Providing Submissions in Electronic Format — Postmarketing Safety Reports for Vaccines: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Providing Submissions in Electronic
Format — Postmarketing Safety
Reports for Vaccines
Guidance for Industry
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring,
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or
from the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida
nces/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or email
address listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
August 2015

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Table of Contents
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	GENERAL INFORMATION ABOUT VACCCINE ICSR SUBMISSIONS ............. 3
A. 	Parts of an ICSR Submission ............................................................................... 4
B. 	Options for Electronic Submission of an ICSR and ICSR Attachments into
VAERS ................................................................................................................... 4
C. 	Technical Specifications for Electronic Submission of ICSRs for Vaccine
Products ................................................................................................................. 4
D. 	Unique Case Identification Numbers for Initial and Follow-up ICSRs .......... 5
E. 	Sending in Submissions ........................................................................................ 5
F. 	Notification of Receipt of Submissions by the FDA ........................................... 5
G. 	Contingencies If the ESG Is Temporarily Unavailable ..................................... 6
IV. 	POSTMARKETING SAFETY REPORTS OTHER THAN ICSRS ........................... 7
V. 	WAIVER REQUESTS ..................................................................................................... 8
A. 	Content of Waiver Requests ................................................................................ 8
B. 	Where to Submit Waiver Requests ..................................................................... 8
C. 	FDA Response to Waiver Requests ..................................................................... 9
The technical specification associated with this guidance is provided in a separate
document and is updated periodically. To ensure that you have the most recent version of
the technical specifications document, check the CBER ICSR Specifications Web page at:
http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/ucm174963.htm

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Providing Submissions in Electronic Format — Postmarketing
Safety Reports for Vaccines
__________________________________________________________
Guidance for Industry
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff
responsible for this guidance as listed on the title page.
I. 	INTRODUCTION
This is one in a series of guidance documents intended to assist you, an applicant, in making
postmarket regulatory submissions in electronic format to the Center for Biologics Evaluation
and Research (CBER) at FDA. The guidance provides information and recommendations
pertaining to the electronic submission of postmarketing safety reports involving vaccine
products, including individual case safety reports (ICSRs) and attachments to ICSRs (ICSR
attachments),1 into the Vaccine Adverse Event Reporting System (VAERS). VAERS is a
national vaccine safety surveillance program established in response to the National Childhood
Vaccine Injury Act2 of 1986, which requires health professionals and vaccine manufacturers to
report specific adverse events that occur after the administration of routinely recommended
vaccines. VAERS is co-sponsored by the Centers for Disease Control and Prevention (CDC)
and FDA. The guidance is applicable to vaccine products marketed for human use with
approved biologics license applications (BLAs) for which CBER has regulatory responsibility.3
The guidance does not apply to any other biologic product.
This guidance finalizes the draft guidance of the same title, dated July 2014, and supersedes the
FDA guidance entitled “Guidance for Industry: How to Complete the Vaccine Adverse Event
Reporting System Form (VAERS-1),” dated September 1998.
Postmarketing ICSRs and ICSR attachments for biological products, which are not addressed by
this guidance, are processed into the FDA Adverse Event Reporting System (FAERS) database.4
1 See section III of this document for a description of ICSRs and ICSR attachments.
2 The National Childhood Vaccine Injury Act of 1986 (Public Law 99-660) created the National Vaccine Injury
Compensation Program (VICP). The VICP was established to ensure an adequate supply of vaccines, stabilize
vaccine costs, and establish and maintain an accessible and efficient forum for individuals found to be injured by
certain vaccines.
3 If an applicant is not sure where to file, the applicant should contact CBER’s OCOD for information.
4 In September 2012, the FAERS database replaced the previously used Adverse Event Reporting System (AERS)
database. The transition to the FAERS database has been an important step in improving FDA’s postmarketing
surveillance capabilities. Information regarding the FAERS database is available on FDA’s Web site at:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.ht
m.

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For general information pertaining to electronic submission of postmarketing safety reports,
including ICSRs and ICSR attachments for these other products, please refer to the FDA draft
guidance entitled, “Providing Submissions in Electronic Format – Postmarketing Safety Reports”
dated June 2014.5 Agency guidance on electronic submissions will be updated as necessary to
reflect the evolving nature of the technology and the experience of those using this technology.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’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 FDA’s guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND
In the Federal Register of June 10, 2014 (79 FR 33072), FDA published a final rule entitled
“Postmarketing Safety Reports for Human Drug and Biological Products; Electronic Submission
Requirements.” This final rule requires, among other things, that certain postmarketing safety
reports required under 21 CFR 310.305, 314.80, 314.98, and 600.80 (§§ 310.305, 314.80,
314.98, and 600.80) and section 760 of the Federal Food, Drug, and Cosmetic Act (FD&C Act)
(21 U.S.C. 379aa) be submitted to FDA in an electronic format that the Agency can process,
review, and archive. This final rule also adds 21 CFR 329.100 (§ 329.100) to address electronic
submission of safety reports required by section 760 of the FD&C Act. These requirements
became effective as of June 10, 2015.6
5 The draft guidance is available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072369.pdf.
When finalized, this guidance will represent FDA’s current thinking on this topic. Further information regarding
regulations and guidances related to postmarketing safety reporting can be found on the FDA Web site,
Postmarketing Safety Reporting Requirements for Drug and Biologic Products, at:
http://www.fda.gov/Drugs/DrugSafety/ucm299833.htm.
6 Section 745A(a) of the FD&C Act (21 U.S.C. 379k-1), added by section 1136 of the Food and Drug
Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144), provides that submissions under section
505(b), (i), or (j) of the FD&C Act or section 351(a) or (k) of the Public Health Service Act (42 U.S.C. 262(a) or
(k)) shall be submitted in such electronic format as specified by FDA in guidance. In section 745A(a), Congress
granted explicit statutory authority to FDA to implement the electronic format for submissions requirement by
guidance. This grant of authority, however, does not preclude FDA from implementing such requirements by notice
and comment rulemaking (5 U.S.C. 553). Accordingly, at this time, even though FDA has concluded that certain
submissions that are addressed in the final rule are also within the scope of section 745A(a), FDA has determined
that it is appropriate to amend the regulations on the submission of postmarketing safety reports to remove
references to paper submissions and to specify that such reports be submitted in an electronic format that FDA can
process, review, and archive. FDA may consider, at a future date, whether to include information pertaining to
submission of postmarketing safety reports in electronic format in guidance pursuant to section 745A(a) of the
FD&C Act.

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III. 	GENERAL INFORMATION ABOUT VACCCINE ICSR SUBMISSIONS
For purposes of this guidance, an ICSR is a description of an adverse experience related to an
individual patient or subject that is associated with the use of a vaccine product. More
specifically, an ICSR is made up of data elements, such as the date and time of the adverse
experience, the name of the suspect vaccine and the name of the manufacturer of a vaccine
administered in the 4 weeks prior to the vaccination at issue. These data elements include those
listed in the relevant regulations at § 600.80, most notably § 600.80(g), as well as VAERS form
data elements used for reports collected from healthcare providers and patients. You should
submit ICSRs electronically in XML7 format in accordance with the International Conference
on Harmonisation’s (ICH) E2B(R3) specification8. See section III.C of this guidance document
for more information about this specification.
ICSR attachments include supporting information for ICSRs, such as relevant hospital discharge
summaries and autopsy reports or death certificates. ICSR attachments also include published
articles for ICSRs based on scientific literature (§ 600.80(d)). Please refer to the draft guidance
entitled “Postmarketing Safety Reporting for Human Drug and Biological Products Including
Vaccines,” dated March 2001 (2001 draft guidance)9 for more information concerning ICSR
attachments. Technical specifications related to the submission of ICSR attachments are
published on the CBER ICSR Implementation webpage at:
http://www.fda.gov/forindustry/electronicsubmissionsgateway/ucm387293.htm for more
information about sending ICSR attachments.
Follow-up ICSRs should provide a complete picture of the current understanding of an adverse
experience, rather than providing only the changes and/or updates to an ICSR. Accordingly,
follow-up ICSRs should include information about an adverse experience that has been
previously reported as an initial ICSR along with any new information, including any new ICSR
attachments. However, any ICSR attachments submitted with an initial ICSR (e.g., literature
articles, hospital discharge summaries) should not be resubmitted with a follow-up ICSR. See
section III.D of this guidance document for information on using unique case identification
numbers for the initial ICSR and follow-up ICSRs to help ensure linkage between the two.
Information obtained from VAERS through CDC’s website (i.e., public use dataset) or other
sources should not be resubmitted to FDA. Because VAERS is co-sponsored by FDA and CDC,
applicants are not required to resubmit ICSRs for adverse event reports obtained from the
VAERS database (i.e., adverse events reports obtained from VAERS data publically available on
CDC’s website or from publications based on VAERS data, or that were forwarded to the
7 For purposes of this guidance, the term “XML” refers to Extensible Markup Language.
8 The ICH E2B(R3) ICSR specification and related files are available for download at:
http://estri.ich.org/e2br3/index.htm.
9 See the 2001 draft guidance, including section V.A.2: Supporting Documentation, section C.1: Content of Follow-
up Reports, section VI.A: Scientific Literature Reports, and Appendix B: Report Checklist, Question A.7: “Have
you included all relevant attachments and eliminated unnecessary attachments?” The guidance is available at:
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Va
ccines/ucm092257.pdf. When finalized, this guidance will represent FDA’s current thinking on this topic.

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applicant by FDA or CDC), unless the applicant obtains additional follow-up information or
corrections. Please refer to the regional technical specifications document posted on the CBER
ICSR Specifications Web page for more information about the resubmission of VAERS reports.
The following sections provide general information related to the electronic submission of initial
and follow-up ICSRs and ICSR attachments. Note that regardless of the type of submission (i.e.,
those submitted as 15-day Alert reports or reports of adverse experiences that are both serious
and expected or nonserious), the electronic submission procedure is the same.
A. 	Parts of an ICSR Submission
For purposes of this discussion of electronic submissions, an initial or a follow-up ICSR
submission is considered to have two parts:
1. 	The ICSR itself; and
2. 	The ICSR attachments, if applicable.
B. 	Options for Electronic Submission of an ICSR and ICSR Attachments into
VAERS
FDA provides two options for electronic submission of ICSRs and ICSR attachments
involving vaccine products for processing into VAERS: the direct database-to-database
submission method and the eSubmitter tool method. The direct database-to-database
submission method is described on FDA’s Electronic Submissions Gateway (ESG) Web
page.10 Electronic submission of ICSRs for vaccine products using the FDA eSubmitter
tool (data entry tool used to create ICSR files) is described on the CBER eSubmitter Web
page.11 Both options involve use of XML files that are submitted to the FDA ESG. The
ESG is the central transmission point for sending information electronically to FDA.
Once received through the ESG, the submitted reports are processed into the VAERS
database.
C. 	Technical Specifications for Electronic Submission of ICSRs for Vaccine
Products
ICSRs and ICSR attachments must be submitted to FDA in an electronic format that we
can process, review, and archive § 600.80(h)(1). For this purpose, CBER will provide
associated technical specification documents that will give more information concerning
how to create and submit FDA-compliant ICSRs on CBER’s ICSR Specifications Web
page.
10 The FDA ESG Web page is available at:
http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm
11 FDA eSubmitter Web page is available at: http://www.fda.gov/ForIndustry/FDAeSubmitter/ucm317156.htm.

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D. 	Unique Case Identification Numbers for Initial and Follow-up ICSRs
Postmarketing safety reporting often involves submitting a series of reports consisting of
the initial ICSR and follow-up ICSRs, along with any associated attachments, over the
life cycle of an individual case. It is important to note that the unique case identification
number must be the same in the initial report and any subsequent follow-up report(s)
(§ 600.80(g)(7)(viii)).12 Using a unique case identification number allows FDA to link
the initial ICSR with any follow-up reports in the VAERS database, regardless of the
time or method of transmission of an individual report. For further information, see the
section on identification numbers for initial and follow-up ICSRs in the ICH E2B(R3)
technical specifications document on CBER’s ICSR Specifications Web page.
E. 	Sending in Submissions
Electronic ICSRs and ICSR attachments should be submitted to FDA through FDA’s
ESG, which is open 24 hours a day, 7 days a week. ICSR attachments should be
submitted to FDA at the same time that the associated ICSR file is submitted or as an
attachment to a follow-up report. Once received through the ESG, the ICSRs and ICSR
attachments will be processed into VAERS.
Before submitting an ICSR in electronic format to FDA for the first time, you should
submit your request to CBER via email at CBERICSRSUBMISSIONS@fda.hhs.gov.
The eVAERS Coordinator will assist you with submission of a test file. For subsequent
submissions in electronic format, it is not necessary to contact the VAERS Coordinator
before submitting the ICSR. For additional information on providing submissions using
the ESG, refer to FDA’s ESG Web page at: http://www.fda.gov/esg.
F. 	Notification of Receipt of Submissions by the FDA
Once a submission (one or more ICSRs and ICSR attachments) reaches the ESG and is
successfully recognized and decrypted, an ESG message delivery notice (MDN) will be
sent to the sender. The date of this ESG MDN will serve as the official FDA receipt date
of each successfully transmitted ICSR and ICSR attachment in the submission. See
FDA’s ESG Web page for further information about receipt of submissions through the
ESG.
After receipt of the submission, CBER will process the ICSRs and ICSR attachments and
a second automated acknowledgement message (CBER receipt acknowledgment) will be
sent to the sender via the ESG. The CBER receipt acknowledgement will serve to inform
the sender that the ICSR submission(s) have successfully reached CBER. We expect that
you will receive your ESG MDN and CBER receipt acknowledgement within 24 hours
after you have submitted an ICSR, including any associated ICSR attachments to the
ESG. A third automated acknowledgment message (VAERS file validation and load
acknowledgment) will be sent to the sender to provide file validation and load status for
12 Note that the unique case identification number replaces the “Manufacturer Report Number” on Form FDA
3500A and the VAERS form.

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each ICSR submission. For additional information about VAERS acknowledgement
message files and format, refer to the FDA regional technical specifications for ICH
E2B(R3) implementation at CBER’s ICSR Specifications Web page.
ICSRs and associated ICSR attachments must be submitted to the Agency within the time
periods specified in § 600.80(c). Please plan your submissions accordingly.
Additional information on the receipt date of submissions is available in the FDA
guidance entitled “Guidance for Industry: Providing Regulatory Submissions in
Electronic Format – Receipt Dates” dated February 2014.13
G. 	Contingencies If the ESG Is Temporarily Unavailable
As stated previously, we expect that you will receive your ESG MDN and CBER receipt
acknowledgement within 24 hours after you have submitted an ICSR or ICSR
attachment(s) to the ESG. If you do not receive these messages within 24 hours, we
recommend that you first check the FDA ESG Web page to determine whether we are
experiencing any problems with the ESG.
• 	If the ESG is functional, and you have not received the CBER receipt
acknowledgement within 24 hours after the end of the transmission, contact
ESGHelpDesk@fda.hhs.gov for assistance. Please be prepared to provide the
Core ID, which is the ID assigned by the FDA ESG for submission tracking, as
well as the company name on the account and the date and time the submission
was sent.
• 	If the ESG is not functional for more than 24 hours, FDA will post a notice on
the FDA ESG Web page to provide further guidance concerning alternative
submission methods. If the ESG is not functional for more than 48 hours, the
FDA ESG email distribution list (listserv) will be used to communicate
procedures on how to proceed with your submission. If you follow these
procedures, it is important that you do not resubmit the ICSRs or ICSR
attachment(s) to FDA using the ESG when it becomes functional. Note that when
you follow the alternate submission method, the official FDA receipt date of the
ICSRs or ICSR attachment(s) will be the date when the submission is received by
the CBER Document Control Room (DCC) or VAERS program (for example, if
the submission is faxed, the receipt date will be the date on the timestamp of the
successful fax).
If you submit ICSRs or ICSR attachment(s) that we are unable to load into the VAERS
database because you did not use the correct data elements or an electronic transport
format that CBER supports, the third automated VAERS acknowledgement message will
indicate that we could not load these ICSRs (or ICSR attachment(s)) into VAERS. The
acknowledgement also will indicate which, if any, ICSRs or ICSR attachment(s) that you
13 The guidance is available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072385.pdf.

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sent to the ESG at the same time were processed into VAERS. You should resubmit to
us only those ICSRs or ICSR attachment(s) that were not processed into VAERS. Your
resubmission should be given a different file name (batch identifier) than the original
submission and should take place within the required reporting timeframe. The date of
the ESG MDN acknowledgement for the resubmission will serve as the official FDA
receipt date of the ICSR or ICSR attachment(s).
IV. 	POSTMARKETING SAFETY REPORTS OTHER THAN ICSRs
Under § 600.80(c)(2), you must submit postmarketing periodic safety reports at prescribed
intervals. Among other things, each periodic safety report must contain a descriptive portion and
the ICSRs for all adverse experiences other than those submitted as 15-day Alert reports or
follow-up reports to 15-day Alert reports for the reporting period (i.e., reports of adverse
experiences that are both serious and expected or nonserious).14 The descriptive portion can be
submitted as a periodic adverse experience report,15 a periodic safety update report,16 or a
periodic benefit–risk evaluation report.17
For purposes of this discussion of electronic submissions, a postmarketing periodic safety report
(§ 600.80(c)(2)) is considered to have three parts:
1. Descriptive information;
2. ICSR(s); and
3. ICSR attachment(s), if applicable.
Submission of ICSR(s) and ICSR attachment(s) are addressed in section III of this guidance
document. The descriptive information portion of the periodic safety report required under §
600.80(c)(2)(ii)(A) should be submitted separately as a portable document file (PDF) to section
5.3.6 of the Electronic Common Technical Document (eCTD).18 Firms should not submit non-
expedited ICSRs to the eCTD in a PDF format together with the descriptive portion of the
periodic safety report.
14 As described in § 600.80(c)(2)(ii)(B). Non-expedited ICSRs were previously referred to as periodic ICSRs.
15 As described in § 600.80.
16 FDA allows firms with approved waivers (see § 600.90) to use the ICH E2C Periodic Safety Update Report
format when submitting the descriptive portion of periodic safety reports. See the 2001 draft guidance, including
section XI concerning waiver requests. When finalized, this guidance will represent FDA’s current thinking on this
topic.
17 FDA allows firms with approved waivers (see § 600.90) to use the ICH E2C(R2) Periodic Benefit-Risk
Evaluation Report format when submitting the descriptive portion of periodic safety reports. See the guidance
document entitled “Guidance for Industry: Providing Submissions in Electronic Format – Postmarket Non-
Expedited ICSRs Technical Questions and Answers” dated July 2013. The guidance is available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM362174.pdf.
18 Information regarding the eCTD is available at:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/
ucm153574.htm.

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V. 	WAIVER REQUESTS
Under § 600.90, an applicant required to submit a postmarketing safety report under § 600.80
may ask FDA to waive temporarily the requirement that the safety report be submitted in
electronic format. We anticipate that temporary waivers for licensed vaccine products regulated
by CBER will be needed only in rare circumstances. Companies experiencing technical
difficulties with transmission of their electronic submissions to FDA should consult FDA for
technical assistance rather than submitting a waiver request. Companies that normally use the
direct database-to-database method to submit reports to FDA could use the eSubmitter tool we
have made available as a backup method during short-term, temporary outages.
A. 	Content of Waiver Requests
An applicant’s request to waive the electronic format requirement must include one of the
following as supporting documentation: An explanation why the applicant’s compliance
with the requirement is unnecessary or cannot be achieved (e.g., acts of nature,
widespread internet outages, temporary issues with the applicant’s adverse event
database(s)); a description of an alternative submission that satisfies the purpose of the
requirement; or other information justifying a waiver (§ 600.90(a)).
We recommend that this request be submitted to FDA in writing by mail. The request
should reference all vaccines that are to be covered by the waiver. If not already
provided as justification for the waiver for purposes of meeting the requirements under §
600.90(a), we recommend that the waiver request include the reason for the request (i.e.,
information justifying the waiver). Reasons could include, for example, acts of nature,
widespread internet outages, and temporary issues with an applicant’s adverse event
database(s). The waiver request also should include a proposed end date for the waiver
and steps being taken to meet the reporting requirements, such as additional training or
system testing, and a company contact. The waiver request also should include a
proposed end date for the waiver and a description of any proposed alternative reporting
method, as relevant to the circumstances. Potential alternative reporting methods could
include (but are not limited to) physical media and fax. The waiver request should be
clearly titled “WAIVER REQUEST – POSTMARKETING SAFETY
REQUIREMENTS” in bold capital letters at the top of the first page of the submission. .
B. 	Where to Submit Waiver Requests
For licensed vaccine products regulated by CBER, waiver requests should be addressed
to:
U.S. Food and Drug Administration
Center for Biologics Evaluation and Research
Office of Biostatistics and Epidemiology
Document Control Center
10903 New Hampshire Avenue
Bldg. 71, Rm. G112
Silver Spring, MD 20993-0002.

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C. 	FDA Response to Waiver Requests
FDA reviews waiver requests on a case-by-case basis. FDA intends to respond in writing
to the requestor,19 stating whether or not the waiver is granted. If the waiver is granted,
FDA intends to also include in its response letter a description of the acceptable alternate
format(s) for the safety report. Waivers of the requirement to submit reports in
electronic format, if granted, will be temporary.
19 To follow up with the company, FDA intends to contact the individual who submitted the waiver request unless
an alternate contact person is provided.