Guidance for Industry
Postmarketing Adverse Event
Reporting for Nonprescription Human Drug Products Marketed without an Approved Application

(PDF version of this document)

DRAFT GUIDANCE

            This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.  Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact Kathleen Frost 301-796-2380.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

October 2007
Clinical/Medical

Guidance for Industry 1.
Postmarketing Adverse Event Reporting for
Nonprescription Human Drug Products Marketed without an Approved Application

I.          INTRODUCTION

This document provides guidance to industry on postmarketing serious adverse event reporting for nonprescription (over-the-counter (OTC)) human drug products marketed without an approved application.  In particular, this document gives guidance on (1) the minimum data elements that should be included in a serious adverse event report, (2) the label that should be included with the report, (3) reporting formats for paper and electronic submissions, and (4) how and where to submit the reports. 

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.  The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II.        BACKGROUND

Public Law 109-462, the Dietary Supplement and Nonprescription Drug Consumer Protection Act, was signed by the President on December 22, 2006. 2.   Public Law 109-462 amends the Federal Food, Drug, and Cosmetic Act (the Act) to add safety reporting requirements for OTC drug products that are marketed without an approved application under section 505 of the Act (21 U.S.C. 355). 3.  Before the enactment of Public Law 109-462, only those OTC drugs marketed with an application approved under section 505 of the Act (21 U.S.C. 355) were subject to mandatory postmarketing safety reporting requirements. 4.   As required by section 2(e)(3) of Public Law 109-462, we are issuing this guidance to describe the minimum data elements for the required reports. 5.   This guidance also describes relevant policies and procedures for making these reports.   

The manufacturer, packer, or distributor 6. whose name (under section 502(b)(1) of the Act (21 U.S.C. 352(b)(1))) appears on the label of an OTC drug marketed in the United States without an approved application (referred to as the responsible person) must submit to FDA any report received of a serious adverse event associated with such drug when used in the United States, accompanied by a copy of the label on or within the retail package of such drug (section 760(b)(1) of the Act).  In addition, the responsible person must submit follow-up reports of new medical information related to a submitted serious adverse event report that is received within 1 year of the initial report (section 760(c)(2) of the Act).  Serious adverse event reports received through the address or telephone number described on the product label, as well as all follow-up reports of new medical information, must be submitted to FDA no later than 15 business days after a report of a serious adverse event or the new medical information is received by the responsible person (section 760(c)(1) and 760(c)(2) of the Act).  We recommend that all serious adverse event reports received by the responsible person be submitted to FDA within 15 business days of receipt. 7.  

The information on data elements included in this document is consistent to the extent possible with guidance on data elements for a safety report for applicants of approved NDAs, ANDAs, and antibiotic applications; manufacturers of marketed prescription drugs for human use without approved NDAs or ANDAs; and licensed manufacturers of approved biologic product license applications (BLAs). 8.  

III.       MINIMUM DATA ELEMENTS FOR AN INDIVIDUAL CASE SAFETY REPORT (ICSR)

A.        Initial ICSR Submission

As discussed in section II of this document, section 760(b)(1) of the Act, as amended, requires responsible persons to submit to FDA any report received of a serious adverse event associated with the use of an OTC drug marketed in the United States without an approved application when the product is used in the United States.  The person who first notifies the responsible person about an adverse drug event is the reporter.  Reporters can include patients, relatives of patients, consumers, doctors, pharmacists, other health care practitioners, or other individuals. 

Reporters convey information on adverse events to the responsible person by various means, including phone, the Internet, fax, e-mail, or regular mail.  Based on the information from the reporter and any other information received or obtained on the adverse event, the responsible person completes an ICSR in one of the formats described in section V of this document and submits it to FDA.    

To complete an ICSR, responsible persons should provide all known or reasonably known applicable elements on FDA Form 3500A or its electronic equivalent identified by FDA for electronic reporting.  Applicable elements on FDA Form 3500A include all sections except those identified as for device manufacturers only (i.e., all sections except D, F, and H).  See Appendix 1 for the specific elements on FDA Form 3500A. 

The quality of reports of serious adverse events submitted to FDA is critical for appropriate evaluation of the relationship between the product and adverse events. 9.   FDA recommends that responsible persons make a reasonable attempt to obtain complete information for case assessment during initial contacts and subsequent follow-up and encourages responsible persons to use trained health care practitioners to query reporters.  Computer-assisted interview technology, targeted questionnaires, or other methods developed to target specific events can help focus the line of questioning.  When the reporter is a patient or consumer, the responsible person should attempt to contact the health care practitioner familiar with the patient’s adverse event, with the patient/consumer's permission, to obtain further medical information and to retrieve relevant medical records, if appropriate.  

FDA considers all of the applicable elements on FDA Form 3500A or its electronic equivalent as critical for case assessment.  In order for FDA to avoid duplication, interpret significance, facilitate follow-up, and detect fraud, at a minimum, the four data elements listed in the bullets below should be included in any serious adverse event report for an OTC drug product that is marketed without an approved application:   

• an identifiable patient
• an identifiable reporter
• a suspect drug
• a serious adverse event or fatal outcome

The responsible person should actively seek information on any minimum data element not initially provided by the reporter and wait to submit a report on the incident to FDA until the information is obtained.  The responsible person should maintain records of the event information and its efforts to obtain the basic elements for an individual report in its files.

The responsible person should actively seek follow-up information for the purposes of completing all the applicable elements for an ICSR.   The responsible person should document its efforts to obtain additional relevant information.  If the responsible person documents these efforts, then the responsible person must maintain the documentation for 6 years and allow FDA to access the records (section 760(e) of the Act). 

1.         Identifiable Patient 

To have an identifiable patient, there should be enough information to indicate the existence of a specific patient or consumer.  One or more of the following automatically qualifies a patient as identifiable: age (or age category, e.g., adolescent, adult, elderly), gender, initials, date of birth, name, or patient identification number.  A report stating that "an elderly woman had anaphylaxis" or "a young man experienced anaphylaxis" would be sufficient.  If a report received by the responsible person refers to groups of unknown size, such as "some” or “a few” college students got anaphylaxis, the responsible person should follow up to find out the number and then submit a separate report to FDA for each identifiable patient.  The responsible person should distinguish each patient so that it is clear that each ICSR is not a duplicate report of a single adverse event.

Patients should not be identified by name or address when reporting to FDA.  Instead, the responsible person should assign a code (e.g., patient initials) to each ICSR.  The assigned code will permit the responsible person to cross-reference with identifying information and contact information in the event follow-up is sought.

2.         Identifiable Reporter 

A reporter is the person who first notifies the responsible person about the serious adverse event and can be the patient, consumer, or some other person (e.g., doctor, family member).  Reports that are received from a third party who has only limited information or lacks first-hand knowledge about the serious adverse event (e.g., “my neighbor told me that a friend became seriously ill after taking Product X”), or that are made anonymously should not be submitted to FDA as an ICSR unless there is sufficient information for the responsible person to follow-up, such as a phone number or e-mail address.  If the reporter requests that the responsible person not forward their contact information to FDA, the responsible person can submit a report without specific identification of the reporter, as long as the responsible person keeps the contact information on file so that it could contact the reporter either upon request by FDA or on its own initiative.  For these reports, the responsible person should fill in the reporter identity fields inan ICSR with a statement such as “Requested Anonymity.”

3.         Suspect Drug  

A suspect drug is easily ascertained when no other drug products have been used by the patient.  However, if a serious adverse event involves multiple drug products that are manufactured, packaged, or distributed by the same responsible person, the responsible person should submit only one ICSR, according to the safety reporting requirements applicable to the drug product considered most suspect by the reporter. 10.   If the reporter views each product as equally suspect, the responsible person should submit only one ICSR, according to the safety reporting requirements applicable to the drug product that is first alphabetically.  In either case, the ICSR would include information on all suspect drug products with one manufacturer report number. 

If the serious adverse event is associated with an OTC drug product(s) marketed without an approved application and a dietary supplement(s) that is also manufactured, packaged, or distributed by the same responsible person, and the reporter views each product as suspect, the responsible person should submit one ICSR about the serious adverse event to both CDER and to CFSAN.  The ICSR should identify both suspect products and use one manufacturer report number.

If a serious adverse event involves multiple suspect drug products that were manufactured, packaged or distributed by more than one responsible person (e.g., manufacturer A and B), and if the event is reported to one of the responsible persons (manufacturer A), then that responsible person (manufacturer A) should submit an ICSR to FDA on the serious adverse event that describes detailed information, including identification of manufacturer B’s product(s).  In such a case, manufacturer A should send manufacturer B a copy of the submitted FDA Form 3500A, including manufacturer A’s report number.  In this case, manufacturer B need not submit to FDA information originally submitted to the Agency by manufacturer A.  In this case, if manufacturer B receives additional information about the serious adverse event, manufacturer B should submit the new medical information as a separate ICSR with its own manufacturer report number and reference manufacturer A’s report number in the narrative section (i.e., section B.5 for reports submitted using FDA Form 3500A or its equivalent in the electronic format).    

4.         Serious Adverse Event 

A serious adverse event, as defined in section 760(a)(3) of the Act, must have one or more of the following patient outcomes or, based on reasonable medical judgment, require a medical or surgical intervention to prevent one of the following patient outcomes:

• death
• a life-threatening experience
• inpatient hospitalization
• a persistent or significant disability or incapacity
• a congenital anomaly or birth defect

Inpatient hospitalization includes initial admission to the hospital on an inpatient basis, even if released the same day, and prolongation of an existing inpatient hospitalization.  

Examples of serious adverse events that based on reasonable medical judgment should be treated medically or surgically to prevent one of the listed outcomes, include allergic bronchospasm that calls for intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 

For reporting purposes, a serious adverse eventshould, at a minimum, be described in terms of signs (including abnormal laboratory findings), symptoms, or disease diagnosis for purposes of reporting.  Thus, a report stating that a patient "experienced unspecified injury" or a patient "suffered irreparable damages" would not be specific enough.  If the reporter does not provide any signs, symptoms, or diagnosis, responsible persons should obtain more information from that person, the patient, or (with the patient’s permission) medical professionals who treated the patient.  A report of a death, even without information about events that led to the death, meets the minimum description of a serious adverse event and should be reported to FDA.  Responsible persons should also provide any available information on the event(s) that led to the death.
As part of the serious adverse event report, we encourage, as appropriate, attachment of the following: (1) hospital discharge summaries, (2) autopsy reports, (3) relevant laboratory data, and (4) other critical clinical data. 

The ICSR must be submitted within 15 business days of receipt of the report of the serious adverse event received through the address or phone number on the label (section 760(c)(1) of the Act).   The date the responsible person receives the four basic elements (i.e., identifiable patient, identifiable reporter, suspect drug, serious adverse event) is Day 0 of the 15-business-day time clock and should be entered into item G.4 of FDA Form 3500A or its electronic equivalent. 

Reports of serious adverse events received by a responsible person in which the initial reporter identifies the suspect drug as one manufactured, packaged, or distributed by another responsible person should be promptly forwarded to that other responsible person.  A responsible person who receives a report of an adverse event regarding one of its products from another responsible person must submit an ICSR to FDA within the same timeframe applicable to any report received from a reporter, unless the ICSR has already been submitted to FDA by the first responsible person (see section III.A.3 of this document). 

If a responsible person does not initially receive sufficient data for a report, but subsequently receives additional information completing the four basic elements concerning a serious adverse event, then an initial report should be submitted within 15 business days of the date the additional information was received, with the date that the additional information was received entered into item G.4 of FDA Form 3500A or its electronic equivalent.

B.        Submission of New Medical Information (Follow-up Reports)

The responsible person must submit a follow-up report when new medical information related to a submitted serious adverse drug event report is received by the responsible person within 1 year of the initial report (section 760(c)(2) of the Act).  Follow-up reports must be submitted no later than 15 business days after the new information is received by the responsible person (section 760(c)(2) of the Act).  Responsible persons should provide a current, comprehensive understanding of the serious adverse drug event, rather than providing only the changes and/or updates to the initial report.  Relevant information from the initial report should be combined with the follow-up information to present an accurate and comprehensive, but concisely written, description of the event as it is understood at the time of the follow-up report.  This description and note of any changes or corrections to any fields should be provided in section B.5 for reports submitted using FDA Form 3500A or its equivalent in the electronic format.

Any information from the initial report later found to be inaccurate should not be repeated in the follow-up report.  All new information, including correction of previously submitted inaccurate information that is included in a follow-up report, should be highlighted.  To highlight new information or corrections included in follow-up reports submitted using FDA Form 3500A, use an asterisk or underline the new information.  For example, if new dose information is received, it should be included in field C.1, and a statement such as “Dose has been updated,” underlined or highlighted with an asterisk, should be included in section B.5.  Any unchanged attachments submitted with an initial report (e.g., hospital discharge summaries, lab results) should not be resubmitted with a follow-up report.   

If a new, serious adverse event occurs that is associated with the initial serious adverse event, a follow-up report should be submitted.  However, if the new, serious adverse event is not associated with the initial serious adverse event (e.g., occurs after a subsequent administration of the product), an initial report with a new manufacturer report number should be submitted for the new, serious adverse event and the manufacturer report number for the original serious adverse event should be included in the narrative section of the report.  In these cases, the responsible person should consider the clinical relevance of the serious adverse events to each other when determining whether an initial report or follow-up report should be submitted.

Follow-up reports should use the same identification number as used in the initial ICSR (i.e., the number in section G.9 for reports submitted using FDA Form 3500A).  This allows the initial ICSR and all of its follow-up reports to be linked in FDA’s Adverse Event Reporting System database (AERS) (see section V.B of this document for information on AERS).  The identification number used to submit follow-up reports to FDA should be the same as the identification number used in the initial ICSR, even if the responsible person reassigns identification numbers to internal files for submitted ICSRs (e.g., if duplicate reports are consolidated, or data handling procedures are changed).  No characters should be added to the initial manufacturer report number on submitted reports to denote that the report is a follow-up or to denote the sequence of the reports.  The initial identification number of the follow-up reports should continue to be used, but the reassigned internal identification number can be noted in the narrative section of the follow-up report (e.g., “This event has been reassigned Company A ID number COA12345”). 

IV.       SUBMITTING THE LABEL

Each ICSR of a serious adverse event associated with an OTC drug marketed in the United States without an approved application must be accompanied by a copy of the current label on or within the retail package of the drug (see section 760(b)(1) of the Act).  The labels submitted with the report should include the full outer carton/container label and immediate container label, including the Drug Facts panel and the principal display panel.  For ICSRs submitted on paper (FDA Form 3500A), responsible persons should submit legible paper copies of these labels, no smaller than actual size, as an attachment to the form.  For ICSRs submitted in an electronic format, labels should be submitted in an appropriate electronic format that FDA can process, review, and archive (see section V.B of this document).  A copy of the label should not be resubmitted with a follow-up report unless there have been changes to the label since the initial submission.

V.        REPORTING FORMATS FOR PAPER OR ELECTRONIC SUBMISSIONS

As described in section III of this document, under sections 760(b)(1) and (c)(2) of the Act, responsible persons must submit initial and follow-up ICSRs of serious adverse events associated with the use of OTC drugs marketed in the United States without an approved application when the products are used in the United States.  In addition, as described in section IV of this document, under section 760(b)(1) of the Act, the report must be accompanied by a copy of the label on or within the retail package of the drug.  Responsible persons should use an FDA Form 3500A or an electronic format to submit the ICSRs, as described below.  

This section describes how to (1) acquire, generate, complete, and submit an FDA Form 3500A for reporting ICSRs and (2) submit ICSRs and the copies of the label in an electronic format.

A.        Paper Submission (FDA Form 3500A)

1.         Acquiring Copies of FDA Form 3500A

The form can be acquired from:

• Appendix 1 of this guidance

• the Internet at http://www.fda.gov/medwatch/getforms.htm or http://www.fda.gov/opacom/morechoices/fdaforms/OC.html

• CDER’s Division of Drug Information:
  

–By e-mail:   druginfo@fda.hhs.gov

–By phone:  1-888-INFO-FDA
1-888 463-6332 or (301) 827-4570

–By mail:      Division of Drug Information
5600 Fishers Lane, HFD-240
Rockville, MD 20857

2.         Generating Copies of FDA Form 3500A

Copies of the form can be generated by: 

• Photocopying a blank FDA Form 3500A  
• Producing a printed facsimile of FDA Form 3500A

–Generated by Fillable Forms Software at

http://www.fda.gov/medwatch/safety/FDA-3500A_Fillable_08-16-2006.pdf and included in Appendix 1.

 

–Generated by commercial software that can be used after the format is agreed to in advance by FDA.  For details see item 4 at
http://www.fda.gov/medwatch/report/instruc_10-13-06.htm#obtain.
 

3.         Completing FDA Form 3500A      

 
All FDA Form 3500A submissions should be legibly printed or typewritten and completed with a minimum font size of 8 point.  Legible photostatic copies can be submitted.  However, visual contrast and paper opacity should be adequate to ensure clear readable archival images.  A form reporting a serious adverse event associated with the use of an OTC drug product should have “OTC Product” checked in field G5 of the form.  FDA encourages responsible persons to use an FDA assigned national drug code (NDC) number as the product identifier in field C9 of the form.  The NDC number is the most useful product identifier for FDA.  Alternatively, if the suspect OTC drug product does not have an FDA-assigned NDC number, any other standard product identification code or number should be entered in field C9.  For additional information, see Instructions on completing FDA Form 3500A at http://www.fda.gov/medwatch/report/instruc_10-13-06.htm.

4.         Submitting FDA Form 3500A

Completed FDA Form 3500A should be sent to:

Central Document Room
Center for Drug Evaluation and Research
Food and Drug Administration
5901-B Ammendale Road
Beltsville, MD  20705-1266

Do not include a cover letter with the submission; all information should be included in the FDA Form 3500A and in attachment(s), if any.

B.        Electronic Submission

The AERS system is a computerized information database designed to support FDA's postmarketing safety surveillance program for all marketed drug and biologic products excluding blood components and vaccine products.  FDA has implemented the regulatory and infrastructure changes for full-scale implementation to accommodate electronic submissions of ICSRs and ICSR attachments. 

To fulfill the submission requirements of section 760 of the Act, responsible persons can complete and submit electronic ICSRs with the full outer carton/container and immediate container label, including the Drug Facts panel and principal display panel, as electronic ICSR attachments.  Contact the AERS Electronic Submission Coordinator at the following number(s) or e-mail address to discuss your intent to submit ICSRs and ICSR attachments in an electronic format:

Phone: 301-770-9299
FAX: 301-770-6614
E-MAIL: AERSESUB@cder.fda.gov

For information on electronic submission of ICSRs and ICSR attachments, see http://www.fda.gov/cder/aerssub/default.htm.

Appendix 1: FDA Form 3500A

 Fillable version of the form plus instructions:  http://www.fda.gov/medwatch/safety/FDA-3500A_Fillable_08-16-2006.pdf

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Date created: 10/11/2007

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