Guidance for Industry 
 
Providing Submissions in Electronic Format     
Postmarket Non-Expedited ICSRs   
Technical Questions and Answers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2013 
Electronic Submissions   
Guidance for Industry 
 
Providing Submissions in Electronic Format     
Postmarket Non-Expedited ICSRs   
Technical Questions and Answers 
 
 
 
 
 
Additional copies are available from: 
 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
10903 New Hampshire Ave. 
Silver Spring, MD 20993  
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 (Tel) 240-276-9300 
or 
 
Office of Communication, Outreach and Development, HFM-40 
Center for Biologics Evaluation and Research 
Food and Drug Administration 
1401 Rockville Pike, Rockville, MD 20852-1448 
ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
Phone:  800-835-4709 or 301-827-1800 
  
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
July 2013 
Electronic Submissions  
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  TECHNICAL QUESTIONS AND ANSWERS ............................................................. 3 
1.  Why Is This Guidance Needed? .................................................................................................... 3 
2.  What Steps Should Firms Take if They Have Submitted Non-Expedited ICSRs in an 
Electronic Format Other Than the XML Format? ............................................................................. 3 
3.  What Can Firms Expect After Contacting FDA? ....................................................................... 4 
4.  Where Can Firms Find Information Explaining How to Submit Electronic Non-Expedited 
ICSRs in the XML Format? .................................................................................................................. 4 
i 
  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
 
Providing Submissions in Electronic Format     
Postmarket Non-Expedited ICSRs   
Technical Questions and Answers 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
This guidance provides firms with information on the appropriate electronic file format to use 
when electronically submitting to FDA postmarket, non-expedited individual case safety reports 
(ICSRs) on adverse drug experiences.2  Non-expedited ICSRs are the case reports required to be 
submitted at the time firms submit their periodic adverse (drug) experience reports (21 CFR 
314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B)).  This guidance explains that firms that previously 
submitted non-expedited ICSRs in an electronic format that is not supported by FDA should 
contact the Center for Drug Evaluation and Research (CDER)3 or the Center for Biologics 
Evaluation and Research (CBER) and resubmit their non-expedited ICSRs in a compatible 
electronic format.  
                                                 
1 This guidance has been prepared by the Office of Surveillance and Epidemiology, in consultation with the Office 
of Compliance, in the Center for Drug Evaluation and Research (CDER) in cooperation with the Center for 
Biologics Evaluation and Research (CBER).  
2 For purposes of this guidance, adverse drug experience includes an adverse experience associated with use of drug 
or a biological product, including a therapeutic vaccine.  
3 CDER is responsible for oversight of FDAs Adverse Event Reporting System (FAERS) database and entering 
information into it for both CDER and CBER.  Applicants sending postmarket ICSRs and ICSR attachments in 
electronic format to FAERS for products regulated by CBER should follow procedures for CDER in the draft 
guidance for industry Providing Regulatory Submissions in Electronic Format  Postmarketing Individual Case 
Safety Reports.    
Note: Agency guidance, including on electronic submissions, are updated to reflect the evolving nature of the 
technology and the experience of those using this technology.  To make sure you have the latest version of a 
guidance, go to http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
 
  1  Contains Nonbinding Recommendations 
 
 
This guidance does not apply to reports of adverse experiences associated with use of 
prophylactic vaccines, human cells, tissues, cellular and tissue-based products, whole blood, or 
components of whole blood. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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.4 
  
 
 
II.  BACKGROUND 
 
FDA regulations at 21 CFR 314.80(c)(2) and 600.80(c)(2) require applicants to submit 
postmarket periodic safety reports at prescribed intervals.  Each periodic safety report must 
contain a descriptive portion and the non-expedited ICSRs5 for the reporting interval.  The 
descriptive portion can be submitted as a periodic adverse drug experience report6; a periodic 
adverse experience report7; a periodic safety update report8; or a periodic benefitrisk evaluation 
report.9   
 
Non-expedited ICSRs can be submitted on paper or electronically.10  When submitted 
electronically, the non-expedited ICSRs should be submitted in XML format.  This is because 
FDA is currently able to process electronic submissions of non-expedited ICSRs only in XML, 
prepared according to International Conference on Harmonisation (ICH) standards for database-
                                                 
4 Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), added by section 1136 of the Food 
and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144), provides that submissions under 
505(b), (i), or (j) of the FD&C Act or 351(a) or (k) of the Public Health Service Act be submitted in such electronic 
format as specified by the FDA in guidance.  In section 745A(a), Congress granted explicit statutory authority to 
FDA to implement the electronic format for submissions requirement by guidance.  FDA may consider, at a future 
date, whether to include information pertaining to providing submissions of postmarket non-expedited ICSRs in 
electronic format in guidance pursuant to Section 745A(a) of the FD&C Act. 
5 As described in 21 CFR 314.80(c)(2)(ii)(b) and 600.80(c)(2)(ii)(B).  Non-expedited ICSRs were previously 
referred to as periodic ICSRs.   
6 As described in 21 CFR 314.80. 
7 As described in 21 CFR 600.80.  
8 FDA allows firms with approved waivers (under 21 CFR 314.90 and 600.90) to use the ICH E2C Periodic Safety 
Update Report format when submitting the descriptive portion of periodic safety reports. 
9 FDA allows firms with approved waivers (under 21 CFR 314.90 and 600.90) to use the ICH E2C(R2) Periodic 
Benefit-Risk Evaluation Report format when submitting the descriptive portion of periodic safety reports. 
10 On August 21, 2009, FDA issued a proposed rule entitled Postmarketing Safety Reports for Human Drug and 
Biological Products; Electronic Submission Requirements (74 FR 42184).  Once finalized, the rule will require that 
all mandatory postmarketing safety reports for human drug and biological products be submitted in an electronic 
format that FDA can process, review, and archive, unless a waiver is granted.  
  2  Contains Nonbinding Recommendations 
 
to-database transmission of information.11  When submitted in this compatible electronic format, 
non-expedited ICSRs can be downloaded into the FDA Adverse Event Reporting System 
(FAERS) database through the Electronic Submission Gateway. 
 
We have become aware that some firms have submitted non-expedited ICSRs to the electronic 
Common Technical Document (eCTD) in a portable document file (pdf) format together with the 
descriptive portion of the periodic safety report.   
 
FDA does not have a systematic method to identify non-expedited ICSRs that are submitted to 
the eCTD in pdf format together with the descriptive portion of the periodic safety report.  In 
addition, non-expedited ICSRs submitted to the eCTD in pdf format cannot be downloaded into 
the FAERS database.  Lack of access to non-expedited ICSRs in FAERS hinders FDAs ability 
to monitor product safety and public health.  Furthermore, submission in pdf format prevents 
public access to the non-expedited ICSRs through FAERS.12     
 
 
III.  TECHNICAL QUESTIONS AND ANSWERS 
 
The following technical questions and answers are intended to provide clarity to industry and to 
facilitate the resubmission of non-expedited ICSRs in a compatible electronic file format.  
   
1.  Why is this guidance needed? 
 
Some firms have submitted non-expedited ICSRs to FDA in an electronic file format that cannot 
be processed into the FAERS database.  This guidance explains what steps firms should take if 
they have submitted ICSRs as pdf-formatted documents or in other non-XML formats.  Firms 
should contact FDA as instructed below if they have previously submitted non-expedited ICSRs 
in this format.  
 
2.  What steps should firms take if they have submitted non-expedited ICSRS in an 
electronic format other than the XML format? 
  
A general correspondence letter should be sent by email to inform FDA about previous 
submission(s) of non-expedited ICSRs.  Notifications should be sent to the following addresses: 
  For CDER-regulated drugs and biologics:  contact the CDER Office of Surveillance and 
Epidemiology (OSE) at: cder-ose-pmktregs@fda.hhs.gov   
  For CBER-regulated biologics:  contact the CBER Electronic Submissions Program at: 
esgprep@fda.hhs.gov  
 
                                                 
11 See FAERS Electronic Submissions at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm1158
94.htm. 
12 FAERS data are available to the public as quarterly data files or by written Freedom of Information request to 
FDA.  See 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm0821
93.htm. 
  3  Contains Nonbinding Recommendations 
 
The letter should include the inclusive dates of the previous submission(s), the subject product(s) 
involved, and the numbers of non-expedited ICSRs submitted for each product.   
 
3.  What can firms expect after contacting FDA? 
 
FDA will contact firms to verify which non-expedited ICSRs should be resubmitted and to 
instruct them on how to resubmit these reports.  In most cases, FDA will instruct firms that 
previously submitted non-expedited ICSRs of serious adverse experiences in the pdf format to 
resubmit these ICSRs in the XML format, or in paper form, if firms do not have XML-format 
capability.      
 
4.  Where can firms find information explaining how to submit electronic non-
expedited ICSRs in the XML format? 
 
On November 14, 2011, FDA communicated on its eCTD Web site13 that non-expedited ICSRs 
should not be submitted to the eCTD.  FDA described how to submit them in an electronically 
compatible format.  The Website has since been updated with the following information14:     
 
Important Note  
Submission of periodic safety reports to the eCTD  
Periodic safety reports consist of two parts: a descriptive portion and the 
individual case safety reports (ICSRs).  Only the descriptive portion of the 
periodic safety report can be submitted to the eCTD. 
 
Descriptive portion: 
Firms can submit the descriptive portion of the periodic safety report in the 
following formats: the periodic adverse drug experience report, the periodic 
adverse experience report or, with an approved waiver, either the periodic safety 
update report15 or the periodic benefit-risk evaluation report.16  The descriptive 
                                                 
13 See 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/uc
m153574.htm. The CDER eCTD web page includes Important Notices that are updated periodically.  For the most 
recent information about electronic submissions to CDER, check the eCTD web page at  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/uc
m328835.htm. 
14 For instructions on organizing, preparing, and submitting either expedited or non-expedited ICSRs and ICSR 
attachments in electronic format, see the associated document Specifications for Preparing and Electronically 
Submitting Electronic ICSRs and ICSR Attachments to FAERS.  Also, in June 2008, FDA issued draft guidance for 
industry titled, Providing Regulatory Submissions in Electronic Format  Postmarketing Individual Case Safety 
Reports.  Once finalized, that guidance will provide information on how to submit ICSRs in an electronic format 
that FDA can process, review, and archive. 
15 See FDA guidances for industry E2C Clinical Safety Data Management: Periodic Safety Update Reports for 
Marketed Drugs and E2C Addendum, Clinical Safety Data Management: Periodic Safety Update Reports for 
Marketed Drugs, available on FDAs Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065004.htm.   
  4  Contains Nonbinding Recommendations 
 
portion can be submitted to the eCTD in module 5.3.6 and should indicate that the 
ICSRs have been submitted electronically as XML files to the FDA Electronic 
Submissions Gateway (ESG) or that FDA 3500A forms have been mailed to the 
appropriate document control center. 
 
ICSRs: 
Firms can submit ICSRs electronically using ICH E2B(R) standards17 or by mail using 
Form FDA 3500A. Submission of ICSRs to the eCTD is not acceptable because these 
ICSRs cannot be processed into the FDA Adverse Event Reporting System (FAERS) 
database.   
 
                                                                                                                                                             
16 The ICH guideline Periodic Benefit-Risk Evaluation Report (PBRER) E2C(R2) is available at: 
http://www.ich.org/.  FDA has initiated the process to adopt the ICH E2C(R2) step 4 guideline as final FDA 
guidance. 
17  See FDA guidance for industry E2B(R) Clinical Safety Data Management: Data Elements for Transmission of 
Individual Case Safety Reports, Revision 2, available at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065004.htm . 
   
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