********************************************************************** 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. ********************************************************************** 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 ********************************************************* 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. ********************************************************************** 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. ************************************************************************** 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. ***************************************************************************** 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. ******************************************************************************* 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 ***************************************************************************** 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