Draft Guidance for Industry-Providing Submissions in Electronic Format — Postmarketing Safety Reports for Vaccines

I. INTRODUCTION

II. BACKGROUND

III.  GENERAL INFORMATION ABOUT Vacccine ICSR SUBMISSIONS submissions

A.  Parts of an ICSR Submission
B.  Options for Electronic Submission of an ICSR and ICSR Attachments into VAERS
C.  Technical Specifications for Electronic Submission of ICSRs for Vaccine Products
D.  Unique Case Identification Numbers for Initial and Followup ICSRs
E.  Sending in Submissions
F.  Notification of Receipt of Submissions by the FDA
G.  Contingencies If the ESG Is Temporarily Unavailable

IV. POSTMARKETING SAFETY REPORTS OTHER THAN ICSRS

V. WAIVER REQUEST  

A. Content of Waiver Requests
B. Where to Submit Waiver Requests
C. FDA Response to Waiver Requests

FOOTNOTES

---

 

¹into the Vaccine Adverse Event Reporting System (VAERS).  The guidance is applicable to vaccine products marketed for human use with approved biologics license applications (BLAs) for which CBER has regulatory responsibility. ²Â  The guidance does not apply to any other biologic product.  When finalized, this guidance will supersede the FDA guidance entitled “Guidance for Industry:  How to Complete the Vaccine Adverse Event Reporting System Form (VAERS-1)” dated September 1998 (1998 Guidance).  

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.³Â  For general information pertaining to electronic submission of postmarketing safety reports, including ICSRs and ISCR attachments for these other products, please refer to the FDA draft guidance entitled, “Guidance for Industry:  Providing Submissions in Electronic Format – Postmarketing Safety Reports” dated June 2014. ⁴  When finalized, this guidance will represent our current thinking on this topic.  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.

 Return to TOC

---

⁵

Return to TOC

---

⁶format using the International Conference on Harmonisation’s (ICH) E2B(R3) specification.  See section III.C of this guidance document for more information about this specification.

ICSR attachments include supporting information for ICSRs, such as relevant medical records, hospital discharge summaries, autopsy reports or other documentation.  ICSR attachments also include published articles for ICSRs based on scientific literature (§ 600.80(d)).

Followup 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, followup ICSRs should include information about an adverse experience that has been previously reported as an initial ICSR along with any new information.  However, any ICSR attachments submitted with an initial ICSR (e.g., literature articles, hospital discharge summaries) should not be resubmitted with a followup ICSR.  See section III.D of this guidance document for information on using unique case identification numbers for the initial ICSR and followup ICSRs to help ensure linkage between the two.

The following sections provide general information related to the electronic submission of initial and followupICSRs 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 followup ICSR submission is considered to have two parts:

• The ICSR itself; and
• The ICSR attachments, if applicable.

B. ⁷  Electronic submission of ICSRs for vaccine products using the FDA eSubmitter tool is described on the CBER ICSR eSubmitter Web page.⁸  Both options involve use of XML files that are submitted to FDA through its Electronic Submissions Gateway (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. ⁹  Using a unique case identification number allows FDA to link the initial ICSR with any followup 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 followup ICSRs in the FDA ICH E2B(R3) technical specifications document on CBER’s ICSR Specifications Web page. 

E. [email protected].  The VAERS 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. ¹⁰ 

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 [email protected] 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 e-mail 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 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 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).

Return to TOC

---

¹¹Â  The descriptive portion can be submitted as a periodic adverse experience report,¹²a periodic safety update report, ¹³or a periodic benefit–risk evaluation report.¹⁴ 

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 above.  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 (or PDF) to section 5.3.6 of the Electronic Common Technical Document (eCTD). ¹⁵  Firms should not submit non-expedited ICSRs to the eCTD in a PDF format together with the descriptive portion of the periodic safety report. 

Return to TOC

---

¹⁶stating 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.

---

¹Â  See section III of this document for a description of ICSRs and ICSR attachments.

²If an applicant is not sure where to file, the applicant should contact CBER’s OCOD for information.

³In 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.htm.

⁴The draft guidance is available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072369.pdf.  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.

⁵Section 745A(a) of the FDC 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 FDC 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.  When finalized, this guidance will represent the Agency’s current thinking on certain topics associated with this rulemaking.  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 FDC Act.

⁶For purposes of this guidance, the term “XML” refers to Extensible Markup Language.

⁷The CBER’s ICSR Specifications Web page is available at http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/ucm174963.htm.

⁸The CBER ICSR eSubmitter Web page is available at http://www.fda.gov/ForIndustry/FDAeSubmitter/ucm317156.htm.

⁹Note that the unique case identification number replaces the “Manufacturer Report Number” on Form FDA 3500A and the VAERS form. 

¹⁰The draft guidance is available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072385.pdf. 

¹¹As described in 21 CFR 600.80(c)(2)(ii)(B).  Non-expedited ICSRs were previously referred to as periodic ICSRs. 

¹² As described in 21 CFR 600.80.

¹³FDA allows firms with approved waivers (see 21 CFR 600.90) to use the ICH E2C Periodic Safety Update Report format when submitting the descriptive portion of periodic safety reports.  See the guidance document entitled “Draft Guidance for Industry:  Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines” dated March 2001, including section XI concerning waiver requests.  The draft guidance is available at http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/
Guidances/Vaccines/ucm092257.pdf.  This draft guidance, when finalized, will represent FDA’s current thinking on this topic.

¹⁴ FDA allows firms with approved waivers (see 21 CFR 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.

¹⁵ Information regarding the eCTD is available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ ucm153574.htm.

¹⁶ To follow up with the company, FDA intends to contact the individual who submitted the waiver request unless an alternate contact person is provided.

---

---

Reference Information

About this Guidance Document

How to Comment

Submit one set of either electronic or written comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance.  Submit electronic comments to http://www.regulations.gov.  Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.  You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.

[email protected], or from the Internet at  http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

For Questions Regarding this Document

For questions on the content of this guidance, contact OCOD at the phone numbers or email address listed above.

FDA Offices Issuing This Guidance

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