT VERSION for the Guideline for Adverse
Experience Reporting For Licensed Biological Products is a copy of the document in its 
entirety to facilitate printing a hard-page copy, if desired.
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Guideline for
Adverse Experience Reporting
for Licensed
Biological Products

(Based on 21 CFR 600.80)

Revised
October 15, 1993

FOOD AND DRUG ADMINISTRATION
Center for Biologics Evaluation and Research
Office of Establishment Licensing and Product Surveillance
Division of Biostatistics and Epidemiology (HFM-210)
1401 Rockville Pike, Rockville, MD 20852-1448

Guideline for
Adverse Experience Reporting for Biological Products

TABLE OF CONTENTS

I.   Introduction
II.  Scope
III. Who must report
IV.  What to report
V.   Types of reports
VI.  How to report
VII. Where to report
VIII.     How to obtain forms
IX.  Internal system for identifying and reporting adverse events
X.   Labeling issues
XI.  Notice of Proposed Rule Making
XII. Questions or comments
Definitions
15-day Alert Reports
Followup Reports
Pilot MedWatch Expedited Transmission Study
Increased Frequency Reports
Periodic Adverse Experience Reports 
Distribution Reports 
Special Situations
     1.   Another licensed manufacturer's product
     2.   Clinical or surveillance postmarketing studies
     3.   Clinical trials under an IND 
     4.   Congenital anomaly
     5.   Death
     6.   Drug interactions
     7.   Foreign reports
     8.   Lack of effect
     9.   Multiple suspect products
     10.  Overdose 
     11.  Pediatric patients
     12.  Product defects
     13.  Scientific literature reports
     14.  Unapproved indications
Availability of Data from VAERS
Classification of Events and Diseases
     Adverse Reaction Terminology
     Indication(s) and Pre-existing Medical Condition(s)
Instructions for Licensed Manufacturers Completing Forms
     Form FDA 3500A
     VAERS form
Appendices
     A.   Routes of Administration Codes
     B.   VAERS Abbreviations for Vaccine Type
     C.   Product Codes
******************
I.   INTRODUCTION

Food and Drug Regulations (21 CFR 600.80) require that 
adverse experiences shall be promptly reported by each manufacturer 
having a product license (herein referred to as the licensed manufacturer) under 
21 CFR 601.20. This Guideline has been developed to assist licensed
manufacturers in meeting their reporting requirements.

This document is intended as guidance to manufacturers of biological 
products in preparing and submitting reports of adverse experiences 
related to licensed biological products. If a manufacturer believes 
that factors described in this guidance are inapplicable to a particular 
product and other factors or procedures are appropriate, the 
manufacturer may wish to discuss the matter further with the 
agency to prevent expenditure of money and effort on activities 
that later may be determined to be unacceptable by FDA.

This guidance does not bind the agency and does not create 
or confer any rights, privileges, or benefits for or upon any person, 
manufacturer, or organization.

II.  SCOPE.

This Guidance is intended to assist licensed manufacturers and other
responsible parties in meeting the adverse experience reporting 
requirements for licensed biological products. This Guideline includes 
the reporting of adverse experiences with all licensed vaccines to the 
Vaccine Adverse Event Reporting System (VAERS).

This Guideline does not apply to product manufacturing defects 
(unless the defect is associated with an adverse experience in humans), 
or to in vitro diagnostic products, or to whole blood, or its components.

III.      WHO MUST REPORT.

For licensed biological products, any person whose name appears 
on the label of a licensed biological product as its manufacturer, 
packer, or distributor has reporting responsibilities, as does the individual 
or corporate entity that holds the product license. 

IV.   WHAT TO REPORT.

For licensed biological products, the following adverse experiences 
should be reported:
 
 (a) All spontaneous reports of adverse experiences occurring
 within the United Domestic reports), whether serious, non-serious, 
expected or unexpected.

(b) Serious and unexpected adverse experiences occurring
 outside of the United States (foreign), or reported in scientific and 
medical journals as case reports, or as the result of formal clinical trials.

(c) Serious and expected adverse experience reports detected to 
signal a significant increase in frequency of reporting. Literature and 
study reports would be limited to scientific and medical journal reports 
of formal clinical trials, or epidemiologic studies or analysis of 
experience in a monitored series of patients. This limitation is also 
intended to focus attention on those types of literature reports most 
likely to yield useful information.

V.   TYPES OF REPORTS.

For licensed biological products, the regulations describe four 
types of adverse experience reports:

     (a) 15-day Alert reports
     (b) Increased Frequency reports
     (c) Periodic Adverse Experience reports.
     (d) Distribution reports

Each type of report is discussed in detail in this Guideline.

VI.  HOW TO REPORT.

A form FDA 3500A is used to report adverse experiences 
associated with licensed biological products other than
vaccines. Adverse experiences associated with licensed 
vaccine are to be reported using the VAERS form.

An abbreviated form FDA 3500A, which replaces section D 
with section G, may be used when reporting only drugs or 
biological products.

Computerized Forms. In place of using the preprinted forms, 
a computer-generated report may be submitted if:

     (a) it contains all the elements of information in the identical 
     enumerated sequence of the form;

     (b) is completed according to this Guideline.

The typeset should be clear enough to ensure readable digital copies. 
Each licensed manufacturer's use of a modified form must be 
pre-approved by FDA in writing. To request approval of an FDA 3500A 
form, submit a printed copy with data to illustrate how each data field will 
be reported to:

     MedWatch
     Food and Drug Administration
     (HF-2)
     5600 Fishers Lane
     Rockville, MD 20852-9787

To request approval of a VAERS-1 form, submit a printed copy with 
data to illustrate how each data field will be reported to:

     Division of Biostatistics and Epidemiology (HFM-210)
     Center for Biologics Evaluation and Research, FDA
     1401 Rockville Pike
     Rockville, MD 20852-1448

A computerized graphic of the FDA 3500A form is available 
from the Division of Biostatistics and Epidemiology.

Electronic Submissions. Electronically produced adverse experience 
reports may be submitted; however, each licensed manufacturer 
must obtain prior written approval.

VII.      WHERE TO REPORT. 

15-day Alert Reports and Periodic Adverse Experience Reports

For all licensed vaccines, licensed manufacturers should submit 
two copies of each to:

     VAERS
     P. O. Box 1100
     Rockville, MD 20849-1100

For all licensed biological products other than vaccines, 
licensed manufacturers should submit two copies of each to:

     Division of Biostatistics and Epidemiology (HFM-210)
     Center for Biologics Evaluation and Research, FDA
     Adverse Experience Reporting
     1401 Rockville Pike
     Rockville, MD 20852-1448

Increased Frequency Reports and Distribution Reports:

For all licensed Biologics including vaccines, the licensed 
manufacturer should submit two copies of each to:

     Division of Biostatistics and Epidemiology (HFM-210)
     Center for Biologics Evaluation and Research, FDA
     Adverse Experience Reporting
     1401 Rockville Pike
     Rockville, MD 20852-1448

All submissions should be legible, typewritten. 
Legible photocopies are acceptable.

VIII.     HOW TO OBTAIN FORMS.

Up to 10 copies of the form FDA 3500A and instructions 
may be obtained from:

     Division of Biostatistics and Epidemiology (HFM-210)
     Center for Biologics Evaluation and Research, FDA
     Adverse Experience Reporting
     1401 Rockville Pike
     Rockville, MD 20852-1448.

Additional supplies of the form may be obtained from:

     PHS Forms and Publications Distribution Center
     12100 Parklawn Dr.
     Rockville, MD 20852.

VAERS forms may be obtained from VAERS by calling 1-800 822-7967.

IX.  INTERNAL SYSTEM FOR IDENTIFYING AND REPORTING ADVERSE EVENTS.

Each licensed manufacturer should develop standardized, formal 
procedures for the surveillance and reporting of adverse experiences. 
For those adverse experiences not requiring the submission of form 
FDA 3500A or VAERS form, the licensed manufacturer must maintain 
documentation of the information requested on the form FDA 3500A or
 VAERS form, and make that information available to FDA upon request. 
As a rule, FDA will consider a licensed manufacturer responsible for 
information known to its employees and agents. All licensed manufacturers 
should develop procedures that allow expedited report handling, and the 
licensed manufacturer should keep on file documentation of due diligence. 
This applies to domestic and international surveillance for processing of 
adverse experiences.

X.    LABELING ISSUES.

An unexpected adverse experience is one that is not listed in the 
current labeling for the licensed product; this includes an event that 
may be symptomatically and pathophysiologically related to an event 
listed in the labeling, but differs from the event because of greater 
severity or specificity. In some cases, it may be difficult to decide whether 
the reported experience is expected. In these situations, the event should 
be considered unexpected.

An event is considered expected when it is described in the 
ADVERSE REACTIONS, WARNINGS or PRECAUTIONS section of the 
labeling as required in conformance with 21 CFR 201.57.

To aid in the determination of an unexpected adverse experience, 
within 60 days of the effective date of 21 CFR 600.80, licensed manufacturers 
should submit a list of adverse event terminology they consider as 
expected for each of their products. The Division of Biostatistics and 
Epidemiology, CBER, FDA, will review the submission and determine if the 
list is appropriate. Any differences will be negotiated with the licensed manufacturer. 
This list may be used by the licensed manufacturer to maintain compliance 
with 15-day Alert requirements.

For products pending licensure, the expected adverse event terminology 
should be submitted soon after the labeling is approved.

XI.   NOTICE OF PROPOSED RULE MAKING.

Proposed revisions to adverse experience reporting 
requirements for human drugs and 

Licensed biological products have been published concurrently with 
Final Rule 21 CFR 600.80. The Food and Drug Administration (FDA) 
is proposing to amend 21 CFR 600.80 to revise definitions of serious, and 
the reporting period and format for Periodic reports as recommended by the 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and the Council for 
International Organizations of Medical Sciences (CIOMS). Subsequent 
changes to 21 CFR 600.80 will be incorporated into the next revision of this 
Guideline.

XII.  QUESTIONS OR COMMENTS.

Questions, comments and requests for approval of alternative 
reporting formats should be addressed to:

     Division of Biostatistics and Epidemiology (HPM-210)
     Center for Biologics Evaluation and Research, FDA
     Adverse Experience Reporting
     1401 Rockville Pike
     Rockville, MD 20852-1448
     Phone: (301) 827-3034
     FAX: (301) 827-3529
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DEFINITIONS:

ADVERSE EXPERIENCE - any undesirable event reported to or known by the licensed manufacturer that is associated with the use of the  product in humans, whether or not considered product-related 
by the licensed manufacturer. Reporting an adverse experience does not necessarily reflect a conclusion by the licensed manufacturer or FDA that the event is causally related to the product. An adverse experience may occur in professional practice, as a result of self-medication, from overdose, whether accidental or 
intentional, from withdrawal, or when a product fails to produce the expected pharmacological action (failure of effect).

AFFILIATE - Any corporate entity related to the licensed manufacturer, including all subsidiaries, licensors, etc.

CAUSALITY ASSESSMENT - Determination of whether there is reasonable possibility that the product is etiologically related to the adverse event. Causality assessment includes, for example, assessment of temporal relationships, dechallenge/ rechallenge information, association with 
(or lack of association with) underlying disease, presence (or absence) 
of a more likely cause, plausibility, etc.

CHALLENGE - administration of a suspect product by any route.

	DECHALLENGE - withdrawal of a product from the patient's therapeutic regimen.

	NEGATIVE DECHALLENGE - continued presence of an adverse experience after withdrawal of              	the drug.

     	POSITIVE DECHALLENGE - partial or complete disappearance of an adverse event after 	withdrawal of the product.

     	RECHALLENGE - reintroduction of a product suspected of having caused an adverse event 	following a positive dechallenge.

     	NEGATIVE RECHALLENGE - failure of the product, when reintroduced, to produce signs or 	symptoms similar to those observed when the  product was previously introduced.

     	POSITIVE RECHALLENGE - reoccurrence of similar signs and symptoms upon reintroduction 	of product.

CIOMS FORM - An adverse reaction reporting form developed by the Council for International Organizations of Medical Sciences (CIOMS), intended for notifying the regulatory authorities of countries other than the country where the report originated.

EXPECTED EXPERIENCE - an adverse experience described in the ADVERSE REACTIONS, WARNINGS or PRECAUTIONS section of the current labeling. Also referred to as a labeled experience.

ICD-9-CM - The International Classification of Diseases, ninth revision, Clinical Modification. This coding system, in the context of this Guideline, is used to assign standardized numerical coding and nomenclature for underlying medical conditions and indications.

 INCREASED FREQUENCY - an increase in the reported rate of occurrence of a particular adverse biological product experience after appropriate adjustment for biological product exposure.

 IND - an investigational new drug application for a new biological product that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes.

LICENSED MANUFACTURER- An establishment issued a product license under 21 CFR 601.20.

SERIOUS - an adverse experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, cancer or overdose.

 SPONSOR - a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.

 STUDY - A postmarketing, clinical or surveillance investigation with a  protocol identifying specific objectives and a scientific methodology for collecting and analyzing adverse experience data. Adverse events incidental  to other types of studies should be treated as spontaneous reports.

SUBJECT - a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease.

SUSPECT - a product associated with the adverse experience as determined by the initial reporter, regardless of the opinion of the licensed manufacturer.

UNEXPECTED EXPERIENCE - an adverse experience that is not listed in the current labeling for the product; this includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity. In some cases, 
it may be difficult to decide whether the reported experience is expected. In these situations, the event should be considered unexpected. An  unexpected experience is also referred to as an unlabeled experience. 

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15-DAY ALERT REPORTS

Reports of serious unexpected events must (' 600.80(c)(1)) be reported to FDA 
on the form FDA 3500A or VAERS form as soon as possible but in any case within
 15 working days of the time the licensed manufacturer became aware of the report.
For foreign reports, the 15-day time clock begins when the licensed manufacturer or 
its foreign affiliate has sufficient data to suggest that the 15-day criteria have been 
met. Licensed manufacturers should therefore establish effective mechanisms to 
ensure rapid information transfer from their foreign affiliates.

A criterion for serious should be determined before a report can be identified as 
serious. The term serious means an adverse experience occurring from an 
overdose or that is fatal or life-threatening, is permanently disabling, resulted in 
or prolonged inpatient hospitalization, or is a congenital anomaly, or cancer. More 
than one serious criterion may be identified. Death as an outcome attributed to the
 adverse event should not be selected if the initial reporter did not suspect an 
association between the death and the use of the product.

When using form FDA 3500A, if a report is serious based upon a congenital 
anomaly, cancer or overdose, select the outcome (section B.2 on form) check 
box marked other and describe.

For vaccines, 15-day Alert reports shall ('600.80(1)(c)(i)) be submitted on a 
VAERS form and should contain, at a minimum, the patient name, address and
 telephone number, and information identified on the VAERS form as boxed
 items including date of birth or patient age, description of adverse event(s), 
criterion for serious as appropriate, date of vaccination, adverse event onset, 
and all vaccines given on date of vaccination.

For all other licensed biological products, 15-day Alert reports shall ('600.80(c)(1)) 
be submitted on the form FDA 3500A and should contain, at a minimum, information 
including an identifiable source, a patient (even if not precisely identified by name and 
date of birth, a suspect product and a suspect event.

CIOMS forms will be accepted in place of the form FDA 350OA or VAERS form for 
foreign serious and unexpected reports only and should contain, at a minimum, 
information including an identifiable source, a patient (even if not precisely identified 
by name and date of birth), a suspect product and a suspect event. Whenever 
possible, submission of a foreign 15-day Alert report on the form FDA 3500A or 
VAERS form is preferred.

Submit 15-day Alert reports under separate cover from other types of reports. 
Multiple 15-day Alert reports, both initial and followup, and for several licensed 
products, may be submitted in the same envelope, though they should not be 
stapled together.

When it is not possible to provide all the desired information within 15 working 
days, a preliminary incomplete report should be submitted. Additional followup 
information must be sought and submitted within 15 days after obtaining the new 
information. If the licensed manufacturer seeks, but cannot obtain, additional 
information about an adverse experience, documentation of the procedure
 followed to obtain the additional information should be maintained.

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FOLLOWUP REPORTS

A followup report provides information about an event that has previously 
been reported with a unique Manufacturer Report Number. A followup report 
should provide a complete picture of the current understanding of the adverse 
experience. All the data fields on the form should be completed to present a true 
and comprehensive description of the adverse experience as it is understood 
at the time of the followup. The narrative section of the form should include 
a description of the changes or additions resulting from the followup. Do not 
send a copy of the initial or previous followup form with the latest followup form.

The followup report should include:

(1) correct information contained in the initial report plus the new data; 
any attachments submitted in the initial report (e.g., journal articles, 
discharge summaries) should not be resubmitted,

(2) the Manufacturer Report Number of the initial report,

(3) the number of the followup, the first followup being A1,

(4) the date the followup information was received by the licensed 
manufacturer (on form FDA 3500A under "Date received by mfr., and 
under Date received by mfr./ imm. proj. on the VAERS form.

If the initial report was submitted as a 15-day Alert report, the followup
 report(s) should be submitted as a 15-day Alert followup report even if 
the followup information shows that the event was expected or not serious. 
Conversely, a 15-day Alert followup report should be submitted if the event
 is found to be serious and unexpected, even if the original report was not 
submitted as a 15-day Alert report.

Do not submit a followup report if additional relevant information is not 
obtained. However, the documentation of the procedure followed to 
obtain the additional information should be maintained. FDA may 
request this documentation.

Followup reports for 15-day Alerts should not be submitted in the same 
envelope with Periodic reports, but may be submitted with other 15-day 
Alert reports.

Do not submit as a followup report a new subsequential event in a 
patient for whom a previous experience was reported and submitted. 
Submit an initial report on the form 

FDA 3500A or VAERS form for a new subsequent event. Thus, a 
ollowup report follows an event, not a patient. As an example particular 
o vaccines, a vaccine is administered to an infant at 2 months of age and 
an adverse event is reported. Thirteen months later a booster shot is given 
to the same infant and the same adverse even t is reported; this should be 
submitted as a new initial report. You should reference the previous report 
in the narrative section of the form.

Followup to a blinded study should be submitted after the blind has been 
broken.

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MEDWATCH EXPEDITED TRANSMISSION PROGRAM. 

A licensed manufacturer may participate in a MedWatch Expedited Transmission Program
designed 
to expedite the transmission of serious adverse event reports from FDA to 
the licensed manufacturer. This program will be renewed every six months, 
on January 1 and July 1 every year. Manufacturers must sign up every six 
months if they wish to participate. A report will be mailed out to a manufacturer 
only if all of the following conditions apply:

* The report must be on a New Molecular Entity (NME). Only New 
Molecular Entities (i.e.. Those products classified as 1S or 1P or important 
new biologics by the FDA) that have been on the market for three years or
less will be included. Please note that even though the focus will be on NMEs 
that have been approved within the last three years, it is possible that a 
product could be on the list for up to four years. This may occur because 
products are added to the list as they are approved by FDA but old NMEs 
are deleted only once a year in January. Requests for exceptions to this
limitation will be considered on a case-by-case basis.

* The report must be serious. The determination of seriousness will be 
based solely on the outcome boxes checked by the reporter. Note: the 
report will not have been evaluated by the FDA prior to transmission to 
the manufacturer. The report will NOT be sent out if the ONLY box 
checked by the reporter in B2 on the MedWatch form is "required 
intervention to prevent permanent impairment/damage". However, 
if this outcome does become part of the regulatory definition of serious, 
those type of reports will be included among those mailed to the 
manufacturers.

* The report must include permission to disclose the reporter's identity
to the manufacturer. Only reports where the reporter's name can be 
released to the manufacturer will be sent out. If the report is NOT on 
the MedWatch from or if the reporter checks box E5 on the form in 
response to "If you do NOT want your identity disclosed to the 
manufacturer, place an "X" in this box," the report will not be sent 
to the manufacturer.

* The report must not have been reported to the manufacturer already. 
If the reporter indicates in section F4 on the form that the event was also 
reported to the manufacturer, that report will NOT be sent to the manufacturer.

* The manufacturer of the NME must be a participant in the program. 
Manufacturers must sign up every six months if they wish to participate. 
Please note that there will be a charge for each report (call 301-443-0117 
to get a quotation on current charges) plus ten cents per page for every 
report sent to the manufacturer The manufacturer will be billed by the FDA
 Freedom of Information (FOI) office at the end of each six month period for 
the reports sent to the manufacturer by the MedWatch central triage unit
during that time period. The manufacturer's request to participate in the 
program as well as the reports sent to the manufacturer will be controlled 
as an FOI request. The reports will be available for public disclosure after 
all confidential information, including the reporter's identity, has been 
redacted from each report.

To enroll in the expedited transmission program, you must submit a 
request in writing to the MedWatch office. You may enroll at anytime 
during the six month period. Your company will be entered into the 
program upon receipt of your request letter and reports will be sent to 
out beginning on that date.

To be processed, the request letter must contain:

* a list of your firm's NMEs approved by FDA from January 1991 
to date. (If a participating manufacturer receives approval for an
 NME during the six month period then that NME will automatically 
be added.);

* a statement certifying that you have the regulatory responsibility 
for postmarketing reporting of adverse experiences for the product(s) 
that you have identified;

* a statement that you will conduct your normal follow-up of these 
reports in compliance with the applicable regulations;

* a statement that you will maintain the confidentiality of the names of 
the reporters and the persons who are the subjects of the reports; and

* a statement that you are aware that you will be charged (fill in the 
current amount) plus ten cents per page for each report sent to you 
by MedWatch from the date of enrollment to the end of the six month 
period (either June 30th or December 31 st), and that you agree to pay 
when billed by the FOI staff at the end of the six month period.

* Please identify a single contact person per applicant or licensed 
manufacturer. This contact person will be the individual who will 
receive the adverse event reports for all products listed. In addition, 
the letter should include the address, telephone number, and FAX 
number of the contact person. Finally, the letter must be signed by the 
appropriate "responsible head" for safety surveillance of your firm.

Letters requesting participation should be mailed to:

                     MEDWATCH: The Medical Products Reporting Program
                     Food and Drug Administration
                     5600 Fishers Lane 
                     Rockville, MD 20852-9787

If you have any questions or if you would like to discuss the expedited 
transmission program, please call the MedWatch Office at 301-443-0117.

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INCREASED FREQUENCY REPORT

Licensed manufacturers shall (' 600.80(c)(1)(ii)) conduct periodic 
reviews of the frequency of reports of serious expected adverse 
experiences at least as often as the periodic reporting cycle, or 
when FDA has provided written notice that circumstances warrant 
more frequent periodic reviews. When a determination is made of an 
increased frequency of reporting, an Increased Frequency report shall 
be submitted to the FDA within 15 days of the periodic reporting cycle. 
DO NOT submit this report as part of the Periodic report.

To conduct an increased frequency assessment, analyze together only 
reports from a single source type (e.g., compare spontaneous reports with 
spontaneous reports; compare study reports with reports from comparable 
studies; do not combine spontaneous reports with study reports; do not 
combine foreign reports with domestic reports). If an increase in frequency 
in reporting is detected, an Increased Frequency report shall be submitted.

Each report involving death should be analyzed for an increase in frequency 
of reporting in the following two ways. For one analysis, death reports associated 
with a given expected event should be combined with other serious reports of 
that particular event, and analyzed during the periodic reporting interval for an 
increase in frequency. For the other analysis, unexpected death reports, expected 
death reports and reports of death only should be combined and analyzed for an
 increase in frequency. (Death only reports are those reporting death with no other 
specific adverse event.)

An increased frequency can be determined by comparing the number of reports
 for the most recent report interval to the number of reports for the preceding 
interval (comparison interval). The number of reports for the report interval and the 
comparison interval is first adjusted for product use by dividing the number of reports 
in each interval by the estimated product use for that interval.

An increase in frequency of reporting can be determined using the formula 
below, coupled with the table below.

An increased frequency exists if the number of reports for the report interval is 
greater than or equal to the critical number of reports, C, which is determined 
from the numbers of reports for the two report intervals and the estimated 
product use for the two intervals as follows:

     C=(RXc) + (1.645 /((Xc + Xr)R))
Where
     Xc is the number of reports for the comparison interval
     Xr is the number of reports for the report interval
     R is the marketing ratio of the report interval to the 
          comparison interval

The marketing ratio is defined as

     R = Estimated drug use (e.g. number of prescriptions, 
          unit volumes, sales, etc.) for the report interval
          ( Estimated drug use (same units and scope as in the 
          numerator) for the comparison interval   )

The reference table below is included for routine decision making 
for the reporting of not more than 10 adverse experiences for the 
comparison interval.

To use the table, first calculate the marketing ratio; second, determine 
the number of reports for the comparison interval. The minimum number 
of reports necessary for an increased frequency is the intersection of the 
marketing ratio and number of reports for the comparison interval.

No Increased Frequency report is required if the number of reports 
received during the report interval is less than four.

************************************************************************

TABLE: MINIMUM NUMBERS OF REPORTS FOR THE REPORT INTERVAL
WHICH CONSTITUTE INCREASED FREQUENCY

Marketing
Ratio (R)       Number of Reports for the Comparison Interval
               0    1    2    3    4    5    6    7    8    9    10
0.25           -    -    -    -    4    4    5    5    5    6     6
0.50           -    -    4    5    6    7    8    9    9    11   12
0.75           -    4    6    7    8    10   11   12   13   14   15
1.00           -    6    7    9    11   12   14   15   17   18   19
1.25           4    7    9    11   13   15   17   18   20   21   24
1.50           5    8    10   13   15   17   20   22   24   26   28
1.75           5    9    12   15   17   20   23   25   27   30   32
2.00           6    10   14   17   20   23   25   28   31   34   36
2.25           7    11   12   19   22   25   28   31   34   37   40
2.50           7    12   17   20   24   28   31   35   38   41   45
2.75           8    13   17   22   26   30   34   36   42   45   49
3.00           9    15   20   24   29   33   37   41   45   49   58
3.50           10   17   23   28   33   38   43   46   52   57   61
4.00           11   19   26   32   38   46   49   54   59   65   70
4.50           13   21   29   36   42   48   55   61   67   72   78
5.00           14   24   32   39   47   54   60   67   74   80   87
5.50           15   26   35   43   51   59   66   74   81   88   95
6.00           17   27   38   47   55   64   72   80   88   96   103
6.50           18   30   41   51   60   69   78   86   95   103  112
7.00           19   32   44   54   64   74   84   93   102  111  120

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PERIODIC ADVERSE EXPERIENCE REPORTS

Periodic reports are required (' 600.80(c)(2)(i)) to be submitted, in 
duplicate, quarterly for the first three years from the date of issuance 
of the product license, and annually thereafter. Upon written notice, 
FDA may require that the licensed manufacturer submit reports under 
this section at alternate times; for example, an extension or 
reestablishment of quarterly reports may be required by the FDA if 
marketing is delayed.

Periodic reports must be submitted within 30 days of the dose of 
the quarter for reports due quarterly. Reports due annually must 
be submitted each year within 60 days of the anniversary date 
of issuance of the product license.

A periodic report must (' 600.80(c)(2)(ii)) contain the following 
four components, in the specified order below.

(1)   A copy of form FDA-3500A or VAERS form for each 
adverse experience not reported under paragraph (c)(1)(i) as a 
15-day Alert Report. A separate form should be completed for 
followup as well as for initial reports for each person experiencing 
an adverse event. Initial and follow up reports on the same case 
should be combined and submitted as one initial reporting form.

(2)  Index line listing of reporting forms for each adverse experience 
not reported under paragraph (c)(1)(i) as a 15-day Alert Report.

(3)   A narrative summary and analysis of the information in the 
periodic report and an analysis of the 15-day Alert Reports 
submitted during the reporting period.

(4)  A narrative discussion of actions taken since the last report 
because of adverse experiences (for example, labeling changes 
or studies initiated).

Each page of the Periodic report should be numbered and include 
the product name and Product Code. If information for one of these 
components is not included, an explanatory note should accompany 
that component of the report. Two copies of the report should be 
covered by a transmittal letter that includes the product name, 
License Number and Product Code, period covered, and clearly 
identifies the submission.

When a reportable event involves two or more products from the 
same licensed manufacturer, only one report is submitted to the 
Product Code most suspect by the initial reporter, or to the 
alphabetically-first product. The adverse events to the other product(s) 
should be reported in the narrative component of their Periodic report(s).
There are several instances when you may wish to include 
information that is not reportable on a form FDA 350OA or 
VAERS form. Such information may be included at the end of 
the narrative component of the Periodic report. Such information 
includes spontaneous domestic reports of lack of effect.
 Reports of lack of effect for an unapproved indication, 
spontaneous domestic reports of death only (death only reports 
are those reporting death with no other specific adverse event), 
for multiple suspect products, and expected reports of overdose.

****************************************************************************

DISTRIBUTION REPORTS.

Unless otherwise notified by the Director, Center for Biologics
Evaluation and Research, the licensed manufacturer shall 
(' 600.81) submit at periodic intervals two copies of a report 
containing information about the quantity of the product distributed 
domestically (including distributors) under the product license.

Reports are due within the first six months of licensing, and then 
subsequently at sixmonth intervals. Upon written notice, FDA may 
require that the licensed manufacturer submit reports under this 
section at alternate times.

The information is required to include the bulk lot, fill lot and 
label lot numbers for the total number of dosage units of each 
strength or potency distributed (e.g., 50,000 per 10-milliliter vials), 
labeled date of expiration, date of distribution of fill lot or label lot. 
Include information about any significant amount of a fill lot or label 
lot that may have been returned.

A suggested report format is as follows:

Product name, strength:
                               
Establishment License No.:

Product Code:         

Bulk Lot No.:

Fill Lot No.:

Label Lot No.:

Expiration Date:

Distribution Date:

No. of Doses Distributed:

No. of Doses Returned:

If there is more than one distribution date for a lot, then report each 
distribution date and the number of doses distributed. When reporting 
returned doses, do not repeat reporting the number of doses distributed.

You may wish to use the MedWatch convention when information is not 
available as follows:

     NA for not applicable
     NI for no information at this time (but may be available later)
     UNK for unknown

For vaccines, if available, you may wish to breakdown distribution 
of doses by public, private, or military sectors. Disclosure of financial 
or pricing data is not required.

As needed, FDA may require submission of more detailed product 
distribution information or frequency of reporting. 

***********************************************************************

SPECIAL SITUATIONS.

A number of special situations occur that may complicate reporting 
requirements.

1.   ANOTHER LICENSED MANUFACTURER'S PRODUCT.

Reports of adverse experiences in which the initial reporter identifies 
the suspect product as one marketed by another licensed 
manufacturer should be promptly forwarded to that licensed 
manufacturer. Such reports should NOT be reported by the
 manufacturer to whom the adverse experience was originally reported.

Immunization schedules and multiple administration of vaccines are 
special circumstances that may require a complete description of the 
history of vaccination. A licensed manufacturer may choose to submit 
a report that presents detailed information concerning each dose and 
vaccine product administered, including a product from another 
manufacturer. In such a case, the other manufacturer should be 
informed of the report and the Manufacturer Report Number so that 
the other manufacturer can reference the previous report when providing 
any relevant followup information. The other manufacturer should not 
submit the information already submitted by the first manufacturer.

2.   CLINICAL OR SURVEILLANCE POSTMARKETING STUDIES.

A clinical or surveillance postmarketing study is an investigation 
with a protocol identifying specific objectives and a scientific 
methodology for collecting and analyzing adverse experience data. 
Adverse events incidental to other types of studies should be treated 
as spontaneous reports.

The only study reports that should be considered for submission to FDA 
under 21 CFR 600.80 are:

     (1) 15-day Alert reports of serious unexpected events, and

     (2) Increased Frequency reports of serious expected events.

Study reports should be submitted only if there is a reasonable 
possibility that the event is causally related to the product exposure.

3.   CLINICAL TRIALS UNDER AN IND.

Adverse events from clinical trials under an IND may be
 reportable as 3-day Telephone and 10-day IND Safety reports 
pursuant to 21 CFR 312.32. Form FDA 3500A may be used to 
submit a 10-day IND Safety report.

4.   CONGENITAL ANOMALY.

When a newborn baby is found to have a congenital anomaly 
that the initial reporter considers possibly associated with a 
product administered to the mother during pregnancy, the 
patient is the newborn baby. The event onset date is the date 
of birth.

When a fetus is aborted because of a congenital anomaly,
 or is miscarried, and the initial reporter considers the event 
to be possibly associated with a product administered to the 
mother during pregnancy, the patient is the mother. In this case, 
the outcome attributed to the event is coded as a congenital anomaly, 
not as a death. Please indicate the number of weeks of gestation in the 
narrative. The event onset date is the date pregnancy is terminated.

5.   DEATH.

Death as an outcome attributed to the adverse event should not be 
selected if the initial reporter did not suspect an association between
 the death and the use of the product.

Each 15-day Alert report involving death should be analyzed for 
an increase in frequency of reporting in two ways:

For the first analysis, death reports associated with a given expected
 event should be combined with other serious reports of that particular event,
 and-analyzed periodically for an increase in frequency of reporting.

For the second analysis, unexpected death reports, expected death 
reports and reports of death only should be combined and analyzed for 
an increase in frequency of reporting. (ADeath only reports are those 
reporting death with no other specific adverse event.)

When performing an increased frequency assessment, analyze together 
only reports from a single source type (e.g., compare spontaneous reports 
with spontaneous reports; compare study reports with reports from 
comparable studies; do not combine spontaneous reports with study 
reports; do not combine foreign reports with domestic reports). If an
 increase in frequency of reporting is detected, an Increased
 Frequency report should be submitted.

6.   DRUG INTERACTIONS.

If a licensed manufacturer receives a report classified as a
 drug interaction, each of the products should be identified as 
a suspect product. 

When a drug interaction is reported involving products from more
 than one manufacturer, the licensed manufacturer may wish to 
report both as suspect products. The other manufacturer should be
 informed about the report, including the Manufacturer Report Number 
so that the other manufacturer can reference the previous report when 
providing any relevant followup information. The other manufacturer 
should not submit the information already submitted by the first manufacturer.

7.   FOREIGN REPORTS.

Serious unexpected events reported from foreign sources are to be 
submitted as 15-day Alert reports. Other foreign reports including serious 
expected events and all non-serious events should not be submitted. 
However, reports of serious expected events should be available and 
submitted to FDA if requested.

When an adverse experience is based on a foreign language article or 
manuscript, the licensed manufacturer is expected to promptly translate the 
publication into English. The translation should be attached to the submitted form.

CIOMS forms will be accepted in place of the form FDA 3500A or VAERS 
form for foreign serious and unexpected reports only and should contain, at 
a minimum, information including an identifiable source, a patient (even if not 
precisely identified by name and date of birth), a suspect product and a
suspect event. Submission of a foreign 15-day Alert report using the appropriate 
form FDA 3500A or VAERS form is preferred.

8.   LACK OF EFFECT.

Failure to produce the expected pharmacologic action is synonymous with lack of effect.

Certain products are indicated for immunization where a course of several doses 
is recommended to achieve a specified level of antibody titers to provide seroconversion. 
In this case, lack of effect is synonymous with Afailure to produce the expected pharmacologic 
actiononly if seroconversion is not achieved following the final dose. If seroconversion
 is not achieved following the final dose, or if there is a subsequent loss of 
immunity, thereby leaving recipients susceptible to the targeted disease, 
this is by definition, an adverse experience. If the labeled or recommended 
course of immunization was not followed, and seroconversion was not 
achieved or the patient succumbed to the targeted disease, then it is not a case of lack of effect.

All domestic cases of lack of effect for an approved indication should
 be submitted in the Periodic report. If the report of lack of effect is for 
an unapproved indication, the event is not reportable.

All spontaneous domestic lack of effect reports should be analyzed 
periodically for an increase in frequency of reporting. For products with 
multiple indications, ALack of effect should be analyzed separately 
for each indication. If an increase in frequency of reporting is detected, 
an Increased Frequency report should be submitted within 15 days.

Foreign lack of effect reports should not be reported nor analyzed for 
an increase in frequency.

9.   MULTIPLE SUSPECT PRODUCTS.

If a reportable event involves two or more products, only one form 
should be completed,- unless the products are in the categories 
described below. The reporting form should reference only one 
Manufacturer Report Control Number. The event should be submitted 
to the product license Amost suspect by the initial reporter. If each 
product is equally suspect, the report should be submitted to the product 
first in alphabetical order.

The adverse event should also be reported in the narrative 
assessment portion of the Periodic report of the other product.

If one suspect product is a licensed non-vaccine biological and the 
other is a licensed vaccine, then separate reporting forms should be 
submitted.

If the other product is a drug, then a report should also be filed 
under adverse experience reporting requirements for drugs (see 
21 CFR 312.80 and 21 CFR 312.32). If one of the products is a 
device, then a report should also be filed under reporting
 requirements for devices (see CDRH Final Rule and guideline). 
In the above cases, the report is the same, with the same 
Manufacturer Report Number, but distributed to each appropriate FDA Center.

If a reportable event involves two or more products and two or more 
manufacturers, a licensed manufacturer may choose to submit a report 
that presents detailed information including a product from another 
manufacturer. In such a case, the other manufacturer should be 
informed of the report and the Manufacturer Report Number so that 
the other manufacturer can reference the previous report when 
providing any relevant followup information. The other manufacturer 
should not submit the information already submitted by the first manufacturer.

10.  OVERDOSE.

Reports of overdose should be submitted. The adverse experiences 
associated with the overdose should be reported as are other events.

For licensed biological products, overdose reports associated with a 
given expected event should be combined with other serious reports 
of that particular event and should be analyzed periodically for an
 increase in frequency of reporting.

When performing an increased frequency assessment, analyze reports 
for that event from a single source type (e.g., compare spontaneous 
reports with spontaneous reports; compare study reports with reports 
from comparable studies; do not combine spontaneous reports with 
study reports; do not combine foreign reports with domestic reports). 
If an increase in frequency in reporting is detected, submit an Increased
 Frequency report within 15 days.

11.  PEDIATRIC PATIENTS.

For children under three years of age, express the age in months, e.g., 
28 months; for ages less than 1 month old, express the age in days. 
For all pediatric patients, where relevant, include body weight in the 
narrative section of the VAERS form. The form. FDA 3500A for 
non-vaccines has a specific data field for weight.

12.  PRODUCT DEFECTS.

If a product defect results in an adverse experience, the adverse 
event should be reported as described in this guideline. Form FDA 
3500A is also intended to be used to report product defects. 
See appropriate guidelines for instructions.

13.  SCIENTIFIC LITERATURE REPORTS.

Serious, unexpected adverse events that are reported in the
literature (or in unpublished manuscript) should be submitted as 
15-day Alert reports. A copy of the article or manuscript must ('600.80(d)) 
be attached to the completed form.

If multiple products are mentioned in the article, a 15-day Alert should 
be submitted only by the licensed manufacturer whose product is suspect. 
The suspect product is that identified by the article's author.

A separate 15-day Alert report should be completed for each
identifiable patient (with an identifiable adverse event). Thus if an 
article describes six patients with a given adverse experience, six 
15-day Alert reports should be completed.

14.  UNAPPROVED INDICATIONS.

 An adverse experience associated with the use of a licensed 
product for an unapproved indication should be reported as is 
any other adverse event, that is, as a 15-day Alert of a serious 
unexpected event, Increased Frequency, or a Periodic report.

A lack of effect for an unapproved indication, however, should 
not be reported.

***************************************************************************

AVAILABILITY OF DATA FROM VAERS

The Department of Health and Human Services, in response to the 
National Childhood Vaccine Injury Act of 1986, established the Vaccine
 Adverse Event Reporting System (VAERS), to accept all reports of
 suspected adverse events following the administration of all U.S. licensed 
vaccines. On November 1, 1990, VAERS replaced the Centers for Disease 
Control's MSAEFI (Monitoring System for Adverse Events Following Immunization) f
or public sector reporting and the FDA system for private sector and 
manufacturer reporting.

Information releasable under the Freedom of Information Act is 
available on 3.5 inch diskettes as compressed ASCII files, which 
automatically decompress and may be loaded into a database. 
Instructions for use of the media and descriptions of the datasets 
are included with the diskettes.

The first dataset contains VAERS reports submitted to the FDA 
from July 1, 1990, to October 31, 1990. The second dataset contains
 VAERS reports from November 1, 1990, to December 31, 1991. 
These datasets are archived and will not be updated in the future. 
The current year's data set is updated monthly.

The diskettes may be purchased from:

     U. S. Department of Commerce
     National Technical Information Service
     Springfield, VA 22161
     (703) 487 4650

The NTIS product numbers for ordering these datasets are:

     PB92-501410 July 1, 1990 - October 31, 1990 (archived)

     PB93-504769 November 1, 1990 - December 31, 1991 (archived)

     PB92-592281 January 1, 1992 - December 31, 1992

     PB92-592280 One-year subscription

For Freedom of Information questions contact the Center for 
Biologics Evaluation and Research, Freedom of Information 
Branch, at (301) 594-2000.

***************************************************************************

CLASSIFICATION OF EVENTS AND DISEASES

ADVERSE REACTION TERMINOLOGY. Enter the event terminology
 under the data field marked Adverse Event Term(s), when 
using form FDA 3500A. This terminology may be an accepted 
standard, a verbatim term, or your own terminology. There is no 
requirement for the use of a specific standard terminology. When 
using the VAERS form, the terminology should be included in box 
7. When using FDA 3500A, the terminology should be included 
in item G.8, AAdverse Event Term.

A manual for those who use COSTART (Coding Symbols for 
Thesaurus of Adverse Reaction Terms) may be obtained from:

     National Technical Information Service (NTIS)
     5285 Port Royal Road
     Springfield, VA 22161
     (703) 487-4650

For a complete dictionary and further information on 
WHO Adverse Reaction Terminology, contact:

     WHO Collaborating Center
     for International Drug Monitoring
     Box 26
     Husargatan 8
     S-75103 Uppsala, Sweden
     Phone: +46 18 17 48 50

INDICATION(S) AND PRE-EXISTING MEDICAL CONDITION(S). 
There is space on the form FDA 3500A for indications and 
preexisting medical conditions. When reporting ICD-9 codes
for indication(s) and pre-existing medical condition(s), preface 
each entry with the four-digit ICD-9 code; For example:

     250.0 Diabetes

     346.9 Migraine

     250.8 Diabetic Ulcer

It is not mandatory to report ICD-9 codes.

ICD-9 codes are described in the International Classification of 
Diseases, Ninth Revision Clinical Modification, published by the 
Health Care Financing Administration, USDHHS. This publication, 
No. (PHS) 91-1260, can be obtained from: 

     Superintendent of Documents
     US. Government Printing Office
     Washington, DC 20401

***************************************************************************

INSTRUCTIONS FOR LICENSED MANUFACTURERS COMPLETING FORMS

FDA 3500A

Form FDA 3500A is a two-sided form. It is designed to be used for 
reporting adverse events associated with biologics, devices, drugs 
and other products regulated by the FDA; and for reporting product
 problems. The VAERS form is to be used to report vaccine adverse 
events.

A computer-generated facsimile of form FDA 3500A may be
 submitted in place of the preprinted form if the submitter has
received written preapproval from MedWatch. It is not necessary 
for this form to be generated in the same two-sided format as the
 preprinted form. A two-page front-only form is acceptable.

When reporting only a suspect biologic, only sections A, B, C, E, and G 
are to be filled out. The licensed manufacturer may wish to submit an 
abbreviated one-sided form FDA 3500A that substitutes section D with 
section G.

If the case includes more than two suspect medications or more than
 one suspect medical device, additional pages of form FDA 3500A should 
be submitted, filling out only that additional information required. At the top 
of the form, the field page ___ of ___ should be filled out appropriately, 
and the Manufacturer Report Number should be repeated. If there is 
continuation of other information from the first page, that information may 
be continued on the following page(s).

If there is continuation of other information, but only two or fewer suspect 
medications or one or no suspect medical device is reported, then 
a blank continuation page may be added. The blank page should
 include identification of the licensed manufacturer, and the 
Manufacturer Report Number and should indicate the appropriate 
section and block number of the continuation information.
 Include the phrase A(continued) at the end of each field 
that has additional information onto another page.

All entries should be typed. Complete all sections that apply.

To complete an item when information is not available, use:

     NA for not applicable
     NI for no information at this time (but may be available later)
     UNK for unknown

Dates should be entered as month/ day / year
 (e.g., June 3, 1993 = 06 / 03 / 93). If exact dates are 
unknown, provide the best estimate.

Front Page Report and Page Numbers.

At the top of the front page, enter the page number and the 
total number of pages submitted (include attachments in the total) 
where the phrase page _ of _ is indicated.

At the top-right corner of the front page, enter the Manufacturer 
Report Number. If also reporting a device, also enter the User-facility 
Report Number or the Distributor Report Number in the correspondingly
 labeled box, to cross-reference this report with a report from another 
source on the same event.

Mfr. report # - This is the unique identifier used by the manufacturer for
 this report. For a followup report the manufacturer report number is to be 
identical to the number assigned to the initial report. The Manufacturer 
Report Number is also entered in block G9 of the form. The report number 
can be any number the manufacturer chooses to uniquely identify the report. 
If submitting a followup to a report originally obtained from FDA through the
 expedited transmission of a serious direct report, check the Aother box in
 block G3 and enter the FDA-assigned triage unit sequence number.

Section A: Patient Information.

When a newborn baby is found to have a congenital anomaly
 that the initial reporter considers possibly associated with a
 product administered to the mother during pregnancy, the patient
 is the newborn baby. The event onset date is the date of birth.

When a fetus is aborted because of a congenital anomaly, or is 
miscarried, and the initial reporter considers the event to be possibly 
associated with a product administered to the mother during
 pregnancy, the patient is the mother. The event onset date is 
the date pregnancy is terminated.

     A1: Patient Identifier. Provide the patient's initials or some 
          other type of identifier that will allow both the submitter and the initial 
          reporter (if different), to identify the report if contacted for followup.
           Do not use the patient's name or social security number. 
          The patient's identity is held in strict confidence by FDA and
           protected to the fullest extent of the law.

     A2: Age. Enter the patient's birth date, if known, or the patient's age 
          at the time of event onset. Provide the best estimate if exact age [
          is unknown

     If the patient is 3 years or older, use years (e.g., 4 years)
     If the patient is less than 3 years old, use months (e.g., 24 months)
     If the patient is less than 1 month old, use days (e.g., 5 days)

     A3: Sex. Enter the patient's gender.

     A4: Weight. Indicate whether the weight is in pounds (lb.)
          or kilograms (kg). Make a best estimate if exact weight is unknown

Section B: Adverse event or product problem.

B1: Adverse event and/or product problem. Select the appropriate 
check box. Both boxes should be checked if a product problem may
 have caused or contributed to the adverse event.

B2: Outcomes attributed to adverse event. Indicate all that apply to 
the reported event.

Death. Only check if the death was an outcome of the adverse event. 
Include the date if known. Do not check if the patient happened to 
die while using a medical product but there was no suspected 
association between the death and the use of the product. 
Do not check if a fetus is aborted because of a congenital 
anomaly, or is miscarried.

Life-threatening. Check if suspected that the patient was at 
substantial risk of dying at the time of the adverse event or if 
suspected that the use or continued use of the product might 
have resulted in the death of the patient.

Hospitalization (initial or prolonged). Check if admission to the 
hospital or prolongation of hospitalization was a result of the 
adverse event (e.g., do not check hospitalization if a patient 
in the hospital received a medical product and subsequently
 developed an otherwise nonserious adverse event, unless 
the adverse event prolonged the hospital stay).

Disability. Check if the adverse event resulted in a significant, 
persistent or permanent change, impairment, damage, or disruption 
in the patient's body function / structure, physical activities and, 
or quality of life.

Congenital anomaly. Check if suspected that exposure to a 
medical product prior to conception or during pregnancy may 
have resulted in an adverse outcome in the child or fetus.

Required intervention to prevent permanent impairment or
 damage. Check if believed that medical or surgical intervention 
was necessary to preclude permanent impairment of a body 
function or to prevent permanent damage to a body structure
 that was suspected to be due to the use of a medical product.

Other. Check only if the other categories are not applicable 
to the report. Briefly describe the patient outcome in the space 
provided. Enter actual narrative of the event in block B5. The 
selection of other does not necessarily mean that the report is 
considered serious. The regulatory definition of serious applies. 
For the interim period during which the definition of serious 
includes cancer and overdose, the other category may be 
checked, and cancer or overdose may be entered in the 
space provided.

B3: Date of the event. Provide the best estimate of the date of 
first onset of the adverse event. When a fetus is aborted because 
of a congenital anomaly, or is miscarried, the event onset date 
is the date pregnancy is terminated. When a newborn baby 
is found to have a congenital anomaly, the event onset date 
is the date of birth of the child.

B4: Date of this report. The date the report is filled out.

B5: Describe event or problem. Describe the event in detail
 using the reporter's own words including a description of what
happened and a summary of all relevant clinical information
 (medical status before the event, signs, symptoms, diagnoses, 
clinical course, treatment, outcome, etc.) If available, and if 
relevant, include synopses of any office visit notes or the 
hospital discharge summary. To save time and space
 (and if permitted by the institution) attach copies of these 
records with any confidential information deleted. Do not
 identify any patient, physician or institution by name. The 
initial reporter's identity should be provided in full in section E.

Enter results of relevant tests and laboratory data in block 
B6. Preexisting medical conditions and other relevant history 
belong in block B7.

For a product problem, describe the problem in sufficient 
detail so that the circumstances surrounding the defect or
 malfunction of the medical product can be understood. If 
available, the results of any evaluation of a malfunctioning 
device and, if known, any relevant maintenance or service 
information should be included in this section.

B6: Relevant tests/laboratory data, including dates. Include 
any relevant baseline laboratory data before the administration 
or use of the medical product, or all laboratory data used in 
diagnosing the event and any available laboratory data and 
or engineering analyses (for devices) that provide further 
nformation on the course of the event. Include any available 
pre- and post-event medication levels and dates if applicable. 
Include a synopsis of any relevant autopsy, pathology, engineering 
or lab reports, if available. If preferred, copies of any reports 
may be submitted as attachments with all confidential information 
deleted. Do not identify any patient, physician or institution by 
name. The initial reporter's identity should be provided in full in 
section E.

B7: Other relevant history, including preexisting medical conditions.
 If available, provide information on other known conditions in 
the patient (e.g., hypertension, diabetes, renal or hepatic dysfunction, 
etc.), and significant history (allergies, race or ethnic origin,
 pregnancy, smoking and alcohol use, drug abuse, etc.).

Section C: Suspect medication

C1: Name. Use the trade name or proper name as marketed.
 If unknown, of if no trade name, use the generic name (with the 
manufacturer or labeler's name if known). For foreign reports, use 
both the foreign trade name and the U.S. generic name.

C2: Dose, frequency and route. Describe how the product was
 used by the patient (e.g., 500 mg QID orally or 10 mg every other 
day IV, or 1 ma, 5.86 mci iv. (one dose)). For reports involving 
overdoses, the amount of product used in the overdose should
 be listed, not the prescribed amount.

C3: Therapy dates. Provide the date administration was started 
(or best estimate) and the date stopped (or best estimate). If no dates 
are known, an estimated duration is acceptable (e.g., 2 years) or if 
therapy was less than one day, then duration is appropriate (e.g., 1 
dose or 1 hour for an IV).

C4: Diagnosis for use. Provide the indication for which the product 
was prescribed or used in this particular patient. The ICD-9 code may 
be included.

C5: Event abated after use stopped or dose reduced. Along with 
checking the appropriate box, provide supporting lab tests and dates, 
if available, in block B6.

C6: Lot #. If known, include the lot number(s).

C7: Expiration date. Include with all product problem reports only.

C8: Event reappeared after reintroduction. Along with checking the 
appropriate box, provide supporting lab tests and dates, 
if available, in block B6.

C9: NDC#. The national drug code is only required when 
reporting a drug product problem. Zeroes and dashes should 
be included as they appear on the label.

C10: Concomitant medical products and therapy dates. List 
and provide therapy dates for any other medical products 
(drugs, biologics, medical devices, etc.) that a patient was 
using at the time of the event. Do not include products 
used to treat the event.

Section E: Initial reporter.

E1: Name, address and phone #. Please provide the 
name, mailing address and phone number of the person 
who reported the adverse event to the manufacturer, and 
who can be contacted to provide information on the event
 if followup is necessary.

E2: Health professional? Indicate whether the initial reporter
 is a health professional (e.g., physician' pharmacist, nurse, etc.).

E3: Occupation. Indicate the type of health professional or 
reporter occupation, and include specialty if appropriate.

E4: Initial reporter also sent report to FDA. Indicate whether the
 initial reporter also notified or submitted a copy of this report to FDA. 
This information helps to identify duplicate reports in the Agency 
database.

Section G: All manufacturers.

G1: Contact office. Enter the full name and address of the 
manufacturer. The name of the contact person may also be
 included.

G2: Phone number. Enter the phone number of the contact office.

G3: Report source. Check the box(es) that most accurately 
describes how the manufacturer contact office found out 
about the reported adverse event.

Foreign. Foreign sources include foreign governments, foreign 
affiliates of license holder, foreign licensors and licensees, etc. 
The country of origin should be included to the right of the check 
box.

Study. Postmarketing, clinical trial, surveillance, or other study
 that involves a systematic collection of adverse events from a
 protocol designed specifically to investigate product safety.

Literature. If the report source is the scientific literature or an 
unpublished manuscript, attach a copy of the article or manuscript.
 Foreign language articles should be translated. A separate 3500A 
form is to be completed for each identifiable patient described in the 
article or manuscript.

Consumer. This category includes attorneys. Generally, additional
 information should be sought from the treating health care provider. 
A determined effort should be made to obtain additionally detailed
 information from health professionals for all serious events initially 
reported by consumers. When this additional information is obtained,
 the followup report should check health professional rather than 
consumer in block G3.

Health professional. Self-explanatory.

Company representative. This check box should be selected if a 
company representative reported the event to the contact office 
based upon information received from a health professional. The 
health professional should be listed as the initial reporter on the 
front page of the form.

Distributor. Select this check box for reports received from 
a distributor of the suspect product. The health professional
 should be listed as the initial reporter on the front page of the 
form.

Other. Any source not covered by the previous categories.
 Select this check box when submitting a followup to a 
report originally obtained from FDA through the expedited 
transmission of a serious direct report, and enter the FDA 
assigned Triage Unit Sequence Number. AOther may also 
be used to identify when the source is another manufacturer; 
include the Manufacturer Report Number of the other manufacturer.

G4: Date received by manufacturer. The date when the 
manufacturer, corporate affiliate, etc., initially received information 
that an adverse event occurred. This would apply to a 
report received anywhere in the world. For followup reports, 
use the date that the followup information was received.

G5: PLA number. The 4-digit Establishment License 
Number followed by a slash, followed by the 4 character 
Product Code.

G7: Type of report. Select the appropriate check box

Initial. Check if the report is the first submission from the 
manufacturer.

Followup. Check if the report is a followup to a previously 
submitted manufacturer report. The first followup report is number 1.

G8: Adverse event term(s). Include a list of adverse event 
terms that most accurately characterizes the adverse event 
described in narrative format in block B5. Terms should be
 listed with the most important terms first. The terminology 
may be an accepted standard (e.g., WHOART or COSTART), 
a verbatim term, or the manufacturer's own terminology.

G9: Mfr. report number. Enter the manufacturer report number
 exactly as it appears in the upper right hand corner of the 
front page. For a followup report, the manufacturer report 
number is to be identical to the number assigned to the initial report.

****************************
INSTRUCTIONS FOR LICENSED MANUFACTURERS COMPLETING  FORMS

VAERS FORM

Patient Name. Enter the full name, not initials. Information 
identifying the person who received the vaccine or that person's
 legal representative is required by the National Childhood 
Vaccine Injury Act and will not be made available to the public.

When a newborn baby is found to have a congenital anomaly
 that the initial reporter considers possibly associated with a 
product administered to the mother during pregnancy, the 
patient is the newborn baby. The event onset date is the date of birth

When a fetus is aborted because of a congenital anomaly, or is 
miscarried, and the initial reporter considers the event to be possibly 
associated with a product administered to the mother during pregnancy, 
the patient is the mother. The event onset date is the date 
pregnancy is terminated.

Form Completed By. This information refers to the initial 
reporter, not to the manufacturer.

Item 1. Use state abbreviation.

Item 2. Enter county where the vaccine was administered.

Item 3. Enter the date of birth of the patient (date format month/day/year).

Item 4. Enter the age of the patient at the time of the event. 
For children under the age of 3 years, enter the age in months;
 if less than 1 month old, enter the age in days. Identify years, 
months, days.

Item 5. Select the check box for appropriate gender of the patient; 
if unknown, leave blank.

Item 6. Enter date form completed (date format month/day/year).

Item 7. Describe adverse events. Include a list of adverse
 event terms that most accurately characterizes the adverse 
experience. Terms should be listed with the most important 
terms first. The terminology may be an accepted standard (e.g., 
WHOART or COSTART), a verbatim term, or the manufacturer's
 own terminology. Include any relevant information not requested 
elsewhere. Include the body weight when the product dose is
 expressed in body weight, or the patient is a child.

Item 8. Select each check box applicable. Only check
 death if the death was an outcome of the adverse event.
 Include the date if known. Do not check death if the patient
happened to die but there was no suspected association between 
the death and vaccine. Do not check if a fetus is aborted because 
of a congenital anomaly, or is miscarried.

Item 9. Select the appropriate check box.

Item 10. Enter date of suspect vaccination (date format. month/day/year). 
Enter the time of administration and identify AM or PM if known.

Item 11. Enter date of onset of the adverse even
 (date format month / day / year). Enter the time of onset and identify 
AM or PM if known. Provide the best estimate of the date of first onset 
of the adverse event. When a fetus is aborted because of a congenital 
anomaly, or is miscarried, the event onset date is the date pregnancy is 
terminated. When a newborn baby is found to have a congenital anomaly, 
the event onset date is the date of birth of the child.

Item 12. Enter relevant diagnostic tests and laboratory data, 
and reference normal values, as appropriate.

Item 13. Enter all vaccines given on date of vaccination
 listed in item 10. Under Vaccine (type) you may use the abbreviations 
provided elsewhere in this Guideline. Under route / site, use the abbreviations 
provided elsewhere in this Guideline.

Item 14. List any other vaccinations within 4 weeks of date listed in item 10.

Item 15. Select appropriate check box for location of vaccination.

Item 16. Select appropriate check box for method of purchase of vaccine

Item 17. Identify other medication.

Item 18. Identify any illness at time of vaccination

Item 19. Identify any pre-existing medical conditions

Item 20. Manufacturers may leave this item blank.

Item 21. Select appropriate check box and enter information; for
 "type vaccine" you may use the abbreviations provided in this Guideline.

Item 22. Enter the birth weight only for children 5 years old and under.

Item 23. Enter the number of brothers and sisters for children 
5 years and under.

Item 24. Use your unique identifier, to identify the report. 
All followup reports should have the same number as the 
initial report. You may also include the name of the licensed 
manufacturer here.

Item 25. Enter the date (date format month/ day / year) you 
received information sufficient to determine that a 15-day Alert
 report was required.

Item 26. Select Ayes check box for 15-day Alert report.

Item 27. Select check box for report type; the followup
 number may be included to the right. The first followup is A1.

***************************************************************************
APPENDIX A

ROUTES OF ADMINISTRATION CODES

BLAD 	Intravesicular / intrabladder
BUCC 	Buccal 
CAUD 	Caudal
DENT 	Dental
ED   	Epidural
INF   	Infiltration (INF is IV)
INH   	Inhalation 
IART 	Intra-Arterial, Intra-Aortic(artery)
IA   	Intra-Articular (joint),Synovial in joint
IBUR  	Intrabursal
IC   	Intracardiac
ICAV 	Intracavity 
ID   	Intradermal (within skin)
ISP  	Intradiscal (spinal)
IDCL 	Intraductal
IGAN 	Intraganglion 
ID   	Intralesional 
IL   	Intralymphatic 
IM    	Intra muscular
IO   	Intraocular (eye) 
IP   	Intraperitoneal (if coded CA.P.D.)
IPL  	Intrapleural
IS   	Intrasinal
ISP   	Intraspinal (spinal)
ISY   	Intrasynovial
INTH 	Intrathecal
IT   	Intrathoracic (chest)
ITRC 	Intratracheal (larynx, endotracheal, throat)
ITUM 	Intratumor 
IU   	Intrauterine (uterus, intra amnistic) (amniotic tap ss inj)
IV   	Intravenous
ITVN 	Intraventricular 
IRRG  	Irrigation
NAS   	Nasal
NBLK 	Nerve Block (submu)
OPH  	Ophthalmic (eye) 
PO    	Oral
OTIC  	Otic (ear)
PCER  	Paracervical
PWN   	Periodontal
RTL   	Rectal
RBUL  	Retrobulbar
SC    	Subcutaneous (under skin) SQ
SUBD  	Subdural
SL    	Sublingual
TOP   	Topical
URH   	Urethral
VAG   	Vaginal
POIM  	Oral and intramuscular
POIV  	Oral and intravenous
IMIV  	Intramuscular and Intravenous

*******************************************************************************

APPENDIX  B

VAERS ABBREVIATIONS FOR VACCINE TYPE

ADEN 	Adenovirus Vaccine Live Oral Type 7
ANTH 	Anthrax Vaccine
BCG  	BCG Vaccine
CHOL 	Cholera Vaccine
DT   	Diphtheria and Tetanus Toxoids Adsorbed Pediatric
DTAP 	Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed Pediatric
DTOX 	Diphthena Toxoid Adsorbed
DTP  	Diphthena and Tetanus Toxoids and Pertussis Vaccine Adsorbed Pediatric
DTPH 	Diphtheria and Tetanus Toxoids and Pertussis and Haemophilus B Conjugate Vaccine Adsorbed 	Pediatric
FLU  	Influenza Virus Vaccine
HBPV 	Haemophilus B Conjugate Vaccine
IPV  	Inactivated Polio Virus Vaccine
JEV  	Japanese Encephalitis virus Vaccine Inactivated
M    	Measles Virus Vaccine - Live
MEN  	Meningococcal Polysaccharide Vaccine
MM   	Measles and Mumps Virus Vaccine Live
MMR  	Measles, Mumps, and Rubella Virus Vaccine Live
MR   	Measles and Rubella Virus Vaccine Live
MU   	Mumps Virus Vaccine Live
MUR  	Rubella and Mumps Virus Vaccine Live
OPV 	Poliovirus Vaccine Live Oral Trivalent
P    	Pertussis Vaccine
PLAGUE    Plague Vaccine
PPV  	Pneumococcal Vaccine Polyvalent
R    	Rubella Virus Vaccine Live
RAB  	Rabies Vaccine
SMALL	 Smallpox Vaccine
TD   	Tetanus and Diphtheria Toxoids Adsorbed Adults
TTOX 	Tetanus Toxoid
TYP  	Typhoid Vaccine
YF   	Yellow Fever Vaccine

***************************************************************************

APPENDIX C

PRODUCT CODES

AY-07	Tetanus Antitoxin (Equine)
AY-14	Collagenase
AY-16	Streptokinase
AY-18	Urokinase
AY-19	Asparaginase
AY-20	Anistreplase
BY-07	Botulinum Toxin Type A
CM-25	Hepatitis B Vacc (Recombinant)
CY-02	Influenza Virus Vacc
CY-03	Measles Vir Vacc, Live
CY-04	Measles, Mumps, Rubella Vacc
CY-05	Measles, Rubella Vacc
CY-08	Mumps Vacc
CY-09	Polio Vacc Inact (Monkey Cell) 
CY-11	Polio Vacc Live Oral Trivalent
CY-15	Rabies Vacc
CY-17	Rubella, Mumps Vacc
CY-18	Rubella Vacc
CY-19	Smallpox Vacc
CY-21	Yellow Fever Vacc
CY-22	Measles, Mumps Vacc
CY-25	Hepatitis B Vacc
CY-28	Polio Vacc Inact (Human Cell)
DM-01	Muromonab-CD3
DR-01	Alteplase
DR-02	Epoetin alfa (Erythropoetin)
DY-02	Anti-Inhibitor Coagulant Complex
DY-03	Antihemophilic Factor (Human)
DY-06	Factor IX Complex
DY-10	Fibrinolysin/Deoxyribonuclease (Bovine)
DY-14	Immune Globulin (Human) 
DY-22	Albumin
DY-24	Plasma Protein Fraction
DY-31	Rho(D) Immune Globulin (Human)
DY-33	Tetanus Immune Globulin(Human)
DY-34	Thrombin (Bovine)
DY-43	Rabies Immune Globulin (Human)
DY-50	Hepatitis B Immune Globulin
DY-63	Immune Globulin Intravenous (Human)
DY-65	Lymph IG, Anti-Thymocyte (Eq)
DY-67	Hemin for Injection 
DY-68	Antithrombin III (Human)
DY-69	Antihemophilic Factor (Bovine)
DY-70	Digoxin Immune FAB (Ovine)
DY-71	Alpha 1-Proteinase Inhibitor (Human)
DY-72	CMV Immune Globulin  Intravenous (Human)
DY-77	Coagulation Factor IX (Human)
EY-03	Coccidioidin
EY-05	Histoplasmin
EY-07	Mumps Skin Test Antigen
EY-09	Tuberculin Old
EY-10	Tuberculin PPD
EY-20	 Skin Test Antigens for Cellular Hypersen
EY-21	Positive Skin Test - Histamine
FM-01	Anti-D (Monoclonal-Polycolonal)
FM-05	Anti-A (Monoclonal)
FP-04	Anti-Lea (Monoclonal)
FP-05	Anti-Leb (Monoclonal)
FY-01	HIV-1
FY-02	HIV-1 (Western Blot)
FY-53	Reagent Red Blood Cells
FY-56	HBsAg (RIA)
FY-58	Limulus Amebocyte Lysate
FY-60	Anti-HBs (RIA)
FY-61	Anti-HBs (RPHA)
FY-62	Anti-HBs (ELISA)
GY-02	Allergenic Extract Alum Precip
HC-32	BCG Vaccine
HC-39	Meningococcal Polysacch vacc,Grp C
HC-40     Meningococcal Polysacch Vacc,Grp A
HC-41	Meningococcal Polysacch Vacc, Grp A & C
HC-42	Pneumococcal
HC-44	Meningococcal Polysacch Vacc, Grp A, C, Y
HC-45	Haemophilus b Poly Vacc
HC-46	Haemophilus b Conjugate Vacc
HC-47	Haemophilus b Conj Vacc (DIPHTH CRM197)
HC-48	Haemophilus b Conj Vac(MeningProt Conj)
HC-49	Typhoid Vacc Live Oral Ty21a
HT-01	BCG Live
IY-05	DTP Vacc Adsorbed
IY-13	DT & Acellular Pertussis Vacc Adsorbed
KA-0	Interferon alfa-2b
KA-01	Interferon alfa-2a
KA-02	Interferon gamma- 1b
KA-10	Interlueken-2
KG-01	Filgrastim
KG-02	Sargramostim
KN-0	Interferon alfa-n3 (Human Leuk Derived)
LY-01	Allergen Patch Test