Sponsor Responsibilities
Safety Reporting Requirements 
and Safety Assessment for  
IND and 
Bioavailability/Bioequivalence 
Studies 
 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Paul Gouge, 301-796-2500, or 
(CBER) Office of Communication, Outreach and Development, 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) 
 
June 2021 
Drug Safety 
20238123dft.docx    
Sponsor ResponsibilitiesSafety 
Reporting Requirements and 
Safety Assessment for IND and 
Bioavailability/Bioequivalence 
Studies 
 
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  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
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) 
 
 June 2021 
Drug Safety 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  DEFINITIONS ( 312.32(a)) ............................................................................................ 3 
A.  Adverse Event ( 312.32(a)) .......................................................................................................... 3 
B.  Adverse Reaction and Suspected Adverse Reaction ( 312.32(a)) ............................................. 3 
C.  Unexpected ( 312.32(a)) ............................................................................................................... 5 
D.  Serious ( 312.32(a))....................................................................................................................... 6 
E.  Life-Threatening ( 312.32(a)) ...................................................................................................... 7 
IV.  OVERVIEW OF IND SAFETY REPORTING REQUIREMENTS ........................... 7 
A.  Serious and Unexpected Suspected Adverse Reaction ( 312.32(c)(1)(i)) ................................. 8 
1.  Events That Do Not Require Aggregate Analyses ......................................................................... 10 
2.  Events That Require Aggregate Analyses ...................................................................................... 11 
B.  IND Safety Reporting Criteria for Aggregate Data .................................................................. 12 
1. Serious and Unexpected Suspected Adverse Reactions ( 312.32(c)(1)(i)(C)) ............................. 12 
2. Increased Rate of Occurrence of Serious Suspected Adverse Reactions ( 312.32(c)(1)(iv)) ....... 13 
C.  Other Reporting Requirements .................................................................................................. 14 
1. Findings from Other Sources ( 312.32(c)(1)(ii) and (iii)) ........................................................... 14 
2. IND Safety Reports for Study Endpoints ( 312.32(c)(5)) ............................................................. 14 
V.  SYSTEMATIC APPROACH FOR REVIEW OF SAFETY INFORMATION 
( 312.32(b)) ................................................................................................................................. 15 
A.  Prospective Development of a Plan for Safety Surveillance..................................................... 16 
VI.  CONSIDERATIONS FOR AGGREGATE DATA ANALYSIS FOR IND SAFETY 
REPORTING .............................................................................................................................. 17 
A.  Identify Serious Adverse Events Anticipated to Occur in the Study Population ................... 18 
B.  Aggregate Analyses of Safety Data ............................................................................................. 18 
1. Approach to Aggregate Analyses ................................................................................................... 18 
2. Frequency of Aggregate Analyses ................................................................................................. 20 
3. Considerations When Evaluating Aggregate Data ........................................................................ 20 
C.  Entities That Review Aggregate Data for IND Safety Reporting ............................................ 21 
1. Features and Composition of the Entity ........................................................................................ 21 
2. Identifying the Entities that Review Safety Information ................................................................. 21 
D.  Maintaining Trial Integrity When Reviewing Aggregate Data ............................................... 22 
VII.  OTHER SAFETY REPORTING ISSUES ................................................................... 23 
A.  Alternative Reporting Arrangements ( 312.32(c)(3)) .............................................................. 23 
B.  Importance of Standardized Coding .......................................................................................... 24 
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Draft  Not for Implementation 
C.  Investigations of Marketed Drugs ( 312.32(c)(4)) ................................................................... 24 
D.   Duration of Safety Reporting ..................................................................................................... 25 
VIII.  SUBMITTING AN IND SAFETY REPORT ( 312.32 (c)(1)(v)) .............................. 25 
A.  Report Identification and Format .............................................................................................. 25 
1. Individual Cases ............................................................................................................................ 26 
2. Reports of Events Identified by Aggregate Analyses ..................................................................... 26 
3. Other Reports ................................................................................................................................. 28 
B.  Where and How to Submit .......................................................................................................... 28 
C.  Reporting Time Frame ................................................................................................................ 29 
IX.  FOLLOW-UP INFORMATION ( 312.32(d))............................................................. 30 
X.  SAFETY REPORTING REQUIREMENTS FOR BA AND BE STUDIES.............. 31 
A.  BA/BE Study Safety Reporting Requirements ( 320.31(d)(3)) ............................................... 32 
B.  How and Where to Submit a Report ( 320.31(d)(3)) ............................................................... 32 
REFERENCES ............................................................................................................................ 35 
APPENDIX A:  FLOWCHART FOR DETERMINING WHETHER AN ADVERSE 
EVENT MEETS CRITERIA FOR IND SAFETY REPORTING TO FDA AND 
INVESTIGATORS ..................................................................................................................... 37 
APPENDIX B:  FLOWCHARTS FOR SUBMITTING SAFETY REPORTING FOR 
CONTROL DRUGS ................................................................................................................... 38 
Chart B.1:  IND Sponsor is NOT the NDA or BLA Holder of the Control Drug ........................... 38 
Chart B.2:  IND Sponsor IS also the NDA or BLA Holder of the Control Drug ............................ 39 
APPENDIX C:  FLOWCHART FOR THE TWO APPROACHES TO AGGREGATE 
ANALYSES ................................................................................................................................. 40 
 
 
 
   
 
ii  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Sponsor ResponsibilitiesSafety Reporting Requirements and 
2  Safety Assessment for IND and  
3  Bioavailability/Bioequivalence Studies  
4  Guidance for Industry1 
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page.   
12   
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  This guidance provides recommendations to help sponsors comply with the expedited safety 
19  reporting requirements for human drug and biological products2 that are being investigated (1) 
20  under an investigational new drug application (IND) (21 CFR 312.32) or (2) as part of a 
21  bioavailability (BA) or bioequivalence (BE) study that is exempt from the IND requirements (21 
22  CFR 312.64(b) and 320.31(d)(3)).   
23   
24  This guidance defines terms used for safety reporting, makes recommendations on when and 
25  how to submit a safety report, and provides information on other safety reporting issues raised by 
26  sponsors.   
27   
28  To facilitate appropriate IND safety reporting practices, this guidance also provides 
29  recommendations related to the two IND safety reporting provisions (21 CFR 312.32(c)(1)(i)(C) 
30  and 312.32(c)(1)(iv)) that require assessment of aggregate data. 
31   
32  This guidance merges content from the final guidance for industry and investigators Safety 
33  Reporting Requirements for INDs and BA/BE Studies (December 2012)  (the 2012 final 
34  guidance) and from the draft guidance for industry Safety Assessment for IND Safety Reporting 
35  (December 2015) (the 2015 draft guidance).3  This guidance includes revised recommendations 
36  initially described in the 2015 draft guidance on the following topics:  (1) planned unblinding of 
 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug 
Administration (FDA).  
 
2 This guidance applies to drugs, including biological products.  For the purposes of this guidance, drug or drug 
product is used to refer to human drugs and human biological products that are regulated as drugs. 
 
3 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
37  safety data and implications for trial integrity; (2) increased flexibility regarding the party 
38  reviewing aggregate safety information for IND safety reporting purposes; (3) clarification 
39  regarding the scope and methodology of aggregate analyses; and (4) clarification regarding the 
40  plan for safety surveillance, including what elements should be included in the plan.  The 2015 
41  draft guidance has been withdrawn upon the publication of this guidance.   
42   
43  The content from the 2012 final guidance remains largely unchanged in this draft guidance.  
44  When finalized, this guidance will supersede the 2012 final guidance.  However, until that time, 
45  the 2012 final guidance continues to represent FDAs current thinking about safety reporting 
46  requirements for INDs and BA/BE studies.  This guidance does not incorporate content on 
47  investigator reporting (21 CFR 312.64(b)) from the 2012 final guidance.  FDA plans to publish a 
48  separate draft guidance for clinical investigators on investigators responsibilities for safety 
49  reporting for human drug and biological products.  However, until that draft guidance is 
50  finalized, the 2012 final guidance continues to represent FDAs current thinking about 
51  investigators responsibilities for safety reporting for INDs and BA/BE studies.   
52   
53  This guidance addresses reporting of serious adverse events (SAEs) in the setting of a clinical 
54  investigation conducted under an IND.  Drugs used in such clinical investigations may be 
55  unapproved drugs or those that are already marketed or approved in the United States.  For drugs 
56  already marketed or approved, additional reporting requirements for safety information from 
57  clinical studies are specified by the relevant postmarketing safety reporting requirements (e.g., 
58  under 21 CFR 314.80, 600.80, or 606.170 or under section 760 of the Federal Food, Drug, and 
59  Cosmetic Act (FD&C Act) (21 U.S.C. 379aa); see also  312.32(c)(4)).  This guidance does not 
60  address those obligations. 
61   
62  The contents of this document do not have the force and effect of law and are not meant to bind 
63  the public in any way, unless specifically incorporated into a contract. This document is intended 
64  only to provide clarity to the public regarding existing requirements under the law. FDA 
65  guidance documents, including this guidance, should be viewed only as recommendations, unless 
66  specific regulatory or statutory requirements are cited.   The use of the word should in FDA 
67  guidances means that something is suggested or recommended, but not required.  
68   
69   
70  II.  BACKGROUND 
71   
72  On September 29, 2010, FDA published a final rule (75 FR 59935) amending IND safety 
73  reporting requirements under 21 CFR part 312 and adding safety reporting requirements for 
74  persons conducting BA and BE studies under 21 CFR part 320.  The IND safety reporting 
75  regulations distinguish between circumstances in which it is appropriate to submit IND safety 
76  reports based on individual cases ( 312.32(c)(1)(i)(A) and (B)) and circumstances in which an 
77  IND safety report would need to be based on an aggregate analysis of SAEs to determine 
78  whether the events occur more frequently in the drug treatment group ( 312.32(c)(1)(i)(C)).  
79  Compliance with these requirements increases the likelihood that submitted information will be 
80  interpretable and will meaningfully contribute to the developing safety profile of the 
81  investigational drug and improve the overall quality of safety reporting.   
82   
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Draft  Not for Implementation 
83  Timely reporting of the required safety information allows FDA to consider whether any changes 
84  in study conduct should be made beyond those initiated by the sponsor and allows investigators 
85  to make any changes that are needed to protect subjects.  An effective systematic approach by 
86  sponsors to safety surveillance, coupled with limiting the scope of IND safety reports to FDA 
87  and participating investigators (and subsequent reporting to involved institutional review boards) 
88  to suspected adverse reactions that are both serious and unexpected, allows all parties to 
89  focus on important safety issues and take actions needed to minimize the risks of participation in 
90  a clinical trial.4 
91   
92  The 2010 final rule also requires sponsors to report findings from other studies ( 
93  312.32(c)(1)(ii)) and findings from animal5 or in vitro testing ( 312.32(c)(1)(iii)) that suggest a 
94  significant risk to humans exposed to the drug and to report an increased occurrence of known 
95  serious suspected adverse reactions ( 312.32(c)(1)(iv)).  
96    
97   
98  III.  DEFINITIONS ( 312.32(a)) 
99   
100  A.  Adverse Event ( 312.32(a)) 
101   
102  Adverse event means any untoward medical occurrence associated with the use of a drug in 
103  humans, whether or not considered drug related ( 312.32(a)). 
104   
105  FDA considers an adverse event (also referred to as an adverse experience) to include any 
106  unfavorable sign (e.g., an abnormal laboratory finding), symptom, or clinical outcome 
107  temporally associated with the use of a test drug, active control, or placebo, regardless of 
108  whether the event is thought to be related to the drug.  An adverse event can arise during any use 
109  of a drug or biologic (e.g., use for a purpose other than the FDA-approved indication or in 
110  combination with another drug) and with any route of administration, formulation, or dose, 
111  including an overdose. 
112   
113  B.  Adverse Reaction6 and Suspected Adverse Reaction ( 312.32(a)) 
114   
115  An adverse reaction means any adverse event caused by a drug.  Suspected adverse reaction 
116  means any adverse event for which there is a reasonable possibility that the drug caused the 
117  adverse event.  For the purposes of IND safety reporting, reasonable possibility means there 
 
4 In most cases such events will lead to an update to the investigator brochure and/or informed consent. 
 
5 We support the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible. We 
encourage sponsors to consult with us if they wish to use a non-animal testing method they believe is suitable, 
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency 
to an animal test method.   
 
6 For the purposes of prescription drug labeling, the term adverse reaction is defined to mean an undesirable effect, 
reasonably associated with use of a drug, that may occur as part of the pharmacological action of the drug or may be 
unpredictable in its occurrence.  This definition does not include all adverse events observed during use of a drug, 
only those adverse events for which there is some basis to believe there is a causal relationship between the drug and 
the occurrence of the adverse event (see 21 CFR 201.57(c)(7) and 201.80(g)). 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
118  is evidence to suggest a causal relationship between the drug and the adverse event.  
119  Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
120  reaction[.]  Both an adverse reaction and a suspected adverse reaction require evidence of a 
121  causal relationship between the drug and the adverse event.  Therefore, if no drug has been 
122  administered, an adverse event is not reportable under IND safety reporting regulations.7 
123   
124  The following examples provided in the IND safety reporting regulation ( 312.32(c)(1)(i)) 
125  illustrate the meaning of reasonable possibility with respect to a determination that there may be 
126  a causal relationship between the drug and the adverse event: 
127   
128    A single occurrence of an event that is uncommon and known to be strongly associated 
129  with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). 
130   
131    One or more occurrences of an event that is not commonly associated with drug exposure 
132  but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture). 
133   
134    An aggregate analysis of specific events observed in a clinical trial, indicating that they 
135  occur more frequently in the drug treatment group than in a concurrent or historical 
136  control group.  Such events may be known consequences of the underlying disease or 
137  condition or events that commonly occur in the study population independent of drug 
138  therapy.  Such events could also be related to an intervention or therapy that is standard 
139  of care for the disease (e.g., background treatment).  
140   
141  To determine whether an adverse event should be classified as a suspected adverse reaction, or 
142  an adverse reaction, the sponsor must evaluate the available evidence ( 312.32(b)) and make a 
143  judgment about the likelihood that the drug caused the adverse event.  For an adverse event to be 
144  considered a suspected adverse reaction, the sponsor should conclude that there is a reasonable 
145  possibility that the drug caused the adverse event.  FDA considers the application of the 
146  reasonable possibility causality standard to be consistent with the discussion about causality in 
147  the International Council for Harmonisation (ICH) E2A guideline for industry (the ICH E2A 
148  guidance).8  However, FDA notes there is a difference between the IND safety reporting rule and 
149  the ICH E2A guidance with respect to who is responsible for making the causality judgment for 
150  reporting purposes. The sponsor is responsible for making the causality judgment, according to 
151  the IND safety reporting rule; in contrast, the ICH E2A guidance recommends that the judgment 
152  for reporting be based on either the investigators or the sponsors opinion.  This difference is 
153  addressed in section IV.A of this guidance. 
154   
 
7 However, for clinical investigations that involve an invasive procedure that would not occur other than due to 
participation in the trial (e.g., intrahepatic artery administration or a kidney biopsy), FDA may request that sponsors 
also report SAEs associated with such a procedure, even if the investigational product is not administered. 
 
8 ICH guidance for industry E2A Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting (March 1995), pages 67.  
 
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Draft  Not for Implementation 
155  C.  Unexpected ( 312.32(a)) 
156   
157  An adverse event or suspected adverse reaction is considered unexpected if (1) it is not listed in 
158  the investigators brochure9 or it is not listed at the specificity or severity that has been observed 
159  in the study population; or (2) if an investigator brochure is not required or available, it is not 
160  consistent with the risk information described in the general investigational plan or elsewhere in 
161  the application.  For example, if the listed term in the investigators brochure is erythema, a 
162  reported event of Stevens-Johnson Syndrome is both more specific and more severe than the 
163  term in the investigators brochure and would therefore be considered unexpected.  In addition, if 
164  the event occurs at a rate that is meaningfully higher than listed in the investigators brochure, 
165  that rate would be considered to make the event more specific or severe than that listed in the 
166  investigators brochure, and it would also be considered unexpected.  If there is no investigators 
167  brochure, an unexpected adverse reaction is one that is not consistent with the risk information 
168  described in the general investigational plan or elsewhere in the current IND, as amended.  For 
169  reporting purposes, events should be listed in the investigators brochure if they have been 
170  observed with the particular drug under investigation and for which a causal relationship with the 
171  drug is suspected or confirmed.10 
172   
173  When new adverse event information is received, it is the sponsors responsibility to determine 
174  whether the event is unexpected for IND safety reporting purposes.   
175   
176  For example, under this definition of unexpected, if the investigators brochure referred only to 
177  elevated hepatic enzymes or hepatitis, an event of hepatic necrosis would be unexpected (by 
178  virtue of greater severity).  Similarly, intracerebral hemorrhage and cerebral vasculitis would be 
179  unexpected (by virtue of greater specificity) if the investigators brochure only listed cerebral 
180  vascular accidents.  Unexpected also refers to adverse events or suspected adverse reactions that 
181  are mentioned in the investigators brochure as occurring with a class of drugs or as predicted to 
182  occur from the pharmacological properties of the drug but are not specifically mentioned as 
183  occurring with the particular drug under investigation.  For example, although angioedema is 
184  known to occur in some individuals exposed to drugs in the angiotensin-converting enzyme 
185  (ACE) inhibitor class and therefore would be described in the investigators brochure as a class 
186  effect, a case of angioedema observed with the drug under investigation should be considered 
187  unexpected for reporting purposes until angioedema is included in the investigators brochure as 
188  occurring with the drug under investigation.  Likewise, safety-related findings from animal 
189  studies that have not been observed with the drug under investigation in humans would also be 
190  considered unexpected until such an event occurs in humans and is listed in the investigators 
191  brochure as a known or suspected adverse reaction.   
192   
193  There has been some confusion about the terms expected and anticipated as used for the 
194  purposes of IND safety reporting.  The terms have distinct meanings.  Expected refers to known 
195  or suspected adverse reactions to the drug, as listed in the investigators brochure or, if an 
 
9 For an FDA approved drug, an unexpected adverse event would include adverse events not listed in the FDA-
approved labeling. 
 
10 The investigators brochure should not list adverse events that are unlikely to have been caused by the drug, 
because such lists could dilute clinically meaningful risk information. 
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196  investigator brochure is not required or available, as consistent with the risk information 
197  described in the general investigational plan or elsewhere in the IND.   Anticipated refers to 
198  adverse events that are likely to occur in the study population because the adverse events (1) 
199  reflect consequences of participants underlying disease or factors such as age and (2) are 
200  unrelated to an effect of a drug (e.g., cancer-related deaths in a cancer trial, strokes or acute 
201  myocardial infarctions in an older population).  Thus, as stated above, events that are listed in the 
202  investigators brochure are considered expected adverse reactions for the drug because they are 
203  thought to be caused by the drug.  However, the term expected has also been incorrectly used to 
204  describe adverse events that are anticipated in individuals with the disease being treated or 
205  population being studied but are not listed in the investigators brochure as known or suspected 
206  adverse reactions.  For reporting purposes, events that are anticipated for the disease being 
207  treated or the population being studied are considered unexpected because the events are not 
208  listed in the investigators brochure (i.e., the test drug is not suspected or known to cause the 
209  events).  
210   
211  To summarize, an adverse event that is anticipated in the population being studied refers to an 
212  event that would be seen in this population independent of study drug exposure.  An expected 
213  adverse reaction refers to an adverse event that is known or suspected to be caused by the study 
214  drug and should be listed in the description of the known or suspected adverse drug reactions in 
215  the investigators brochure or, if an investigator brochure is not required or available, as 
216  consistent with the risk information described in the general investigational plan or elsewhere in 
217  the IND. 
218   
219  Because anticipated adverse events occur in the study population, the observations of a single 
220  event or a small number of such adverse events will generally not meet the criteria for being a 
221  suspected adverse reaction.  To conclude that the drug may have caused an anticipated adverse 
222  event, one would perform an unblinded aggregate analysis to compare the rates in the treatment 
223  and comparator groups.  The decision as to whether unblinding of an ongoing trial is appropriate 
224  to make such an assessment is discussed in section VI of this guidance.  Monitoring and 
225  reporting anticipated adverse events are further discussed in section IV.   
226   
227  D.  Serious ( 312.32(a)) 
228   
229  An adverse event, adverse reaction or suspected adverse reaction is considered serious if, in the 
230  view of either the investigator or the sponsor, it results in any of the following:  death, a life-
231  threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
232  persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
233  functions, or a congenital anomaly/birth defect.  Important medical events that might not result in 
234  death, are not life-threatening, and do not require hospitalization may be considered serious 
235  when, based upon appropriate medical judgment, they may jeopardize the patient or subject and 
236  may require medical or surgical intervention to prevent one of the outcomes listed in this 
237  definition.  Examples of such medical events include allergic bronchospasm requiring intensive 
238  treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
239  inpatient hospitalization, and the development of drug dependency or abuse.  
240   
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241  The sponsor and the investigator must evaluate whether an event meets the definition of serious.  
242  See  312.32(c)(1)(i) and 312.64(b).  Because identifying SAEs is critically important for the 
243  evaluation of potential significant safety problems, FDA considers it important to take into 
244  account both the investigators and the sponsors assessments.  Therefore, if the sponsor or 
245  investigator believes that the event is serious, the event must be considered serious and must be 
246  evaluated by the sponsor for expedited reporting ( 312.32(a) and 312.32(c)(1)). 
247   
248  E.  Life-Threatening ( 312.32(a)) 
249   
250  An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
251  either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
252  death.  It does not include an adverse event or suspected adverse reaction that, had it occurred in 
253  a more severe form, might have caused death.  For example, not all seizures are considered life-
254  threatening, although the most severe form, status epilepticus, is a life-threatening medical 
255  emergency. 
256   
257  As with the definition of serious, the determination of whether an adverse event is life-
258  threatening can be based on the opinion of either the investigator or sponsor.  Thus, if either 
259  believes that the adverse event meets the definition of life-threatening, it must be considered life-
260  threatening for reporting purposes ( 312.32(a)). 
261   
262   
263  IV.  OVERVIEW OF IND SAFETY REPORTING REQUIREMENTS  
264   
265  Under  312.32(c), the sponsor is required to notify FDA and all participating investigators 
266  through an IND safety report (i.e., 7- or 15-day expedited report) of potentially serious risks from 
267  clinical trials or any other source as soon as possible but no later than 15 calendar days after the 
268  sponsor receives the safety information and determines that the information qualifies for 
269  reporting in an IND safety report (see section VIII.C of this guidance for a discussion of IND 
270  safety reporting time frames).  Participating investigators include all investigators, at U.S. and 
271  non-U.S. sites, to whom the sponsor is providing the drug under any of its INDs or under any 
272  investigators IND ( 312.32(c)(1)).11  See Appendix A for a flowchart to help determine 
273  whether an adverse event meets the criteria for IND safety reporting to FDA.   
274   
275  The sponsor must identify in each IND safety report all IND safety reports previously submitted 
276  to FDA concerning a similar suspected adverse reaction and must analyze the significance of the 
277  suspected adverse reaction in light of previous, similar reports or any other relevant information 
278  (i.e., conduct an analysis of similar events) ( 312.32(c)(1)).  The analysis must include similar 
279  IND safety reports from all INDs for the same drug held by the sponsor, any other relevant 
280  information known to the sponsor ( 312.32(c)(1)), and should include related reports or adverse 
281  events available from pre- and postmarketing studies. 
282   
 
11 Although not required by regulations, FDA recommends that sponsors notify investigators at non-IND sites of 
information meeting IND safety reporting criteria in a similar time frame as required for IND safety reports to 
protect subject safety. 
 
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283  Sponsor-investigators, as defined in  312.3(b), are required to comply with both the sponsor and 
284  the investigator responsibilities under part 312.  FDA recognizes that a sponsor-investigator may 
285  not have access to complete safety data maintained by a commercial sponsor or other sponsor-
286  investigators, but sponsor-investigators are responsible for evaluating all safety information 
287  available to them, including data from reports in the scientific literature and reports from foreign 
288  commercial marketing experience, if known.  See  312.32(b).  To protect human subjects, FDA 
289  recommends that entities that provide a drug to or receive a drug from other entities share safety 
290  information with each other. 
291   
292  A.  Serious and Unexpected Suspected Adverse Reaction ( 312.32(c)(1)(i)) 
293   
294  The sponsor must report in an IND safety report any suspected adverse reaction to study 
295  treatment (including active comparators) that is both serious and unexpected ( 
296  312.32(c)(1)(i)).12  Before submitting an IND safety report, the sponsor needs to ensure that the 
297  event meets three criteria:  (1) it is serious; (2) it is unexpected (i.e., not listed in the 
298  investigators brochure or is not listed at the specificity or severity that has been observed), or, if 
299  an investigator brochure is not required or available, is not consistent with the risk information 
300  described in the general investigational plan or elsewhere in the IND; and (3) there is evidence to 
301  suggest a causal relationship between the drug and the adverse event (i.e., it is a suspected 
302  adverse reaction).  If the adverse event does not meet all three criteria, it should not be 
303  submitted as an IND safety report.13 
304   
305  Deciding whether the SAE meets the definition of a suspected adverse reaction is usually the 
306  most difficult determination, but this decision is critical to avoiding the submission of 
307  uninformative IND safety reports.  Once the adverse event is determined to be serious and 
308  unexpected, the sponsor should evaluate the available information and decide whether there is a 
309  reasonable possibility that the drug caused the adverse event and, therefore, that the event also 
310  meets the definition of a suspected adverse reaction.  Serious and unexpected suspected adverse 
311  reactions must be reported in an IND safety report ( 312.32(c)(1)(i)). 
312   
313  Under  312.64(b), investigators are required to provide a causality assessment for each SAE 
314  reported to the sponsor.  The sponsor should consider the investigators assessment but must 
315  submit an IND safety report only for those events for which the sponsor determines there is a 
316  reasonable possibility that the drug caused the event ( 312.32(c)(1)(i)).  Thus: 
317   
 
12 The sponsor must submit an IND safety report for any suspected adverse reaction to study treatment that is both 
serious and unexpected, including suspected adverse reactions to active comparators that are marketed or approved 
in the United States.  Postmarketing safety reporting requirements ( 314.80 and 600.80) apply to the NDA or BLA 
holder but not to the IND sponsor.  As a result, unless the IND sponsor and NDA/BLA holder are the same, or the 
NDA/BLA holder becomes aware of the suspected adverse reaction, these reactions would not be submitted as a 
postmarketing 15-day Alert Report.  Requiring sponsors to report all suspected adverse reactions that meet the 
standard for reporting, even those that occur with the control drug, in IND safety reports will minimize the risk that 
suspected adverse reactions will not be reported to FDA.  Such reporting is essential for participant safety.   
 
13 Adverse events that do not meet the criteria for reporting in an IND safety report must still be reported in 
accordance with the periodic reporting regulations, when applicable (e.g.,  312.33 IND annual report). 
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318    The sponsor should not report events for which the investigators assessment is positive 
319  for causality but the sponsors evaluation did not find evidence to suggest a causal 
320  relationship between the drug and the event. 
321   
322    The sponsor must report events for which the investigators assessment is negative for 
323  causality but the sponsors evaluation found evidence to suggest a causal relationship 
324  between the drug and the event ( 312.32(c)(1)(i)). 
325   
326  The investigators assessment of causality must be included in the report submitted to the 
327  sponsor.  See  312.64(b).  If the investigator fails to provide a causality assessment or assesses 
328  the causality as unknown, the sponsor will need to evaluate the event without the investigators 
329  assessment.  See  312.32(b) and (c). 
330   
331  Serious and unexpected suspected adverse reactions reported in an IND safety report can be 
332  divided into four categories depending on the type of event.  As discussed below in section 
333  IV.A.1.a and b, the first two categories ( 312.32(c)(1)(i)(A) and (B)) can generally be assessed 
334  on the basis of an individual or a small number of events.  Aggregate analyses are needed for (1) 
335  anticipated adverse events for which it is difficult or impossible to make a causal determination 
336  based on a single case or a small number of cases and where an aggregate analysis comparing the 
337  rate of such events in the intervention arm compared to a control is needed (see 
338   312.32(c)(1)(i)(C)); or (2) adverse or suspected adverse reactions that must be reported if the 
339  incidence is higher than described in the protocol or investigators brochure ( 312.32(c)(1)(iv)) 
340  and therefore for which an aggregate analysis comparing the rate of the adverse or suspected 
341  adverse reaction in the study to past rates is needed.    
342   
343  If the study under an IND has an active control group but the sponsor is not the new drug 
344  application (NDA) or biologics license application (BLA) holder for the control drug, serious 
345  and unexpected adverse events in the control group that can be assessed as suspected adverse 
346  reactions based on an individual or small number of events must be reported as individual events 
347  as described in  312.32(c)(1)(i)(A) and (B).  If the sponsor is also the NDA or BLA holder for 
348  the control drug, the serious and unexpected suspected adverse reaction must also be submitted 
349  as required under postmarketing regulations.  See  312.32(c)(4).  (See flowcharts in 
350  Appendix B.) 
351   
352  During an aggregate analysis to determine whether there is an increase in serious anticipated 
353  adverse events in the group receiving the investigational drug that would need to be reported 
354  under  312.32(c)(1)(i)(C), a sponsor who is not the NDA or BLA holder for the control drug 
355  may discover that the rate of the anticipated adverse event is higher in the control arm than in the 
356  test drug arm.  FDA recognizes that additional context may be needed to interpret such aggregate 
357  analysis results (e.g., if the aggregate event rate is higher in the active control group than in the 
358  test drug group, it could be that the test drug is protective rather than that the control drug is 
359  causing an increased rate of the adverse event).  For imbalances suggesting a substantially higher 
360  rate in the control group (rather than a protective effect of the study drug), the sponsor should 
361  report such an imbalance to FDA; FDA acknowledges that the reporting threshold for a well-
362  characterized approved control drug could be higher in light of previous knowledge of the drug.  
363  The sponsor should consider sharing with the NDA or BLA holder the events that suggest a 
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364  higher rate in the active control group even if the events do not rise to the level of IND safety 
365  reporting. 
366   
367  If the sponsor is not the NDA or BLA holder for the control drug, they are not expected to 
368  perform aggregate analyses to assess whether there is an increased occurrence of serious 
369  expected adverse reactions for the control drug (i.e., events reportable under  312.32(c)(1)(iv)).  
370  In general, it should be expected that the control drug is marketed and its safety profile is well 
371  established and described in labeling.  If, however, it becomes apparent that the expected serious 
372  adverse reaction that is listed in the package insert of the control drug occurs at a much higher 
373  frequency than is expected, the sponsor should report this finding to FDA in an IND safety 
374  report.  
375   
376  1.   Events That Do Not Require Aggregate Analyses  
377   
378  a.  Individual occurrences ( 312.32(c)(1)(i)(A)) 
379   
380  Certain SAEs are informative as single cases because they are uncommon and known to be 
381  strongly associated with drug exposure[.]  Some examples include angioedema, certain blood 
382  dyscrasias (e.g., agranulocytosis), rhabdomyolysis, hepatic injury, anaphylaxis, and Stevens-
383  Johnson Syndrome.  The occurrence of even one case of such adverse events would meet the 
384  definition of suspected adverse reaction (i.e., there is a reasonable possibility that the drug 
385  caused the event) and therefore must be reported in an IND safety report ( 312.32(c)(1)(i)(A)).   
386   
387  The blind should ordinarily be broken for these types of IND safety reports that are submitted to 
388  FDA and all participating investigators.  Knowledge of the treatment received is necessary for 
389  interpreting the event and determining whether it is a suspected adverse reaction.  Further, such 
390  knowledge may be essential for the medical management of the subject and may provide critical 
391  safety information about a drug that could have implications for the ongoing conduct of the trial 
392  (e.g., monitoring, informed consent).  FDA generally does not anticipate that unblinding single 
393  or small numbers of serious and unexpected adverse event cases will compromise trial integrity, 
394  in part because such unblinding should be infrequent.  For example, a single case of liver injury 
395  would be unblinded but would have no effect on overall study integrity.  The challenges arising 
396  from unblinding safety data for aggregate data analyses are discussed in sections VI.B through 
397  VI.D of this guidance.   
398   
399  If the blind is broken and a subject with an adverse event that would meet the criteria for 
400  reporting as a single event was receiving placebo, the event should not be reported in an IND 
401  safety report because it is not possible that the drug caused the adverse event.  If the blind is 
402  broken and this subject was receiving drug treatment (test drug or active comparator), it must be 
403  reported in an IND safety report ( 312.32(c)(1)(i)(A)).   
404   
405  b.  One or more occurrences ( 312.32(c)(1)(i)(B)) 
406   
407  One or more occurrences of an SAE that is not commonly associated with drug exposure but is 
408  otherwise uncommon in the population exposed to the drug meets the definition of a suspected 
409  adverse reaction and therefore must be reported in an IND safety report ( 312.32(c)(1)(i)(B)).  If 
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410  the event occurs in association with other factors strongly suggesting causation (e.g., strong 
411  temporal association, event recurs on rechallenge), a single case may be sufficiently persuasive 
412  to report in an IND safety report.  Often, more than one occurrence from one or multiple studies 
413  would be needed before the sponsor could determine that there is a reasonable possibility that 
414  the drug caused the event.  Examples include tendon rupture or heart valve lesions in young 
415  adults or intussusception in healthy infants.  For reasons similar to those given above in section 
416  IV.A.1.a regarding individual occurrences, such events should be unblinded. 
417   
418  2.   Events That Require Aggregate Analyses  
419   
420  a.  Events anticipated to occur in the study population, independent of drug 
421  exposure ( 312.32(c)(1)(i)(C)) 
422   
423  Certain SAEs can be anticipated to occur in the study population independent of drug exposure.  
424  Such events include:   
425   
426    Events common in the study population, such as: 
427   
428    Events related to the underlying disease or condition under investigation (e.g., death 
-
429  due to progressive disease in an oncology trial, pneumonia in participants with 
430  chronic obstructive lung disease, diabetic ketoacidosis in a trial of type 1 diabetes 
431  management, hospitalization for gait disturbance reported in a multiple sclerosis trial) 
432   
433    Events that are common in a population regardless of the underlying condition being 
-
434  studied (e.g., cardiovascular events or hip fracture in an older adult population) 
435   
436    Events known to occur with drugs administered as part of a background regimen (e.g., 
437  neutropenia with a myelosuppressive chemotherapeutic agent, intracerebral hemorrhage 
438  with an anticoagulant, cytomegalovirus colitis with an immunosuppressive regimen) 
439   
440  Although these anticipated SAEs meet the definition of unexpected in  312.32(a) because they 
441  are not listed in the investigators brochure (see section III.C of this guidance), they do not 
442  warrant expedited reporting as individual cases or even when there are many such events where 
443  the incidence is consistent with expected background rates in the study population.  Such 
444  anticipated SAEs will occur even if the drug does not cause them, and their occurrence alone will 
445  generally not support a conclusion that there is a reasonable possibility that the drug caused the 
446  events.  To assess whether the drug could have caused the SAE that is anticipated in the 
447  population, the sponsor should perform an aggregate analysis that will enable an assessment of 
448  whether the rates of the anticipated adverse event in a population exposed to the drug differ from 
449  the rate of the same SAE in a similar population not exposed. 
450   
451  Such anticipated adverse events should be monitored at appropriate intervals, and the numbers of 
452  events in treated versus control trial participants should be compared using a safety monitoring 
453  process that protects the integrity of blinding (see section VI.D of this guidance).  The adverse 
454  event must be reported to FDA in an IND safety report if an aggregate analysis reveals there is 
455  an imbalance between arms that is sufficient to conclude that there is a reasonable possibility that 
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456  the drug caused the adverse event ( 312.32(c)(1)(i)(C)).  The sponsor should consider all 
457  relevant drug development data (in addition to the clinical trial data) when determining whether 
458  there is a reasonable possibility that the drug caused the adverse event. 
459    
460  b.  Increased occurrence of serious suspected adverse reactions 
461  ( 312.32(c)(1)(iv)) 
462   
463  The sponsor must report any clinically important increase in the rate of a serious suspected 
464  adverse reaction over that listed in the protocol or investigators brochure ( 312.32(c)(1)(iv)).  
465  An incidence rate for such suspected adverse reactions may not always be available, but when 
466  one is available or can be estimated from data or analyses in the investigators brochure (e.g., 
467  from a table), a clinically important increase over that rate must be reported ( 312.32(c)(1)(iv)).  
468  The sponsor should perform an aggregate analysis to compare the rate of a serious suspected 
469  adverse reaction seen in the study to the rate listed in the protocol or investigators brochure.   
470  The decision about when to report is a matter of judgment based on a variety of factors, 
471  including the study population, the nature and seriousness of the reaction, and the magnitude of 
472  the observed increase in the incidence rate.  Monitoring the rate of these events in a blinded trial 
473  requires a systematic safety surveillance process that will protect the integrity of the trial; this is 
474  discussed in section VI of this guidance. 
475   
476  B.  IND Safety Reporting Criteria for Aggregate Data 
477   
478  Determining when the aggregate safety data provide evidence suggesting (1) a causal 
479  relationship between the drug and a serious adverse medical outcome (e.g., myocardial ischemia) 
480  or (2) that there has been a clinically important increase in the rate of an expected serious 
481  adverse reaction (i.e., determining whether the reporting threshold has been met) is a complex 
482  judgment.  It is almost never a simple application of a planned statistical analysis, and the 
483  determination may change as data accumulate.  FDA recognizes that these determinations can be 
484  difficult and require judgment.  It may be helpful for sponsors to document in internal records all 
485  aggregate analyses of SAEs, including those that are determined not to meet the reporting 
486  threshold.  This is because FDA will focus primarily on the robustness of the sponsors process 
487  and the reasoning underlying the sponsors decision if, during FDAs review of trial safety data, 
488  FDA reaches a different conclusion about whether an IND safety report was warranted.  The 
489  sponsor may also prespecify reporting thresholds in its safety surveillance plan that, if exceeded, 
490  would lead to submission of an IND safety report. 
491   
492  1.  Serious and Unexpected Suspected Adverse Reactions ( 312.32(c)(1)(i)(C)) 
493   
494  As noted previously, for the purposes of IND safety reporting, a suspected adverse reaction 
495  means there is a reasonable possibility that the drug caused the event (i.e., evidence to suggest a 
496  causal relationship between the drug and the adverse event) ( 312.32(a)).  To interpret 
497  imbalances in aggregate data, clinical and statistical (if applicable) expertise will be needed to 
498  determine whether that reasonable possibility exists, based on the totality of available 
499  information.     
500   
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501  Factors to consider when determining whether the reasonable possibility threshold has been met: 
502   
503    Extent of the increase in incidence seen in the test group compared to the control groups 
504   
505    Evidence of a dose response 
506   
507    Temporal relationship (for example, early increase post drug initiation, such as drug-
508  induced liver injury occurring in the usual 1- to 6-month window, or malignancy events 
509  occurring after a lag period between the dates of exposure and date of event onset)  
510   
511    Consistency of the increase in multiple trials 
512   
513    Presence of a plausible mechanism of action 
514    
515    Nonclinical evidence (from toxicology or pharmacology animal studies, genetic studies 
516  such as knock-out or knock-in mouse models, or human genetic data) to support the 
517  finding 
518   
519    Pharmacology of the drug (including results from receptor, transporter, or enzyme 
520  binding or activation studies, and animal models) and known class effects 
521   
522    Pattern across the study population (for example, the event is observed more frequently in 
523  individuals likely to be susceptible to it (e.g., acute kidney injury in individuals with prior 
524  chronic kidney disease, myocardial infarctions in older individuals or those with existing 
525  coronary heart disease, hyperkalemia in individuals on ACE inhibitors)) 
526    
527    Occurrence of other potentially related adverse events (e.g., occurrence of both strokes 
528  and transient ischemic attacks, unexpectedly large increase in creatine kinase and events 
529  of rhabdomyolysis) 
530   
531  2.  Increased Rate of Occurrence of Serious Suspected Adverse Reactions 
532  ( 312.32(c)(1)(iv)) 
533   
534  For previously recognized serious suspected adverse reactions, clinical judgment is needed to 
535  determine whether a suspected adverse reaction to the investigational drug is occurring at a 
536  clinically important increased rate relative to the rate provided in the investigators brochure.  
537  Factors to consider when making the judgment may include (1) the size of the increase in rate of 
538  occurrence for the test drug treatment group over the rate listed in the investigators brochure or 
539  elsewhere in the current IND application and (2) the consistency of the increase over time and 
540  across multiple trials, if applicable. 
541   
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542  C.  Other Reporting Requirements 
543   
544  1.  Findings from Other Sources ( 312.32(c)(1)(ii) and (iii)) 
545   
546  The sponsor must also report any findings from clinical, epidemiological, or pooled analysis of 
547  multiple studies and any findings from animal or in vitro testing that suggest a significant risk in 
548  humans exposed to the drug ( 312.32(c)(1)(ii) and (iii)).  These reports are required for studies 
549  from any source, regardless of whether they are conducted under the IND or by the sponsor ( 
550  312.32(c)(1)(ii) and (iii)).  A finding that suggests a significant risk would ordinarily . . . result 
551  in a safety-related change in the protocol, informed consent, investigator brochure (excluding 
552  routine updates of these documents), or other aspects of the overall conduct of the clinical 
553  investigation.  For example, actions often taken in response to a significant risk finding include 
554  (1) immediate revision of the informed consent, (2) intensification of subject monitoring, (3) 
555  revised eligibility criteria or screening procedures, (4) enrollment hold, or (5) consideration of 
556  discontinuation of the trial.  The sponsor is also required to submit protocol amendments that 
557  describe certain changes to the protocol ( 312.30(b)) in addition to the IND safety report.  
558   
559   a.  Findings from other studies ( 312.32(c)(1)(ii))  
560   
561  Findings that suggest a significant risk generally arise from ongoing or completed clinical 
562  studies, pooled data from multiple studies, epidemiological studies, and published and 
563  unpublished scientific papers.  Findings from clinical studies that are subject to this requirement 
564  are those that have not already been reported under  312.32(c)(1)(i).  For example, any 
565  significant risk finding from a drug interaction study, a study evaluating the QT interval, or a 
566  study of a marketed drug would be reported under this provision.  An example of such a finding 
567  would be a significant prolongation of the QT interval in subjects receiving the investigational 
568  product. 
569   
570  b.  Findings from animal or in vitro testing ( 312.32(c)(1)(iii))  
571   
572  Findings from animal studies, such as carcinogenicity, mutagenicity, teratogenicity, or reports 
573  of significant organ toxicity at or near the expected human exposure are examples of the types 
574  of findings that suggest a significant risk.  Before reporting a finding to FDA, the sponsor should 
575  use judgment to decide whether the finding suggests a significant risk in humans or is too 
576  preliminary to interpret without replication or further investigation. 
577   
578  2.  IND Safety Reports for Study Endpoints ( 312.32(c)(5)) 
579   
580  Generally, study endpoints refer to outcomes that sponsors are measuring to evaluate efficacy.  
581  For trials designed to evaluate the effect of a drug on disease-related mortality or major 
582  morbidity, endpoint information should be collected, tracked, and monitored, usually by a data 
583  monitoring committee (DMC), during the course of the trial (see the guidance for clinical trial 
584  sponsors Establishment and Operation of Clinical Trial Data Monitoring Committees (March 
585  2006)).  The study endpoints, including unblinded study endpoints, are not ordinarily reported in 
586  IND safety reports, except when there is evidence of a causal relationship between the drug and 
587  the event ( 312.32(c)(5)).  For example, a death ordinarily would not be reported as an 
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588  individual case in an expedited report from a trial designed to compare all-cause mortality in 
589  subjects receiving either an investigational drug or a placebo.  If, however, the death occurred as 
590  a result of an anaphylactic reaction that coincided with initial exposure to the drug or was the 
591  result of fatal hepatic necrosis, the death must be reported as an individual case in an IND safety 
592  report because of the evidence suggesting a causal relationship between the drug and the event 
593  ( 312.32(c)(5)).  This is analogous to a single uncommon event required to be reported under 
594   312.32(c)(1)(i)(A).   
595   
596  In addition to the study endpoints described above, some trials also evaluate the effect of the 
597  drug on several other pre-identified specific adverse events, often called safety endpoints.  These 
598  safety endpoints should be identified in the protocol and monitored and reported by the sponsor 
599  as specified in the protocol.  
600   
601   
602  V.  SYSTEMATIC APPROACH FOR REVIEW OF SAFETY INFORMATION 
603  ( 312.32(b)) 
604   
605  Sponsors should have a systematic approach to safety surveillance14 to comply with the IND 
606  safety reporting requirements and to improve the overall quality of safety reporting.  Such an 
607  approach should include a process for promptly reviewing, evaluating, and managing 
608  accumulating data on SAEs from the entire drug development program that are sent from 
609  domestic or foreign sources.  
610   
611  During the course of drug development, investigators who conduct clinical trials generally report 
612  to the sponsor adverse event information; however, a sponsor may become aware of new safety 
613  information from a variety of sources, both domestic and foreign.   
614   
615  The sponsor must review and evaluate safety information from any source regardless of whether 
616  the data came from studies conducted under the IND ( 312.32(c)(1)(ii) and (iii)) to determine if 
617  there is a newly identified significant risk to trial participants.15  Sources include but are not 
618  limited to: 
619   
620    Animal or in vitro studies  
621   
622    Clinical or epidemiological investigations  
623   
 
14 For more discussion of this subject, see the guidance for clinical trial sponsors Establishment and Operation of 
Clinical Trial Data Monitoring Committees (March 2006), the guidance for industry Premarketing Risk Assessment 
(March 2005), and additional sources listed in the references section of this guidance. 
 
15 Although sponsors must examine all information relevant to the safety of the drug obtained ( 312.32(b)), not all 
safety information from available sources will need to be reported in an IND safety report.  For example, sponsors 
do not have to submit to the IND spontaneous reports of adverse events for a drug marketed or approved in the 
United States resulting from commercial marketing experience for the same drug (see section VII.C of this 
guidance). 
 
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624    Reports in the scientific literature, including unpublished reports of which the sponsor 
625  becomes aware  
626   
627    Information presented at professional or scientific meetings (e.g., abstracts)  
628   
629    Reports from foreign regulatory authorities  
630   
631    Reports from commercial marketing experience, including outside the United States  
632   
633  The sponsors review should include examining data from all sources and deciding whether the 
634  information meets the criteria for expedited reporting (see section IV of this guidance), as well as 
635  evaluating all accumulating data at regular intervals to update safety information and to identify 
636  new safety signals.  Monitoring the progress of investigations is necessary to identify previously 
637  undetected potential serious risks ( 312.56(a)), to update investigators brochures, protocols, 
638  and consent forms with new information on adverse events, and, when necessary, to take steps to 
639  protect subjects (e.g., modifying dosing, participant selection, or monitoring) that will allow an 
640  investigational drug to be safely developed despite potential risks or to discontinue investigations 
641  for drugs with unreasonable and significant risks ( 312.56(d)).   
642   
643  A.  Prospective Development of a Plan for Safety Surveillance 
644   
645  The prospective development of a plan for assessing SAEsparticularly those SAEs that are 
646  only interpretable in the aggregateand other important safety information is usually an 
647  important component of IND safety reporting.  The plan (also referred to as a safety monitoring 
648  plan) should describe processes and procedures for assessing SAEs and other important safety 
649  information in a drug development program.   
650   
651  A plan for safety surveillance should include descriptions of the following elements:  
652   
653    Clearly defined roles and responsibilities of the entities and participating individuals that 
654  have responsibility for any or all of following:  reviewing, analyzing, and making 
655  decisions regarding IND safety reporting 
656   
657    A plan for regular review of SAEs and other important safety information, with 
658  unblinding as necessary for interpretation 
659   
660    A process for aggregate safety reviews (see section VI of this guidance for considerations 
661  for aggregate data analysis), including:  
662   
663    A list of adverse events that are anticipated for the study population that the sponsor 
664  does not plan to report individually, regardless of the investigators assessment of 
665  causality.  The preferred terms (PTs) for such events should be specified in a 
666  standardized coding convention or dictionary such as MedDRA (Medical Dictionary 
667  for Regulatory Activities).  The events should each reflect a cohesive medical concept 
668  and not necessarily a single PT:  an event may be reflected by a number of different 
669  PTs.  For example, the serious event of myocardial infarction may include a range of 
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670  specific PTs.  Thus, each anticipated serious event may be reflected by a list of PTs 
671  (see section VII. B of this guidance).  Sponsors may discuss the anticipated SAEs 
672  with the applicable FDA review division during protocol development and prior to 
673  trial initiation, as appropriate.  It is not expected that the list of anticipated events will 
674  cover all clinical events that may be background clinical events in the population; 
675  hence, reported SAEs coding to PTs that are not on the anticipated event list (and not 
676  on the list of expected events) do not necessarily require IND safety reporting.  
677  Rather, such events should be carefully reviewed to determine if they meet the criteria 
678  for IND safety reporting when such a determination cannot be made based on a single 
679  case. 
680   
681    For studies that will use a trigger approach (see section VI.B.1.a of this guidance) to 
682  decide when such SAEs should be unblinded, the predicted rates of anticipated SAEs 
683  and the basis for the predicted rates should be specified. 
684   
685    A plan to monitor the incidences of all events other than those that do not require 
686  aggregate reporting (which would be reported without requiring aggregate analysis; 
687  see section IV.A.1 above).  These include anticipated events (both pre-specified and 
688  those not on the anticipated event list but reviewed and assessed as consistent with a 
689  background event in the population and hence not immediately reported) and 
690  expected events (those listed in the package insert or investigators brochure). 
691   
692    The frequency with which aggregate reviews of safety data will be performed. 
693   
694    Pre-planned assessments of the trial and program safety database when trials within 
695  the program are completed and unblinded, when safety information from trials of 
696  other drugs in the same class are reported, or when any information relevant to safety 
697  is presented (e.g., pharmacology, toxicology, genetic).   
698   
699    Methods that may be used to evaluate events, including graphical, tabular, or   
700  statistical approaches. 
701   
702    Unblinding practices and controls and processes for maintaining trial integrity. 
703   
704  The sponsor should evaluate the safety surveillance plan as the development program progresses 
705  and the safety profile of the product evolves to determine whether the plan should be updated.  
706  The plan should be maintained by the sponsor and must be available for FDA inspection as 
707  required for all sponsor records and reports of an investigation under  312.58(a).   
708   
709   
710  VI.  CONSIDERATIONS FOR AGGREGATE DATA ANALYSIS FOR IND SAFETY 
711  REPORTING 
712   
713  Analyses of aggregate data to identify imbalances for those events of the types discussed in 
714   312.32(c)(1)(i)(C) or 312.32(c)(1)(iv)) generally will become more informative as drug 
715  development progresses and data accumulate.  Unless differences are large, however, detection 
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716  of a clinically meaningful imbalance often requires a database of significant size.  Regardless of 
717  the size of the program, clinical judgment is important because imbalances of events between 
718  arms may result from chance.  Interpreting imbalances may be particularly challenging for 
719  smaller programs where the number of events is small.16  Even nonstatistically significant 
720  imbalances may be relevant, and interpretation may require a broader evaluation including 
721  detailed assessment of trial data such as time to event, detailed case assessments, and reliance on 
722  information outside of the trial, such as the pharmacology of the drug, class effects, and non-
723  clinical findings.  Waiting for a statistically significant difference in event rates, when other 
724  evidence points to a potential causal association, may unduly delay reporting serious events of 
725  concern.  It is particularly difficult to detect differences in rates of adverse events that may be 
726  anticipated in the population being studied but are not common (e.g., prostate cancer in middle-
727  aged men).  Recognizing the complexity of the judgements, FDA will focus on the sponsors 
728  process and reasoning underlying the sponsors decision in the event the FDA and sponsor reach 
729  different conclusions regarding whether SAEs evaluated by analyses of aggregate data meet IND 
730  safety reporting criteria.    
731   
732  A.  Identify Serious Adverse Events Anticipated to Occur in the Study 
733  Population  
734   
735  As discussed in section V of this guidance, regarding the safety surveillance plan, the first step in 
736  preparing for an aggregate analysis of anticipated events is developing a list of these events in 
737  the protocol or in the plan for safety surveillance and documenting a plan for monitoring these 
738  events.  This will enable the safety assessment team to identify events that should not be 
739  individually reported in an IND safety report, even if they are assessed by the investigator as 
740  drug-related.  As discussed in section V.A above, the fact that the sponsor did not prospectively 
741  identify an adverse event as anticipated in its safety surveillance plan does not mean that it needs 
742  to be reported as a single event.   
743   
744  For drug development programs in rare diseases, external data sources used to establish 
745  anticipated adverse event rates are often limited.  Furthermore, the clinical trial to support 
746  effectiveness may be an unblinded single-arm trial (i.e., a trial with no concurrent comparator 
747  group).  These settings are especially challenging, and sponsors should use judgement in 
748  determining whether there is a reasonable possibility that the drug caused the event.  Sponsors 
749  may wish to discuss their plans regarding when an anticipated adverse event should be reported 
750  as an IND safety report with the relevant review division. 
751     
752  B.  Aggregate Analyses of Safety Data 
753   
754  1.  Approach to Aggregate Analyses 
755   
756  For SAEs that are interpretable only based on aggregate data (reportable under 
757   312.32(c)(1)(i)(C) and 312.32(c)(1)(iv)), the entity or entities that conduct the aggregate 
758  analyses generally should use one of two possible approaches to identify events that are 
 
16 For smaller programs, sponsors may need to assess events typically requiring aggregate analysis on an individual 
case basis and to only report if the event meets the criteria under  312.32(c)(1)(i)(A) or (B).   
 
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Draft  Not for Implementation 
759  reportable.  One approach (a) estimates and prespecifies the estimated background rate of the 
760  event in the population (e.g., myocardial infarctions in an older adult population) and then 
761  utilizes an unblinding trigger rate, based on the rate in the blinded data from the study 
762  population.  If that rate is exceeded, an unblinded analysis by treatment group is conducted.  The 
763  other approach (b) regularly analyzes unblinded safety data on SAEs by treatment group to 
764  assess whether there is a meaningful increase in a particular event in the intervention group 
765  compared to the control group.  Appendix C illustrates these two approaches to aggregate 
766  analyses.   
767   
768  Sponsors should have processes for comparing the rates of expected serious adverse reactions to 
769  the rates listed in the protocol or investigators brochure in order to determine whether they must 
770  be reported under  312.32(c)(1)(iv).   
771   
772  a.  Unblinding trigger approach 
773   
774  In the unblinding trigger approach, if the results of the overall blinded analyses demonstrate that 
775  the rate of events in the pooled treatment groups substantially exceeds the predicted rate, the next 
776  step is to examine the rates by treatment group using an unblinded analysis.  The trigger for 
777  unblinding by group is that the overall rate for a particular adverse event is substantially higher 
778  than the rate that was predicted for the overall study population.  To follow this approach, 
779  sponsors would prespecify predicted rates for the anticipated SAEs (note that this would involve 
780  grouping events reported as preferred terms; see section VII.B of this guidance for information 
781  about the importance of standardized coding).  Once the unblinding trigger rate is met, the 
782  numbers of events for the specific event in each arm would then be compared to determine 
783  whether the IND safety reporting criteria in  312.32(c)(1)(i)(C) have been met.  The unblinding 
784  trigger rate is set based on information available on anticipated events applicable to the specific 
785  study population (based on age, comorbidities, concomitant treatments, etc.).  This approach 
786  allows for the detection of a possible increase in event rates in the treated population without 
787  routine unblinding, and, if the trigger is met, with unblinding only of the event at issue.   
788   
789  Sponsors should use all available data, including placebo databases, historical data, literature, 
790  external epidemiological databases, electronic health records, and disease-specific registries, to 
791  estimate rates of SAEs anticipated to occur in the study population.  The predicted rates should 
792  be included in the plan for safety surveillance (see section V of this guidance). 
793   
794  FDA recognizes that it may be challenging to use a trigger approach because data on the rates of 
795  some anticipated SAEs in the specific trial population are not always available.  For example, 
796  although it may be possible to find data on the rates of cardiovascular events in the general 
797  population aged 4070 years, data specific to a similarly aged population with rheumatoid 
798  arthritis may not be available.  In addition, even when population rates are available from 
799  external sources, such as surveys or health care databases, if the population enrolled in a trial is 
800  healthier than the general population from which the rate is derived, this could lead to a less 
801  sensitive trigger rate (too high) than is appropriate for the trial population.   
802   
803  Therefore, a sponsor may choose to predict rates of certain anticipated SAEs, using a trigger 
804  approach, and to not predict rates of others.  For example, many SAEs on the anticipated list, as 
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Draft  Not for Implementation 
805  well as SAEs not placed on the anticipated list but assessed as background events, are not 
806  interpretable as single events, but may be expected to occur relatively infrequently (e.g., sepsis or 
807  hemorrhagic stroke or hip fracture), especially in a trial of relatively short duration (e.g., 36 
808  months).  Unblinding to assess incidence by treatment group may be specified for all such less 
809  common events when, for example, four or five or more events (depending on the event) are 
810  reported.  One approach to setting the trigger for such less common background events is to 
811  consider what imbalance would suggest a suspected adverse reaction and lead to submitting an 
812  IND safety report.  Such an assessment may include a detailed review of the individual events, 
813  considering all of the factors listed in section IV.B.1 of this guidance.  The rationale behind the 
814  choice of events for which a prespecified threshold is identified is important, and the sponsor 
815  should document how that threshold is determined.  
816   
817  b.  Analyses of all events by treatment group 
818   
819  An alternative to the trigger approach is to conduct periodic aggregate analyses of all SAEs, or at 
820  least those occurring in more than three or four participants (i.e., a cutpoint where the most 
821  extreme unfavorable imbalance would raise concern), comparing numbers of those events across 
822  treatment arms, to determine if there is a numerical imbalance that needs further evaluation to 
823  determine whether the IND safety reporting criteria in  312.32(c)(1)(i)(C) have been met.  This 
824  approach is preferable when it is not possible to accurately predict rates of anticipated SAEs.  
825  This approach does not require identifying predicted rates of events and directly assesses rates in 
826  treatment and control groups, the issue of primary interest.  The routine unblinding of SAEs that 
827  occurs with this approach requires scrupulous, thoroughly planned and well-documented efforts 
828  to protect data integrity, assuring that the entity carrying out the review is completely firewalled 
829  from the staff conducting the trial and assessing efficacy.  
830   
831  2.  Frequency of Aggregate Analyses 
832   
833  In the absence of a specific concern, it is reasonable to conduct the aggregate analyses at 
834  intervals based on volume of safety data collected or based on subject accrual into the trial (e.g., 
835  as each 25 percent of the recruitment target is reached) or on event rates (e.g., that might be 
836  higher in a relatively sick study population).  It is likely that the need to conduct aggregate 
837  analysis will happen at regular intervals (e.g., 6 months or more frequently as appropriate).  The 
838  frequency may be modified, as needed, if safety concerns arise that require follow-up (e.g., an 
839  imbalance might be determined not to require an IND safety report but could lead to more 
840  frequent monitoring).  In addition, in determining the appropriate frequency of aggregate 
841  reviews, the sponsor should consider factors such as experience with the drug, the condition 
842  being treated, the study population, and enrollment rates.  The frequency of review and the 
843  rationale behind it should be described in the plan for safety surveillance (see section V.B of this 
844  guidance). 
845   
846  3.  Considerations When Evaluating Aggregate Data 
847   
848  Aggregate analyses should generally be performed across multiple studies under the IND and, as 
849  appropriate, across all INDs for the drug held by the sponsor, including both completed and 
850  ongoing trials.  Clinical and statistical judgment is needed to evaluate the totality of the 
20  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
851  information related to a specific adverse event, including information from trials in different 
852  populations, particularly when the trials have different study designs (e.g., different dosing 
853  schedules, varying durations of follow-up, different indications).  FDA recognizes that these 
854  differences between studies may make it difficult to compare event rates across trials; therefore, 
855  documentation of this clinical assessment is recommended.  The draft guidance for industry 
856  Meta-Analyses of Randomized Controlled Clinical Trials to Evaluate the Safety of Human Drugs 
857  or Biological Products (November 2018)17 provides recommendations regarding combining data 
858  from multiple trials.   
859   
860  C.  Entities That Review Aggregate Data for IND Safety Reporting 
861   
862  Under  312.32, sponsors are responsible for promptly reviewing all information relevant to the 
863  safety of the drug, determining whether safety information meets the IND safety reporting 
864  criteria, notifying FDA and all participating investigators in an IND safety report of potential 
865  serious risks, and promptly investigating all follow-up safety information it receives.  Sponsors 
866  may choose to designate an entity (an individual or group of individuals) to review the 
867  accumulating safety information in a drug development program (e.g., over time in a late-stage 
868  clinical trial, across trials, across INDs for the same drug) and to make a recommendation to the 
869  sponsor regarding whether the safety information must be reported under  312.32.18  Sponsors 
870  have flexibility in determining which entity or entities should perform this function.  The entity 
871  used to assess individual occurrences or a small number of adverse events (reported under  
872  312.32(c)(1)(i)(A) and (B)) may be different from the entity assessing aggregate adverse events 
873  reported under  312.32(c)(1)(i)(C).  
874   
875  1.  Features and Composition of the Entity 
876   
877  The entity or entities reviewing aggregate safety information should include an individual or 
878  individuals with knowledge about the investigational drug; the disease being treated, including 
879  the epidemiology of the disease; and the characteristics of the study population (e.g., natural 
880  history of the disease being treated, background rates of anticipated adverse clinical events) and 
881  be qualified by training and experience to make clinical judgments about the safety of the drug.  
882  Identification of a new type of clinical safety concern (e.g., ocular toxicity, renal toxicity) may 
883  warrant adding additional expertise to the entity reviewing safety data.   
884   
885  The roles and responsibilities of each individual or group of individuals in the entity should be 
886  clearly defined in the plan for safety surveillance (see section V.A of this guidance). 
887   
888  2.  Identifying the Entities that Review Safety Information 
889   
890  If a DMC is in place, the DMC may be used to conduct aggregate analyses to help the sponsor 
891  assess whether the reporting criteria in  312.32(c)(1)(i)(C) and 312.32(c)(1)(iv) have been met.  
892  An advantage of having a DMC conduct this review is that the DMC routinely sees unblinded 
893  data and can utilize existing controls for maintaining trial integrity.  FDA recognizes that 
 
17 When final, this guidance will represent FDAs current thinking on this topic. 
 
18 See  312.52 (Transfer of obligations to a contract research organization). 
21  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
894  analyzing these data for the purpose of providing a recommendation to the sponsor regarding 
895  whether the IND safety reporting criteria have been met would be a new role for most DMCs.  
896  While DMCs monitor risks and benefits to make recommendations for trial continuation or 
897  modification, entities that review safety information for the purpose of IND safety reporting 
898  focus on identifying and characterizing risks of the test drug (i.e., suspected adverse reactions).  
899  Although there is certainly overlap in these activities, the assessments may differ in certain 
900  circumstances and the DMC could fulfill this new role by (1) reviewing the accumulating safety 
901  data collected over time in late-stage drug development and across multiple trials, across INDs 
902  for the particular drug, and from other sources, if applicable, and (2) assessing whether the IND 
903  safety reporting criteria have been met.  If this role is allocated to the DMC, the DMC charter 
904  should reflect this new role.   
905   
906  If the sponsor does not use a DMC for the purpose of reviewing safety analyses to detect events 
907  meeting the criteria for IND safety reporting, the sponsor should identify an entity within or 
908  outside the sponsors organization for this purpose.  If the entity consists of more than one 
909  individual, it may have both sponsor representation and/or external representation.  It is 
910  important that no unblinded effectiveness data, including references to masked treatment group 
911  assignments (e.g., treatment groups A, B, or C), be revealed to internal or external personnel 
912  participating in the conduct or analysis of an ongoing clinical trial program except for DMC 
913  members and any personnel designated to conduct unblinded analyses of safety data and who 
914  have been appropriately firewalled from those conducting the trial and performing other analyses 
915  (See section VI.D of this guidance).    
916     
917  Sponsors may also consider a triage approach in which more than one entity participates in the 
918  review.  Blinded review by sponsor personnel most familiar with the product and program would 
919  be conducted to determine if the number of events being seen in the trial population as a whole 
920  meets certain criteria that would trigger an unblinded comparison of event rates in the treatment 
921  and control groups.  The unblinded analyses would be conducted by a separate firewalled 
922  internal or external entity (e.g., a DMC).  It is also possible that the initial unblinded analyses by 
923  treatment group could be by an individual that is firewalled from the personnel responsible for 
924  conducting the trial, and only if there is an imbalance by treatment group19 would that individual 
925  refer the events to an internal or external entity responsible for determining if the threshold for 
926  IND reporting is met.  Whatever approach a sponsor uses should be documented in the safety 
927  surveillance plan.   
928   
929  D.  Maintaining Trial Integrity When Reviewing Aggregate Data 
930   
931  Recommended steps to protect trial integrity include ensuring that: 
932   
933    Internal personnel conducting unblinded safety reviews do not participate in the conduct 
934  or analysis of the trial or trials.   
935   
936    Appropriate procedural controls and processes are prospectively specified in the safety 
937  surveillance plan to prevent sponsor personnel involved with the conduct or analysis of 
 
19 It is possible that the number of events seen in the trial population is above expected but there is no imbalance 
between treatment groups.  
22  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
938  the trial(s) from being unblinded to individual subjects treatment assignments.  If a 
939  firewalled entity other than the DMC is set up to look at aggregate data, it should have 
940  access only to the unblinded data necessary to evaluate the event.  For example, it may be 
941  necessary to unblind the treatment assignment of the subjects who experienced an SAE, 
942  or it may be necessary to unblind additional data that is relevant to interpreting the 
943  observed imbalance (e.g., related clinical adverse events).  Study endpoints, efficacy data, 
944  and other data collected for the trial that do not pertain to the adverse event should not be 
945  unblinded.     
946   
947  FDA acknowledges that serious suspected adverse reactions may be unblinded at the site level if 
948  knowledge of the treatment received is assessed as necessary for the medical management of the 
949  subject.   
950   
951  To address sponsor concerns about unblinding large numbers of subjects treatment assignments 
952  to investigators when submitting aggregate reports, FDA considers the sending of the narrative 
953  portion of the IND safety report based on data in the aggregate to all participating investigators, 
954  instead of sending a completed Form FDA 3500A for each individual event, to meet the 
955  requirement of  312.32(c)(1) for a sponsor to notify all participating investigators in an IND 
956  safety report of potential serious risks. 
957   
958  If the sponsor proposes and follows a reporting format different from that otherwise required in 
959   312.32(c), it must be agreed to in advance by the director of the FDA review division 
960  responsible for reviewing the IND ( 312.32(c)(3)).  
961   
962   
963  VII.  OTHER SAFETY REPORTING ISSUES 
964   
965  A.  Alternative Reporting Arrangements ( 312.32(c)(3)) 
966   
967  The requirement in  312.32(c)(1) specifies the format and time frame for reporting potentially 
968  serious risks in an IND safety report (see section VIII of this guidance).  Sponsors may request 
969  and adopt different reporting formats or frequencies if agreed to in advance by the director of the 
970  FDA review division responsible for reviewing the IND ( 312.32(c)(3)).  In addition, FDA may 
971  require a sponsor to submit IND safety reports in a different format or at a different frequency 
972  than required under  312.32(c)(1) (see  312.32(c)(3)).  FDA may require a sponsor to continue 
973  to report expeditiously a medically significant suspected adverse reaction that is listed in the 
974  investigators brochure as observed with the drug (i.e., expected) so that its rate can be carefully 
975  monitored ( 312.32(c)(1)(v)).  For example, if a single occurrence of Stevens-Johnson 
976  Syndrome was observed in a subject receiving the investigational drug (and hence listed in the 
977  investigators brochure), FDA may nonetheless require expedited reporting of additional cases of 
978  rash of a lesser severity.  FDA may also require an alternative format or frequency for reporting 
979  suspected adverse reactions.  For example, once a drug has been identified as posing a potential 
980  or previously unforeseen risk to participants in a clinical trial, FDA may require expedited 
981  reporting of specific suspected adverse reactions for monitoring purposes.      
982   
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Draft  Not for Implementation 
983  B.  Importance of Standardized Coding 
984   
985  As part of the sponsors responsibility to promptly review all SAEs under  312.32(b), sponsors 
986  should review the verbatim (reported) term and how it was coded to a MedDRA preferred term 
987  to ensure that coding was appropriate.  To define these medical concepts, sponsors should plan to 
988  prospectively group adverse event terms that represent closely related medical concepts (e.g., for 
989  the medical concept of renal failure, appropriate preferred terms might include PTs of renal 
990  failure, renal failure acute, renal failure chronic, renal impairment, acute prerenal failure, 
991  azotemia, urine output decreased, postoperative renal failure, and other relevant terms). 
992  Standardized MedDRA queries (SMQs) or Higher Level Terms (HLTs) or sponsor-defined 
993  groupings that reflect the anticipated event should be employed.  See the guidance for industry 
994  Premarketing Risk Assessment (March 2005) for additional discussion of coding. 
995   
996  C.  Investigations of Marketed Drugs ( 312.32(c)(4)) 
997   
998  According to  312.32(c)(4), a sponsor of a clinical study of a drug marketed or approved in the 
999  United States that is conducted under an IND must submit IND safety reports for suspected 
1000  adverse reactions that meet reporting criteria under  312.32 and are observed in the study at 
1001  domestic or foreign sites.  If the sponsor is not the NDA or BLA holder,20 the sponsor should 
1002  also forward the report to the NDA or BLA holder, manufacturer, packer, or distributor of the 
1003  marketed drug.  If the sponsor is also the NDA or BLA holder, the sponsor must also submit 
1004  safety information from the clinical study as prescribed by the relevant postmarketing safety 
1005  reporting requirements (e.g., under  314.80 or 600.80).     
1006   
1007  In addition, under  312.32(c)(1)(ii) a sponsor must report events from other studies, including 
1008  clinical studies that are not conducted under an IND or by the sponsor, that suggest a significant 
1009  risk in humans exposed to the drug.  Generally, such a finding would result in a safety-related 
1010  change in the protocol, informed consent, investigator brochure, or other aspect of study conduct.  
1011  Therefore, as long as the sponsor maintains an open IND for its marketed or approved drug, 
1012  safety information from foreign and domestic studies, including non-IND studies, must be 
1013  reported to the IND.  If the sponsor is also the NDA or BLA holder, such safety information 
1014  must be reported in accordance with the postmarketing requirements if it also meets the criteria 
1015  for reporting. 
1016   
1017  If the IND sponsor (who may also be the NDA or BLA holder) for a drug approved in the United 
1018  States becomes aware of a spontaneous report of an adverse event from U.S. or foreign 
1019  commercial marketing experience for the drug that is under investigation (i.e., an experience 
1020  occurring outside of a clinical trial), the report would be submitted based on required 
1021  postmarketing reporting and does not also need to be submitted to the IND, even if it meets 
1022  criteria for being a serious and unexpected suspected adverse reaction.      
1023   
 
20 We note that the postmarketing reporting requirements concerning the submission of postmarketing 15-day Alert 
reports ( 314.80(c)(1)(i) through (ii)) apply not only to the NDA or BLA holder but also to any other person whose 
name appears on the label of an approved drug product as the manufacturer, packer, or distributor of the marketed 
drug.  See  314.80(c)(1)(iii). 
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Draft  Not for Implementation 
1024  If a drug is not approved and not marketed in the United States but is approved outside the 
1025  United States, a sponsor conducting a study under an IND must submit an IND safety report for 
1026  adverse reactions received through foreign commercial marketing experience if the event meets 
1027  reporting criteria for IND safety reports ( 312.32(c)(1)).  Because the drug is not approved and 
1028  is not marketed in the United States, such reports would not come to FDA as a postmarketing 
1029  report.  Therefore, the only way for FDA to receive such safety information is through the IND 
1030  for the investigational product.  
1031   
1032  D.    Duration of Safety Reporting 
1033   
1034  The purpose of sending IND safety reports to investigators is to provide investigators with 
1035  information they need to protect subjects participating in clinical trials.  Once investigators are 
1036  no longer enrolling or monitoring subjects and the site is officially closed, this information is no 
1037  longer necessary.  Cutoff dates for sending IND safety reports to investigators may be described 
1038  in the protocol.  If no cutoff dates are specified, once a site has been officially closed out, the 
1039  sponsor usually does not need to continue sending IND safety reports to that site, and an 
1040  investigator does not need to receive or review them.  See generally  312.32(c)(1). 
1041   
1042  In unusual cases, safety information related to delayed toxicity may be reported after a site is 
1043  officially closed out.  For example, if a late toxicity is discovered that would affect subjects who 
1044  received the investigational drug, the investigator should be notified so subjects can be followed 
1045  up with if necessary (e.g., serious unexpected suspected adverse reactions that are detected and 
1046  reported during the long-term follow-up for gene therapy products). 
1047   
1048   
1049  VIII.  SUBMITTING AN IND SAFETY REPORT ( 312.32 (c)(1)(v))21 
1050   
1051  A.  Report Identification and Format 
1052   
1053  Each report must prominently identify its contents ( 312.32(c)(1)(v)).  Reports should be 
1054  labeled as follows: 
1055   
1056    IND Safety Report for 15-day reports 
1057   
1058    Follow-up IND Safety Report for follow-up information 
1059   
1060    7-day IND Safety Report for unexpected fatal or life-threatening adverse reaction 
1061  reports 
1062   
 
21 Under section 745A(a) of the FD&C Act, at least 24 months after issuance of the final guidance document in 
which FDA has specified the electronic format for submitting submission types to the Agency, such content must be 
submitted electronically and in the format specified by FDA. (See the draft guidance for industry Providing 
Regulatory Submissions in Electronic Format: IND Safety Reports (October 2019).  When final, this guidance will 
represent FDAs current thinking on this topic.) 
 
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Draft  Not for Implementation 
1063  For reports made on Form FDA 3500A, the type of report should be checked in box G6 on FDA 
1064  Form 3500A.   
1065   
1066  The format for IND safety reports should be based on whether the report involves an individual 
1067  case or events identified by aggregate analysis.  
1068   
1069  1.  Individual Cases 
1070   
1071  For reports of individual cases, a sponsor should ordinarily use Form FDA 3500A.22  FDA will 
1072  accept foreign suspected adverse reaction reports on a CIOMS I Form instead of Form FDA 
1073  3500A ( 312.32(c)(1)(v)).  These forms should be completed with all available information, 
1074  including a brief narrative describing the suspected adverse reaction and any other relevant 
1075  information.  Like all other IND safety reports, the narrative must also include identification of 
1076  all previously submitted IND safety reports concerning a similar suspected adverse reaction and 
1077  an analysis of the significance of the suspected adverse reaction in light of previous, similar 
1078  reports or any other relevant information ( 312.32(c)(1)).  Sponsors should include the 
1079  manufacturer report number for previously submitted IND safety reports for identification 
1080  purposes. 
1081   
1082  2.  Reports of Events Identified by Aggregate Analyses 
1083   
1084  IND safety reports required for submission based on aggregate analyses must be submitted to 
1085  FDA in the format of a narrative summary report.  See  312.32(c)(v).  The narrative summary 
1086  report should include a summary of the analysis of the individual cases and should list the unique 
1087  case identifiers for each case (or copies of such individual cases if they have not been previously 
1088  submitted) that are reportable because of aggregate analysis findings.  Sponsors should use 
1089  judgment in deciding what to include in the summary of the analysis.  Generally, this summary 
1090  should include: 
1091   
1092  1.  A description of the suspected adverse reaction, along with a brief overall summary of 
1093  the cases.  This summary could include demographic factors, symptoms, comorbid 
1094  conditions, medical history, pertinent test results, concomitant medications, and timing of 
1095  events relative to drug exposure.   
1096   
1097  2.  A description of the characteristics and results of the analysis, including a description of 
1098  the safety data sources, how the conclusion was reached, who reviewed the analysis, any 
1099  planned changes in monitoring or to study documents (e.g., informed consent, 
1100  investigators brochure), and any additional analyses planned. 
1101   
1102  Additionally, the narrative summary report must identify previously submitted IND safety 
1103  reports concerning a similar suspected adverse reaction, and the sponsor must analyze the 
1104  significance of the suspected adverse reaction in light of previous, similar reports or any other 
1105  relevant information ( 312.32(c)(1)).  For example, if the sponsor plans to submit an IND safety 
1106  report for pulmonary embolus, the sponsor should look to see if IND safety reports were 
 
22 Form FDA 3500A is available at 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm. 
26  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1107  previously submitted for other thrombotic events (e.g., deep vein thrombosis) to analyze the 
1108  occurrence of medically related adverse events.  Similarly, for an IND safety report for fracture, 
1109  the sponsor should consider whether IND safety reports previously submitted for falls are 
1110  relevant to the analysis of the significance of the event.  Narrative summary reports and other 
1111  reports required to be submitted in narrative format under  312.32(c)(1)(v) (see section VIII.A.3 
1112  of this guidance) should not be submitted on Form FDA 3500A, which is for individual-case 
1113  safety reports consisting of individual subject data.   
1114   
1115  At the time the narrative summary report is submitted, the sponsor should submit all reports for 
1116  the individual cases that made up the analysis that were identified in the narrative summary report 
1117  (e.g., a completed FDA Form 3500A for each case), if not previously submitted.  If individual cases 
1118  were previously submitted as IND safety reports in electronic common technical document 
1119  (eCTD) format, the sponsor should list the eCTD sequence number23 and date of submission 
1120  with a hyperlink to the IND safety report to facilitate review.  For INDs that are not in eCTD 
1121  format, sponsors should attach previously submitted IND safety reports as PDF attachments to 
1122  the narrative summary report and clearly identify them as duplicate submissions.24  Before 
1123  submission to FDA, each individual case report should be unblinded to include data that is 
1124  necessary to evaluate the event.  FDA considers sending only the narrative summary report to 
1125  participating investigators without the individual unblinded case safety reports that are 
1126  summarized in the narrative report to meet the requirement under  312.32(c)(1) for a sponsor to 
1127  notify all participating investigators in an IND safety report of potential serious risks.  
1128     
1129  For aggregate analysis, after an adverse event anticipated to occur in the study population is 
1130  reported under  312.32(c)(1)(i)(C) or the increased rate of occurrence of an expected serious 
1131  suspected adverse reaction is reported under  312.32(c)(1)(iv), the investigators brochure, the 
1132  protocol, and other safety-related information should be updated as appropriate and as soon as 
1133  possible during the conduct of the ongoing clinical trial.  After the anticipated event is listed in 
1134  the investigators brochure, the event should no longer be reported in IND safety reports because 
1135  it would then be considered expected, unless there is a clinically important increase in the event 
1136  rate.  Similarly, the increased rate of occurrence of an expected serious suspected adverse 
1137  reaction reported under  312.32(c)(1)(iv) should no longer be reported in IND safety reports 
1138  after the investigators brochure, the protocol, and other safety-related information have been 
1139  updated to reflect the updated rate of occurrence, unless a further increase in occurrence is 
1140  observed and meets the reporting criteria. 
1141   
1142  The IND sponsor should in some circumstances develop, in consultation with the FDA review 
1143  division and other safety oversight bodies (e.g., a DMC), an approach for reporting subsequent 
1144  occurrences of certain events in an IND safety report that the sponsor has added, as expected 
1145  events, to the investigators brochure, the protocol, and other safety related information.  
1146  Although IND safety reporting is no longer required after an SAE is listed in the investigator 
 
23 The eCTD sequence number is the unique four-digit number for each IND submission the sponsor submits in the 
us-regional.xml file for the eCTD submission. 
 
24 For more information see the draft guidance for industry Providing Regulatory Submissions in Electronic Format:  
IND Safety Reports and the technical specifications documents Electronic Submissions of IND Safety Reports 
Technical Conformance Guide (October 2019) and Specifications for Preparing and Submitting Electronic ICSRs 
and ICSR Attachments (October 2019). 
27  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1147  brochure, ongoing reporting of subsequent events may still be appropriate.  For example, for 
1148  certain events that are infrequent with immediate health implications or an event that is 
1149  uncommon in a specific study population (e.g., stroke in young adults) prompt notification of 
1150  subsequent events after the first IND safety report may be warranted to ensure that the risk: 
1151  benefit ratio remains acceptable to continue the trial.  See  312.56(d).  A plan for reporting 
1152  should be developed in consultation with the FDA review division and other safety oversight 
1153  bodies (e.g., a DMC).  For an event that is known to occur independent of drug exposure in the 
1154  study population, the sponsor may specifically describe an approach for reporting to FDA and all 
1155  participating investigators (e.g., an updated aggregate narrative summary report once a certain 
1156  number of additional cases are identified or after a specified period of time, as appropriate).  
1157  Additionally, the sponsor must submit to FDA any additional data or information that FDA 
1158  deems necessary as soon as possible but in no case later than 15 calendar days after receiving the 
1159  request ( 312.32(c)(1)(v)). 
1160   
1161  3.  Other Reports 
1162   
1163  For reports of overall findings or pooled analyses from published and unpublished in vitro, 
1164  animal, epidemiological, or clinical studies, a narrative format must be used ( 312.32(c)(1)(v)).  
1165  If the findings are published, in full or in abstract form, the sponsor should include a copy of the 
1166  publication. 
1167     
1168  B.  Where and How to Submit 
1169   
1170  The IND safety report must be transmitted to the Center for Drug Evaluation and Research 
1171  (CDER) or the Center for Biologics Evaluation Research (CBER) review division responsible for 
1172  reviewing the IND ( 312.32(c)(1)(v)).  IND safety reports should be submitted to all of the 
1173  sponsors INDs under which the drug is being administered.  For example, if a drug is found to 
1174  cause drug-induced liver injury, this should be reported to any IND under which the drug is 
1175  being administered.  The sponsor should reference in the subject line of the cover letter all INDs 
1176  to which the IND safety report is being submitted.  If applicable, the sponsor should also identify 
1177  (e.g., by underlining) the specific IND under which the suspected adverse reaction occurred (e.g., 
1178  Suspected adverse reaction occurred under IND XXXX1, reference to INDs XXXX2, 
1179  XXXX3). 
1180   
1181  FDA recommends that sponsors submit IND safety reports electronically in the eCTD25 if the 
1182  IND is in eCTD format or if the sponsor intends to convert the IND to eCTD format.  Complete 
1183  information on eCTD specifications and guidance can be found on the FDA eCTD website, and 
1184  assistance may be obtained by contacting ESUB@fda.hhs.gov.  If the IND is not in eCTD 
1185  format, other means of rapid communication (e.g., telephone, fax, email) may be used.  If the 
1186  IND is not in eCTD format and the sponsor intends to submit IND safety reports by fax or email, 
 
25 Although FDA has exempted noncommercial INDs from the electronic submissions requirements under section 
745A(a) of the FD&C Act, FDA also accepts electronic submissions from these INDs.  For additional information 
on this subject, see the guidance for industry Providing Regulatory Submissions in Electronic FormatCertain 
Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (February 
2020). 
 
28  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1187  the sponsor should address the submissions to the Regulatory Project Manager and the Chief, 
1188  Project Management Staff in the FDA review division that has responsibility for review of the 
1189  IND.  In addition, if the sponsor intends to submit IND safety reports by email, FDA 
1190  recommends that the sponsor obtain a secure email account with FDA.26 
1191   
1192  C.  Reporting Time Frame 
1193   
1194  The time frame for submitting an IND safety report to FDA and all participating investigators is 
1195  as soon as possible but no later than 15 calendar days after the sponsor determines that the 
1196  suspected adverse reaction or other information qualifies for reporting ( 312.32(c)(1)).  The 
1197  IND safety reporting regulations were modified describing the reporting time frame applicable to 
1198  IND safety reports of more than one event (e.g., reports of events qualifying for reporting under 
1199   312.32(c)(1)(i)(B) and (C) and increases in rates of occurrence of serious suspected adverse 
1200  reactions ( 312.32(c)(1)(iv)), because these events generally require more than one occurrence 
1201  to make the determination that the event meets the criteria for reporting.  Thus, the date of initial 
1202  receipt of the first event would likely be well before it was determined that the information must 
1203  be reported. 
1204   
1205  FDA expects that events that are interpretable as single cases (i.e., uncommon and known to be 
1206  strongly associated with drug exposure) will be reported to FDA within 15 calendar days from 
1207  sponsors initial receipt of the information because it will be immediately apparent that such 
1208  events meet the reporting criteria ( 312.32(c)(1)).  For events that require more than one 
1209  occurrence to assess causality and events evaluated in the aggregate, the time clock starts from 
1210  whatever date the sponsor determines that the events qualify for expedited reporting.  This means 
1211  that, for example, incomplete cases must be promptly followed up for additional information so 
1212  that a determination can be made about whether the event is reportable as an IND safety report ( 
1213  312.32(d)).  
1214   
1215  Under  312.32(d)(3), if the results of a sponsors investigation show that an adverse event not 
1216  initially determined to be reportable under paragraph (c) of this section is determined to be 
1217  reportable, the sponsor must report such a suspected adverse reaction in an IND safety report as 
1218  soon as possible but in no case later than 15 calendar days after the determination is made.  This 
1219  applies to reporting of single and aggregate events and to events that would individually or in the 
1220  aggregate qualify for either 7- or 15-day reporting.  FDA expects that any entity responsible for 
1221  making recommendations to the sponsor regarding submitting an IND safety report based on 
1222  aggregate data will promptly provide the recommendation to the sponsor so that the sponsor can 
1223  meet its obligations under  312.32.  The sponsor must promptly review the information to 
1224  determine whether the IND safety reporting criteria have been met ( 312.32(b)). 
1225   
1226  Unexpected fatal or life-threatening suspected adverse reactions represent especially important 
1227  safety information and must be reported more rapidly to FDA ( 312.32(c)(2)).  The requirement 
1228  for reporting any unexpected fatal or life-threatening suspected adverse reaction to FDA is as 
1229  soon as possible but no later than 7 calendar days after the sponsors initial receipt of the 
 
26 For details on obtaining a secure email account with FDA, visit 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/d
efault.htm. 
29  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1230  information ( 312.32(c)(2)).  If the safety report submitted within 7 calendar days is complete, 
1231  an additional submission within 15 calendar days from day zero is not required. 
1232   
1233  Day zero is considered as (1) the day the sponsor initially receives information for a case that is 
1234  interpretable as a single case or (2) the day the sponsor determines that multiple cases qualify for 
1235  expedited reporting.   
1236   
1237  If FDA requests any additional data or information, the sponsor must submit it to FDA as soon as 
1238  possible but no later than 15 calendar days after receiving the request ( 312.32(c)(1)(v)).  See 
1239  section IX of this guidance for reporting time frames for follow-up information. 
1240   
1241  Finally, because of the potential for delay between the occurrence of an adverse event and the 
1242  reporting of the adverse event to the sponsor, the date of the event on Form FDA 3500A is not 
1243  determined by the reporting time frames and is the actual or best estimate of the date of first 
1244  onset of the adverse event.  FDA interprets the date of first onset of the adverse event27 to be 
1245  the date that the subject first experienced the symptoms that were related to the adverse event.  
1246  FDA recognizes that this determination is not always straightforward and requires clinical 
1247  judgment to relate the prodromal symptoms to the adverse event.      
1248   
1249   
1250  IX.  FOLLOW-UP INFORMATION ( 312.32(d)) 
1251   
1252  Most IND safety reports are derived from observations from clinical trials.  In the setting of a 
1253  clinical trial, information is usually collected in a controlled environment so that the information 
1254  needed to evaluate the suspected adverse reaction (e.g., information that would be contained in a 
1255  narrative report or on Form FDA 3500A) is generally readily available.  If any information 
1256  necessary to evaluate the suspected adverse reaction is missing or unknown, the sponsor should 
1257  actively seek such information from the source of the report.  In the event that the participant 
1258  withdraws consent from participating in a clinical trial, FDA recognizes that the sponsor cannot 
1259  continue to provide adverse event reports related to that subject once the consent is withdrawn 
1260  unless those reports are associated with publicly available records. 
1261   
1262  Any relevant additional information obtained by the sponsor that pertains to a previously 
1263  submitted IND safety report must be submitted as a Follow-up IND Safety Report without delay, 
1264  as soon as the information is available ( 312.32(d)(2)) but should be submitted no later than 15 
1265  calendar days after the sponsor receives the information.  The sponsor should maintain records of 
1266  its efforts to obtain additional information. 
1267   
1268  For example, if information on concomitant medications is obtained after the initial IND safety 
1269  report is submitted, and such information is relevant to evaluating the suspected adverse reaction, 
1270  a sponsor must immediately submit a Follow-up IND Safety Report ( 312.32(d)(2)).  However, 
1271  if the sponsor obtains other information that is not relevant to evaluating the suspected adverse 
1272  reaction, records of such information should be maintained by the sponsor and, if applicable, 
1273  submitted in an information amendment ( 312.31) or in an IND annual report ( 312.33). 
 
27 See Form FDA 3500A Supplement (4/16)  Form Instructions, available at 
https://www.fda.gov/media/82655/download. 
30  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1274   
1275  To help sponsors determine whether follow-up information is relevant to an IND safety report, 
1276  FDA provides in this section additional guidance on the types of information that generally 
1277  would require a follow-up IND safety report. 
1278   
1279  For an individual case that was submitted as an IND safety report under  312.32(c)(1)(i)(A) and 
1280  (B), examples of the types of information that trigger the follow-up IND safety reporting 
1281  requirements include (1) a change in diagnosis of the adverse event, (2) important change in 
1282  outcome of the adverse event (e.g., death), (3) autopsy findings, and (4) other new information 
1283  that significantly impacts the assessment of causality.   
1284   
1285  For aggregate data that were submitted as an IND safety report under  312.32(c)(1)(i)(C) and 
1286  312.32(c)(1)(iv), examples of the type of information that would trigger follow-up IND safety 
1287  reporting requirements include:  (1) additional occurrences of the adverse event that, in the 
1288  aggregate, suggest a significant change in the rate of occurrence from the initial aggregate report, 
1289  and (2) information about individual events that comprise the aggregate report that significantly 
1290  impacts the assessment of causality such that there is no longer a reasonable possibility that the 
1291  drug caused the event or strengthens the causal relationship between the adverse event and the 
1292  drug.  The sponsor should evaluate whether additional occurrences of the adverse event represent 
1293  a clinically important increase in the rate of a serious suspected adverse reaction over that listed 
1294  in the protocol or investigators brochure, which must be reported under  312.32(c)(1)(iv).   
1295   
1296   
1297  X.  SAFETY REPORTING REQUIREMENTS FOR BA AND BE STUDIES 
1298   
1299  The IND safety reporting requirements under  312.32 apply to BA and BE studies that are 
1300  conducted under an IND.  BA and BE studies that meet the conditions for IND exemption under 
1301   320.31(d) are not conducted under an IND and are not subject to the IND safety reporting 
1302  requirements.  Earlier iterations of  320.31(d) that also exempted certain in vivo BA and BE 
1303  studies in humans from the requirements of part 312, including the IND safety reporting 
1304  requirements under  312.32, did not establish separate safety reporting requirements for these 
1305  studies.  As FDA stated in its preamble to the final rule updating  320.31(d) in 2010, the 
1306  Agency determined that the occurrence of a serious adverse event is very unusual in a [BA or 
1307  BE] study because the number of subjects enrolled in the study is small, the subjects are usually 
1308  healthy volunteers, and drug exposure is typically brief.28  However, for these same reasons, 
1309  the occurrence of any serious adverse event [in a BA or BE study] is of interest.   Therefore, 
1310  FDA revised  320.31(d) to require reporting of SAEs as one of the conditions under which 
1311  certain BA and BE studies are exempt from the requirements of part 312, including from the 
1312  IND safety reporting requirements in  312.32.  See  320.31(d)(3).   
1313   
1314  Timely review of this safety information is critical to ensuring the safety of BA/BE study 
1315  subjects, whether they are healthy volunteers or individuals with the specified medical condition 
1316  and whether the trial has a single-dose or steady-state design. 
 
28 Final Rule, Investigational New Drug Safety Reporting Requirements for Human Drug and Biological roducts and 
Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans (75 FR 59953) published 
September 29, 2010. 
31  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1317   
1318  A.  BA/BE Study Safety Reporting Requirements ( 320.31(d)(3)) 
1319   
1320  The company conducting an IND-exempt BA or BE study, including any contract research 
1321  organization, must notify FDA and all participating investigators of any SAE observed for the 
1322  test or reference drug during conduct of the study, regardless of whether the event is considered 
1323  drug-related, as soon as possible but in no case later than 15 calendar days after becoming aware 
1324  of its occurrence ( 320.31(d)(3)).  This includes, for example, SAEs listed in the reference listed 
1325  products approved labeling, the investigators brochure, and the protocol.    
1326   
1327  If any information necessary to evaluate the SAE is missing or unknown, the company 
1328  conducting the study should actively seek such information and maintain records of efforts to 
1329  obtain additional information.  Any relevant additional information obtained that pertains to a 
1330  previously submitted safety report must be submitted as a Follow-up 
1331  Bioavailability/Bioequivalence Safety Report as soon as the information is available ( 
1332  320.31(d)(3)) but should be submitted no later than 15 calendar days after the company receives 
1333  the information.  In addition, upon request from FDA, the company conducting the study must 
1334  submit to FDA any additional data or information that FDA deems necessary as soon as possible 
1335  but in no case later than 15 calendar days after receiving the request (e.g., hospital record, 
1336  autopsy report) ( 320.31(d)(3)).  Study drug exposure for the subject who experienced the SAE 
1337  should be unblinded. 
1338   
1339  If the adverse event is fatal or life-threatening, the company conducting the study must also 
1340  notify the Director in CDERs Office of Generic Drugs as soon as possible but in no case later 
1341  than 7 calendar days after becoming aware of its occurrence ( 320.31(d)(3)).  In doing so, the 
1342  company should also notify the appropriate review division in CDERs Office of New Drugs or 
1343  the Clinical Safety Surveillance Staff in CDERs Office of Generic Drugs. 
1344   
1345  The requirements under  320.31(d)(3) do not apply to human BA and BE studies that are 
1346  exempt from IND requirements and conducted outside the United States.  However, as part of 
1347  the information required to establish that the proposed drug product can be expected to have the 
1348  same therapeutic effect as the reference listed product, adverse event information from foreign 
1349  clinical studies must be included in the NDA supplement or the abbreviated new drug application 
1350  (ANDA) submission as appropriate, based on the purpose of the BA/BE study.29 
1351   
1352  B.  How and Where to Submit a Report ( 320.31(d)(3)) 
1353   
1354  For a BA/BE study conducted to support changes to an already approved NDA or abbreviated 
1355  new drug application (ANDA), SAE reports must be submitted to FDA and should be submitted 
1356  to the FDA Adverse Event Reporting System (FAERS). 
1357   
1358  For a BA/BE study conducted to support a new ANDA for a generic drug product, the entity 
1359  conducting or sponsoring the study should request a pre-assigned application number at  
 
29 See 21 CFR 314.50(d)(5)(iv) and 75 FR 59935 at 59954 (September 29, 2010) (interpreting 21 CFR 314.97(a)(7) 
to require adverse event reports that occurred in foreign clinical studies to be included in the ANDA submission). 
32  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1360  https://www.fda.gov/drugs/developmentapprovalprocess/formssubmissionrequirements/electroni
1361  csubmissions/ucm114027.htm.  FDA recommends requesting this application number prior to 
1362  starting the BA/BE study, to avoid delays in expedited reporting.  As stated on the website, it can 
1363  take up to 3 business days following the online request to receive the pre-assigned application 
1364  number. 
1365   
1366  The entity should use this application number for the following: 
1367   
1368  1.  Submission of all adverse event reports from BA/BE studies 
1369   
1370  2.  Submission of the ANDA for the test drug, when complete 
1371   
1372  FDA encourages electronic submission of BA/BE safety reports to FAERS.  FDA provides two 
1373  methods for electronically submitting safety reports from BA/BE studies conducted to support 
1374  the approval of generic drugs: 
1375   
1376  1.  FAERS Database-to-Database (E2B) Transmission 
1377   
1378    For more information about adverse event reporting via E2B submission, visit 
1379  https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/surveillanc
1380  e/adversedrugeffects/ucm115894.htm.  
1381   
1382  2.  HHS Safety Reporting Portal (SRP) submission, available at  
1383  https://www.safetyreporting.hhs.gov/SRP2/en/Home.aspx?sid=3e955502-ce7f-4112-
1384  b379-87967ae2e4be. 
1385   
1386    The portal requires entering the six-digit pre-application ANDA number for 
1387  submission of an adverse event report. 
1388   
1389  For fatal or life-threatening adverse events that require 7-day expedited reporting, notifications 
1390  generally submitted via E2B or SRP, FAERS will automatically route the submissions to the 
1391  appropriate group in the Office of Generic Drugs for review.  In situations when the E2B and 
1392  SRP routes of submission are unavailable, sponsors should submit expedited reports of SAEs 
1393  from BA/BE studies via email to OGD-PremarketSafetyReports@fda.hhs.gov.  
1394   
1395  SAE reports not submitted via E2B transmission or the SRP should be submitted to FDA via 
1396  email using Form FDA 3500A completed with all the available information, including a brief 
1397  narrative describing the SAE, an assessment of causality, and any other relevant information ( 
1398  320.31(d)(3)).  If applicable, the narrative should also include identification of other similar 
1399  reports and an analysis of the significance of the SAE.  A summary of the study protocol should 
1400  be submitted with the report. 
1401   
1402  Each report must prominently identify its contents ( 320.31(d)(3)).  Reports should be labeled 
1403  as follows: 
1404   
1405    Bioavailability/Bioequivalence Safety Report for 15-day reports 
33  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1406   
1407    Follow-up Bioavailability/Bioequivalence Safety Report for follow-up information 
1408   
1409    7-day Bioavailability/Bioequivalence Safety Report for unexpected fatal or life-
1410  threatening adverse reaction reports 
1411   
1412  Box G4 of Form FDA 3500A should include the pre-application ANDA number, and the Pre-
1413  ANDA box should be checked.  The type of report should be checked in box G6 on Form FDA 
1414  3500A.  The report can also be identified in box B5 and/or in a cover letter submitted with Form 
1415  FDA 3500A. 
1416   
1417  Each field in the C subsection of Form FDA 3500A should be completed appropriately.  For 
1418  example, in box C1, the study drug or drugs to which the subject was exposed prior to onset of 
1419  the SAE should be listed (this may include active drug, placebo, and/or vehicle depending on the 
1420  study).  In box C2, the subjects concomitant medications should be listed.  If the SAE began 
1421  prior to administration of a study drug but after study enrollment, this event should not be 
1422  submitted, because it is unassociated with study drug exposure.  In box B5, the timeline of drug 
1423  exposures as they relate to the SAE or SAEs should be clearly described.  
1424   
1425     
34  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1426  REFERENCES 
1427   
1428  For additional information on a systematic approach to safety surveillance, please refer to the 
1429  following: 
1430   
1431    Literature: 
1432   
1433  Council for International Organizations of Medical Sciences (CIOMS), Management of 
1434  Safety Information from Clinical Trials, Report of CIOMS Working Group VI, Geneva 2005, 
1435  ISBN 92 9036 079 8. 
1436   
1437  Crowe, BJ, HA Xia, JA Berlin, DJ Watson, H Shi, SL Lin, J Kuebler, RC Schriver, NC 
1438  Santanello, G Rochester, JB Porter, M Oster, DV Mehrotra, Z Li, EC King, ES Harpur, and 
1439  DB Hall, 2009, Recommendations for Safety Planning, Data Collection, Evaluation and 
1440  Reporting During Drug, Biologic and Vaccine Development: A Report of the Safety 
1441  Planning, Evaluation, and Reporting Team (SPERT), Clin Trials, 6(5):430440.  
1442   
1443  Xia, HA, BJ Crowe, RC Schriver, M Oster, and DB Hall, 2011, Planning and Core Analyses 
1444  for Periodic Aggregate Safety Data Reviews, Clin Trials, 8(2):175182.  
1445   
1446    Guidances for Industry: 
1447   
1448  Guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data 
1449  Monitoring Committees (March 2006)  
1450   
1451  Guidance for industry Premarketing Risk Assessment (March 2005) 
1452   
1453  For additional information on topics related to aggregate analysis, please refer to the following: 
1454   
1455    Literature: 
1456   
1457  Wittes, J, B Crowe, C Chuang-Stein, A Guettner, D Hall, Q Jiang, D Odenheimer,  HA Xia, 
1458  and J Kramer, 2015, The FDAs Final Rule on Expedited Safety Reporting: Statistical 
1459  Considerations, Stat Biophar Res, 7(3):174190.  
1460   
1461    Guidance for Industry: 
1462   
1463  Draft guidance for industry Meta-Analyses of Randomized Controlled Clinical Trials to 
1464  Evaluate the Safety of Human Drugs or Biological Products (November 2018) 
1465   
35  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1466  For additional information on submitting IND safety reports in electronic format, please refer to 
1467  the following: 
1468   
1469    Guidances for Industry: 
1470   
1471  Draft guidance for industry Providing Regulatory Submissions in Electronic Format:  IND 
1472  Safety Reports (October 2019)   
1473   
1474  Technical Conformance Guide Electronic Submission of IND Safety Reports (October 2019)  
1475 
36  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1476  APPENDIX A:  FLOWCHART FOR DETERMINING WHETHER AN ADVERSE 
1477  EVENT MEETS CRITERIA FOR IND SAFETY REPORTING TO FDA AND 
1478  INVESTIGATORS 
1479   
 
 
Refer to section III.D  of the    Is the AE serious (as assessed by either the  NO  Include the AE in an 
annual report (see 21 
guidance and 21 CFR 312.32(a) for    investigator or sponsor)? 
CFR 312.33) or an 
definition of serious 
information amendment 
to the IND (see 21 CFR 
YES 
312.33), as appropriate. 
Refer to section III.C of the guidance  Is the SAE unexpected (as assessed by the 
and 21 CFR 312.32(a) for definition  sponsor)? 
of unexpected 
YES  NO 
Is there a reasonable possibility that the drug  Does the expected SAE indicate a 
caused the SAE (as assessed by the sponsor)?  clinically important increase in the rate 
Examples of evidence suggesting a causal  of a serious suspected adverse reaction 
relationship between the drug and the SAE include:   over that listed in the protocol or 
  A single occurrence of an event that is  investigators brochure? 
uncommon and known to be strongly 
associated with drug exposure (i.e.,  YES  NO 
angioedema, hepatic injury, Stevens-
Refer to section III.B of 
the guidance and 21  Johnson Syndrome) 
CFR 312.32(a) for    One or more occurrences of an event that is 
definition of suspected  not commonly associated with drug  Include the SAE in an 
adverse reaction, and  exposure, but is otherwise uncommon in  annual report (see 21 
section III.B of the  the population exposed to the drug (i.e.,  CFR 312.33) or an 
guidance and 21 CFR  tendon rupture)  information 
312.32(c)(1)(i) for    An aggregate analysis of specific events  amendment to the IND 
examples of evidence  observed in a clinical trial (such as known  (see 21 CFR 312.33), 
which suggest a causal  as appropriate. 
consequences of the underlying disease or 
relationship between the 
condition under investigation or other 
drug and the SAE 
events that commonly occur in the study 
population independent of drug exposure) 
that indicates those events occur more 
frequently in the drug treatment group than 
in a concurrent or historical control group 
YES  NO 
Include the SAE in an 
annual report (see 21 
CFR 312.33) or an 
 
information amendment 
 
to the IND (see 21 CFR 
 
312.33), as appropriate. 
AE = adverse event, SAE = serious adverse event 
1480 
37  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1481  APPENDIX B:  FLOWCHARTS FOR SUBMITTING SAFETY REPORTING FOR CONTROL DRUGS 
1482   
1483  Chart B.1:  IND Sponsor is NOT the NDA or BLA Holder of the Control Drug 
1484   
1485   
1486     
 
38  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1487  APPENDIX B (continued): 
1488  Chart B.2:  IND Sponsor IS also the NDA or BLA Holder of the Control Drug 
1489   
1490   
 
39  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1491  APPENDIX C:  FLOWCHART FOR THE TWO APPROACHES TO AGGREGATE ANALYSES 
 
Refer to section IV.B of 
  Events Requiring Aggregate Analyses 
the guidance for events 
  Serious Adverse Events (SAEs) Anticipated to Occur 
requiring aggregate 
 
analyses and Section  in the Study Population 
  VI.B.1 for approach to    Expected Serious Suspected Adverse Reactions 
aggregate analyses 
U nblinding   Analyses of All 
Tr igger   Refer to section VI.A of the  Events by Treatment 
guidance for identifying  Is it possible to identify the events upfront and to 
Ap  proach  SAEs anticipated to occur  accurately predict rates for the events?  Group 
in the study population 
 
YES  NO 
 
Refer to section  Refer to section 
VI.B .1.a of the  VI.B.1.b of the 
guidance for  Calculate overall rate of event across treatment  Calculate rates of event by treatment group  guidance for 
 unblinding  groups  analyses of all 
trigger approach  events by 
 
treatment group 
YES 
 
Does the overall rate of the event across treatment 
  Is there a numerical imbalance in event rates 
groups substantially exceed the predicted rate (i.e., 
between/amongst treatment arms? 
  the unblinding trigger rate)?  
  NO  NO  YES  Refer to section 
Refer to section  IV.D of the 
 V.A of the  guidance for 
guidance for  Continue monitoring as described in the plan for  factors to 
  Is the reporting threshold met? 
planned periodic  safety surveillance   NO  consider in 
 review of  determining 
accumulating  when aggregate 
s afety data  YES  safety data 
meets reporting 
The entity conducting the unblinded safety 
criteria  
review should be firewalled from the staff 
conducting the trial and assessing efficacy 
1492   
 
40