Providing Regulatory 
Submissions in 
Electronic Format: 
IND Safety Reports 
Guidance for Industry 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (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 (CDER) Meredith Chuk at 301-796-2340 or 
(CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402-
8010.  
 
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) 
Oncology Center of Excellence (OCE) 
 
October 2019 
Electronic Submissions 
28957842dft.docx 
10/08/19   
Providing Regulatory 
Submissions in 
Electronic Format: 
IND Safety Reports 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
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https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
and/or 
 
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Food and Drug Administration 
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Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances 
 
 
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) 
Oncology Center of Excellence (OCE) 
 
October 2019 
Electronic Submissions 
   
RELATED DOCUMENTS 
 
Technical specifications associated with this guidance are provided as separate documents and 
are updated periodically.  
 
For a complete listing of all documents and supportive files needed to submit investigational new 
drug application safety reports to FDAs Adverse Event Reporting System (FAERS), refer to the 
FAERS Electronic Submissions web page at https://www.fda.gov/drugs/fda-adverse-event-
reporting-system-faers/fda-adverse-event-reporting-system-faers-electronic-submissions. 
  
 
   
Revision History 
 
Date  Version  Summary of Revisions 
October 2019  1.0  Initial Version 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  SCOPE OF THIS GUIDANCE ....................................................................................... 3 
A.  Types of Submissions That Will Be Required to Comply With the Electronic Submission  
  Requirement Described in This Guidance ................................................................................... 3 
B.  Types of Submissions For Which the Electronic Submission Requirement Described in This  
  Guidance Does Not Apply ............................................................................................................. 4 
C.  Types of Submissions That Are Exempted From the Electronic Submission Requirement  
  Described in This Guidance .......................................................................................................... 4 
IV.  REQUIREMENT TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE5 
A.  Timetable for Implementation of Electronic Submission Requirements .................................. 5 
B.  Specifications for Submission of IND Safety Reports to FAERS .............................................. 5 
C.  Presubmission Considerations ...................................................................................................... 5 
D.  Waiver Requests ............................................................................................................................ 6 
1. Content of Waiver Requests ............................................................................................................. 6 
2. Where to Submit Waiver Requests ................................................................................................... 6 
3. FDA Response to Waiver Requests .................................................................................................. 7 
 
  Draft  Not for Implementation 
1  Providing Regulatory Submissions in Electronic Format: 
2  IND Safety Reports 
3  Guidance for Industry1 
4   
5   
6  I.  INTRODUCTION 
7   
8  This draft guidance describes the electronic format sponsors will be required to use when they 
9  electronically submit to the Food and Drug Administration (FDA or Agency) investigational new 
10  drug application (IND) safety reports for serious and unexpected suspected adverse reactions that 
11  are required under 21 CFR 21 CFR 312.32(c)(1)(i).  FDA is establishing the electronic format 
12  requirements described in this guidance under section 745A(a) of the Federal Food, Drug, and 
13  Cosmetic Act (FD&C Act).2  When finalized, this guidance will supersede the effective version 
14  of the guidance for industry Providing Regulatory Submissions in Electronic Format  Certain 
15  Human Pharmaceutical Product Applications and Related Submissions Using the eCTD 
16  Specifications (eCTD Guidance) for the submission of IND safety reports required under 21 
17  CFR 312.32(c)(1)(i) that are within the scope of this guidance (see section III., Scope of This 
18  Guidance).  This guidance will not replace any requirements in the eCTD Guidance other than 
19  those relating to the submission of IND safety reports required under 21 CFR 312.32(c)(1)(i) that 
20  are within the scope of this guidance.  This guidance also references several technical 
21  specification documents, which provide additional details regarding the format for electronic 
22  submission of IND safety reports to FAERS.3 
23   
24  This guidance implements the electronic submission requirements of section 745A(a) of the 
25  FD&C Act for the electronic format of the content submitted for IND safety reports that are 
26  required under 21 CFR 312.32(c)(1)(i) for serious and unexpected suspected adverse reactions.  
27  This guidance applies to such IND safety reports that are submitted to the Center for Drug 
28  Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER).  
29  This guidance changes the electronic submission requirements for this category of IND safety 
30  reports by requiring sponsors to submit the IND safety reports to the FDA Adverse Event 
31  Reporting System (FAERS) in accordance with this guidance.  This requirement will be effective 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research in cooperation with the Center 
for Biologics Evaluation and Research at the Food and Drug Administration.  
 
2 For additional information on how FDA interprets and intends to implement the electronic submission 
requirements of section 745A(a) of the FD&C Act, please see the guidance for industry Providing Regulatory 
Submissions in Electronic Format  Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic 
Act (December 2014).  We update guidances periodically.  To make sure you have the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents.  
 
3 See the technical specifications document Specifications for Preparing and Submitting Electronic ICSRs 
[Individual Case Study Reports] and ICSR Attachments (October 2019) and the Electronic Submission of IND Safety 
Reports: Technical Conformance Guide (October 2019), available on the FDA Adverse Event Reporting System 
(FAERS) Electronic Submissions web page at https://www.fda.gov/drugs/fda-adverse-event-reporting-system-
faers/fda-adverse-event-reporting-system-faers-electronic-submissions.  
 
  1  Draft  Not for Implementation 
32  24 months after the publication of the final guidance on this topic.  Before the effective date of 
33  this requirement, FDA will accept IND safety reports to FAERS as part of a voluntary 
34  submission program.  We intend to update the FAERS website with information indicating when 
35  we will begin to accept voluntary submissions.  Until the requirements in this guidance become 
36  effective, the most recent effective version of the eCTD Guidance will continue to apply to 
37  sponsors submitting IND safety reports electronically for serious and unexpected suspected 
38  adverse reactions.4  
39   
40  Once the requirement is effective, sponsors of INDs subject to this guidance are required to 
41  submit IND safety reports electronically in the format specified in this guidance, unless the 
42  sponsor is exempted from the electronic submission requirements (see section III.C, Types of 
43  Submissions That Are Exempted From the Electronic Submission Requirement Described in 
44  This Guidance) or a waiver is obtained (see section IV.D., Waiver Requests).    
45   
46  In section 745A(a) of the FD&C Act, Congress granted explicit statutory authorization to FDA 
47  to specify in guidance the format for the electronic submissions required under that section.  
48  Accordingly, as indicated by the use of the words must or required, this document is not subject 
49  to the usual restrictions in FDAs good guidance practice (GGP) regulations, such as the 
50  requirement that guidances not establish legally enforceable responsibilities (see 21 CFR 
51  10.115(d); see also the guidance for industry Providing Regulatory Submissions in Electronic 
52  Format  Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act 
53  (745A(a) Implementation guidance)). 
54   
55  To comply with the GGP regulations and make sure that regulated entities and the public 
56  understand that guidance documents are nonbinding, FDA guidances ordinarily contain standard 
57  language explaining that guidance documents should be viewed only as recommendations unless 
58  specific regulatory or statutory requirements are cited.  FDA is not including this standard 
59  language in this guidance document because it is not an accurate description of all of the effects 
60  of this guidance document.  Insofar as this document specifies the format for electronic 
61  submissions or provides criteria for waivers of and exemptions from the requirements of section 
62  745A(a) of the FD&C Act, it will have binding effect, 24 months after the publication of the 
63  final guidance in the Federal Register. 
64   
65   
66  II.  BACKGROUND 
67   
68  Section 745A(a) of the FD&C Act applies to certain submissions under section 505(b), (i), or (j) 
69  of the FD&C Act and under section 351(a) or (k) of the Public Health Service (PHS) Act, 
70  including certain INDs.  Section 745A(a) also applies to all subsequent submissions, including 
71  amendments, supplements, and reports, to the submission types identified.  FDA considers IND 
72  safety reports to fall within the scope of requirements set forth in section 745A(a).  
73   
                                                 
4  For further information about IND safety reports, see 21 CFR 312.32 and the guidance for industry and 
investigators Safety Reporting Requirements for INDs and BA/BE Studies (December 2012). 
 
  2  Draft  Not for Implementation 
74  A sponsor of clinical trials conducted under an IND must report serious and unexpected 
75  suspected adverse reactions to FDA in an IND safety report within 7 or 15 days depending on the 
76  type of event (21 CFR 312.32(c)).5  These reports have traditionally been submitted to FDA on 
77  MedWatch Form FDA 3500A or on a Council for International Organizations of Medical 
78  Sciences (CIOMS) I Form or other narrative forms.  Currently, FDA requires sponsors of 
79  commercial INDs that make electronic IND safety report submissions to use eCTD format.6 
80  Sponsors submit these safety reports within the eCTD structure using PDF files, but review and 
81  tracking of these reports in PDF format is inefficient and labor intensive.  Submission of this 
82  important safety information to FAERS as structured data elements will improve FDAs ability 
83  to review and track these potential safety signals that occur during the conduct of clinical trials, 
84  and will provide sponsors with a reporting format that is consistent with International Council for 
85  Harmonisation (ICH) guidelines and reporting requirements to other regulatory agencies. 
86   
87   
88  III.  SCOPE OF THIS GUIDANCE 
89   
90  A.  Types of Submissions That Will Be Required to Comply With the Electronic 
91  Submission Requirement Described in This Guidance 
92   
93  This guidance only applies to IND safety reports for serious and unexpected suspected adverse 
94  reactions required under 21 CFR 312.32(c)(1)(i).  Under 21 CFR 312.32(c)(1)(i), sponsors must 
95  report any suspected adverse reaction that is both serious and unexpected if there is evidence to 
96  suggest a causal relationship between the drug and the adverse event, such as in the following 
97  circumstances:  
98   
99    A single occurrence of an adverse event that is uncommon and known to be strongly 
100  associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
101  syndrome) (21 CFR 312.32(c)(1)(i)(A)) 
102   
103    One or more occurrences of an adverse event that is not commonly associated with drug 
104  exposure but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
105  rupture) (21 CFR 312.32(c)(1)(i)(B)) 
106   
107    An aggregate analysis of specific adverse events observed in a clinical trial (e.g., known 
108  consequences of the underlying disease or condition under investigation, other adverse 
109  events that commonly occur in the study population independent of drug therapy) that 
110  indicates those events occur more frequently in the drug treatment group than in a 
111  concurrent or historical control group (21 CFR 312.32(c)(1)(i)(C)) 
112   
                                                 
5 Additional information regarding IND safety reporting requirements under 21 CFR 312.32 is addressed in the 
guidance for industry and investigators Safety Reporting Requirements for INDs and BA/BE Studies and the draft 
guidance for industry Safety Assessment for IND Safety Reporting (December 2015), which, when final, will 
represent FDAs current thinking on this topic.  Those guidance documents do not cover electronic submissions 
requirements. 
 
6 Section 745A(a) of the FD&C Act and eCTD Guidance, section III.A.  See also Specifications for File Format 
Types Using eCTD Specifications available at https://www.fda.gov/media/85816/download.   
  3  Draft  Not for Implementation 
113  B.  Types of Submissions For Which the Electronic Submission Requirement 
114  Described in This Guidance Does Not Apply 
115   
116  This guidance does not apply to IND safety reports for anything other than serious and 
117  unexpected suspected adverse reactions covered by 21 CFR 312.32(c)(1)(i).    
118   
119  Below are examples of IND safety reports for which the requirements of this guidance do not 
120  apply:7 
121   
122    Findings from other studies, as required under 21 CFR 312.32(c)(1)(ii); 
123   
124    Findings from animal or in vitro testing, as required under 21 CFR 312.32(c)(1)(iii); 
125   
126    Increased rate of occurrence of serious suspected adverse reactions, as required under 21 
127  CFR 312.32(c)(1)(iv). 
128   
129  This guidance also does not apply to IND safety reports for devices that are regulated by CBER 
130  as biological products under section 351 of the PHS Act and that require the submission of an 
131  IND before the submission of a biologics license application.8   
132   
133  C.  Types of Submissions That Are Exempted From the Electronic Submission 
134  Requirement Described in This Guidance 
135   
136  Section 745A(a) allows FDA to establish exemptions from the electronic submission 
137  requirements.  Accordingly, FDA has exempted all submissions regarding noncommercial INDs 
138  from the requirements under section 745A(a).9  For purposes of the section 745A(a) exemption, 
139  the term noncommercial products refers to products that are not intended to be distributed 
140  commercially and includes investigator-sponsored INDs and expanded access INDs (e.g., 
141  emergency use INDs).10  Although noncommercial INDs (and IND safety reports associated with 
142  them) are exempt from the requirements of section 745A(a), FDA encourages the submission of 
143  IND safety reports from sponsors of noncommercial INDs using the format described in this 
144  guidance. 
                                                 
7 For information on the electronic format requirements for the types of IND safety reporting required under 21 CFR 
312.32(c)(1)(ii)9(iv), sponsors should consult the eCTD Guidance and the Electronic Submission of IND Safety 
Reports: Technical Conformance Guide. 
 
8 Although a discussion of which devices CBER regulates as biological products is outside the scope of this 
guidance, in general, this category of INDs would include investigational devices that are used to screen blood 
donors for certain transfusion-transmissible diseases and to test human cells, tissues, or cellular or tissue-based 
products to make a donor-eligibility determination.  These submissions are subject to the requirements under section 
745A(b) of the FD&C Act.  See the guidance for industry and FDA staff eCopy Program for Medical Device 
Submissions (December 2015), which implements the electronic copy provisions of section 745A(b) for medical 
device submissions to FDA. 
 
9 See the 745A(a) Implementation guidance, section III.B. 
 
10 See the 745A(a) Implementation guidance, section III.B. 
 
  4  Draft  Not for Implementation 
145   
146   
147  IV.  REQUIREMENT TO SUBMIT ELECTRONICALLY UNDER THIS GUIDANCE 
148   
149  The following section sets forth the requirements for electronic submission of IND safety reports 
150  that are within the scope of this guidance. 
151   
152  A.  Timetable for Implementation of Electronic Submission Requirements 
153   
154  The requirement to submit IND safety reports as described in this guidance will become effective 
155  24 months after the publication of the final version of this draft guidance.  FDA will accept IND 
156  safety report submissions as described in this guidance before the date that the requirement is in 
157  effect as noted in section I., Introduction. 
158   
159  B.  Specifications for Submission of IND Safety Reports to FAERS 
160   
161  Sponsors must submit IND safety reports to FAERS using either the Electronic Submission 
162  Gateway (ESG) or the Safety Reporting Portal (SRP).  For sponsors using the ESG, consult the 
163  FDA Data Standards Catalog11 for information about the ICH E2B data standard currently 
164  supported by FDA.  
165   
166  For additional information about submitting IND safety reports to FAERS, please consult the 
167  following technical specification documents:12 
168   
169    Electronic Submission of IND Safety Reports: Technical Conformance Guide  
170    Specifications for Preparing and Submitting Electronic ICSRs and ICSR Attachments 
171   
172  Instructions for submitting IND safety reports to FAERS as individual case safety reports 
173  (ICSRs) can be found on the FAERS Electronic Submissions web page.13 
174   
175  C.  Presubmission Considerations 
176   
177  Before submitting an IND safety report to FAERS for the first time, whether through the ESG or 
178  SRP, the sponsor should notify the FAERS electronic submission coordinator at 
179  faersesub@fda.hhs.gov of the intent to submit.  The FAERS coordinator will assist the sponsor 
180  to ensure that all steps have been completed for successful submission and provide instructions 
181  for optional test submissions.  It is not necessary to contact the FAERS coordinator before 
182  submitting subsequent IND safety reports in electronic format.   
183   
                                                 
11 The FDA Data Standards Catalog is available on the Study Data Resources web page at 
https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources.  
 
12 Available on the FAERS Electronic Submissions web page at https://www.fda.gov/drugs/fda-adverse-event-
reporting-system-faers/fda-adverse-event-reporting-system-faers-electronic-submissions. 
 
13 Ibid. 
 
  5  Draft  Not for Implementation 
184  D.  Waiver Requests 
185   
186  Section 745A(a) allows FDA to establish criteria for waivers from the electronic submission 
187  requirements.  The Agency anticipates that temporary waivers will be needed only in rare 
188  circumstances.  FDA may grant temporary waivers of the requirement for submission of certain 
189  IND safety reports in FAERS, as described in this guidance, if one or more of the following 
190  events or circumstances exist:14  
191   
192    Extraordinary events or circumstances occur that are beyond the control of the submitter 
193  that justify a waiver, including but not limited to, natural disasters that impact computer 
194  operations. 
195   
196    An unplanned long-term internet disruption or other unplanned event occurs that would 
197  preclude the sponsor from submitting in FAERS (e.g., malware attacks).   
198   
199  1.  Content of Waiver Requests 
200   
201  The sponsor should make a request in writing to waive the requirement to submit IND safety 
202  reports to FAERS.  Include the IND number for which the request is being made, the reason for 
203  the request, and information justifying the waiver.15  The waiver request also should include a 
204  proposed end date for the waiver and the proposed alternative reporting method, such as 
205  submission on physical media.   
206   
207  2.  Where to Submit Waiver Requests 
208   
209  Waiver requests for drug and biological products conducted under an IND may be sent through 
210  the following means: 
211   
212    CDER 
213   
214    In eCTD via ESG, if possible 
215   
216  or 
217   
218    By email to ESUB@fda.hhs.gov  
219   
220    CBER  
221   
222    By email to ESUBPREP@cber.fda.gov 
223   
                                                 
14 See 21 CFR 312.10. 
 
15 See 21 CFR 312.10. 
  6  Draft  Not for Implementation 
224  3.  FDA Response to Waiver Requests 
225   
226  FDA reviews waiver requests on a case-by-case basis.  FDA plans to respond in writing to the 
227  requestor, stating whether the waiver is granted.  If the waiver is granted, FDA plans for the 
228  response to include the agreed-upon alternative method for submission as well as the timeframe 
229  for the waiver.  In most circumstances, FDA intends for any waivers from the requirements in 
230  this guidance to be temporary. 
  7