Sponsor Responsibilities - Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies: Guidance for Industry

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

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Sponsor Responsibilities —
Safety Reporting Requirements
and Safety Assessment
for IND and
Bioavailability/Bioequivalence
Studies
Guidance for Industry
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)
December 2025
Drug Safety

Sponsor Responsibilities —
Safety 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., 4 th 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
Phone: 800-835-4709 or 240-402-8010
Email: industry.biologics@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)
December 2025
Drug Safety

Contains Nonbinding Recommendations
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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DEFINITIONS .................................................................................................................. 3
A. 	Adverse Event (§ 312.32(a)) .......................................................................................................... 3
B. 	Adverse Reaction and Suspected Adverse Reaction (§ 312.32(a)) ............................................. 4
C. 	Unexpected (§ 312.32(a)) ............................................................................................................... 5
D. 	Serious (§ 312.32(a))....................................................................................................................... 7
E. 	Life-Threatening (§ 312.32(a)) ...................................................................................................... 7
IV. 	OVERVIEW OF IND SAFETY REPORTING REQUIREMENTS ........................... 8
A. 	Serious and Unexpected Suspected Adverse Reaction (§ 312.32(c)(1)(i) and (c)(1)(iv)) .......... 9
1. Events That Do Not Require Aggregate Analyses ......................................................................... 11
2. Events That Require Aggregate Analyses ...................................................................................... 12
B. 	IND Safety Reporting Criteria for Aggregate Data .................................................................. 13
1. Serious and Unexpected Suspected Adverse Reactions (§ 312.32(c)(1)(i)(C)) ............................. 14
2. Increased Rate of Occurrence of Expected Serious Suspected Adverse Reactions
(§ 312.32(c)(1)(iv))............................................................................................................................. 14
C. 	Other Reporting Requirements .................................................................................................. 15
1. Findings From Other Sources (§ 312.32(c)(1)(ii) and (iii)) .......................................................... 15
2. IND Safety Reports for Study Endpoints (§ 312.32(c)(5)) ............................................................. 16
V. 	SYSTEMATIC APPROACH FOR REVIEW OF SAFETY INFORMATION
(§ 312.32(b)) ................................................................................................................................. 16
A. 	Prospective Development of a Plan for Safety Surveillance..................................................... 17
VI. 	CONSIDERATIONS FOR AGGREGATE DATA ANALYSES FOR IND SAFETY
REPORTING .............................................................................................................................. 19
A. 	Identify Serious Adverse Events Anticipated to Occur in the Study Population ................... 20
B. 	Entities That Review Aggregate Data for IND Safety Reporting ............................................ 20
1. Features and Composition of the Entity ........................................................................................ 20
2. Identifying the Entities That Review Safety Information ............................................................... 21
C. Aggregate Analyses of Safety Data ............................................................................................... 21
1. Approach to Aggregate Analyses ................................................................................................... 21
2. Considerations for Small Programs/Rare Diseases ...................................................................... 24
3. Considerations When Evaluating Aggregate Data Across a Development Program .................... 24
4. Updating Safety Information.......................................................................................................... 25
D. 	Maintaining Trial Integrity When Reviewing Aggregate Data ............................................... 26
VII. 	OTHER SAFETY REPORTING ISSUES ................................................................... 26

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A. 	Alternative Reporting Arrangements (§ 312.32(c)(3)).............................................................. 26
B. 	Importance of Standardized Coding .......................................................................................... 27
C. 	Investigations of Marketed Drugs (§ 312.32(c)(4)) ................................................................... 27
D. 	Duration of Safety Reporting ..................................................................................................... 28
VIII. 	SUBMITTING AN IND SAFETY REPORT (§ 312.32(c)(1)(v))................................ 28
A. 	Method of Submission for IND Safety Reports to FAERS ...................................................... 29
B. 	Method of Submission for IND Safety Reports in eCTD Format ........................................... 30
C. 	INDs That Are Exempted From Electronic Submission Requirements ................................. 30
1. Alternate Electronic Format .......................................................................................................... 31
2. Other Means of Rapid Communication ......................................................................................... 31
D. 	Submitting IND Safety Reports Based on Aggregate Analyses ............................................... 32
E. 	Reporting Time Frame ................................................................................................................ 33
IX. 	FOLLOW-UP INFORMATION (§ 312.32(d))............................................................. 34
X. 	SAFETY REPORTING REQUIREMENTS FOR BA AND BE STUDIES ............. 35
A. 	BA/BE Study Safety Reporting Requirements (§ 320.31(d)(3))............................................... 36
B. 	How and Where to Submit a Report (§ 320.31(d)(3)) ............................................................... 37
APPENDIX: FLOWCHART FOR DETERMINING WHETHER AN ADVERSE EVENT
MEETS THE CRITERIA FOR IND SAFETY REPORTING TO FDA AND
INVESTIGATORS ....................................................................................................................... 1

Contains Nonbinding Recommendations
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Sponsor Responsibilities — Safety Reporting Requirements and
Safety Assessment for IND and Bioavailability/Bioequivalence
Studies
Guidance for Industry1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
I. 	INTRODUCTION
This guidance provides recommendations to help sponsors comply with the expedited safety
reporting requirements for human drug and biological products2 that are being investigated
(1) under an investigational new drug application (IND) (21 CFR 312.32); or (2) as part of a
bioavailability (BA) or bioequivalence (BE) study that is exempt from the IND requirements
(21 CFR 320.31(d)(3)).
This guidance provides interpretations of terms used for safety reporting, makes
recommendations on when and how to submit a safety report, and provides information on other
safety reporting issues raised by sponsors.
To facilitate appropriate IND safety reporting practices, this guidance also provides
recommendations related to the two IND safety reporting provisions (§ 312.32(c)(1)(i)(C) and
(c)(1)(iv)) that require assessment of aggregate data.
This guidance finalizes the draft guidance of the same title issued in June 2021 (the June 2021
draft guidance), which incorporated content from the final guidance for industry and
investigators Safety Reporting Requirements for INDs and BA/BE Studies (December 2012) (the
2012 final guidance) and from the draft guidance for industry Safety Assessment for IND Safety
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. In this guidance, drug or drug product is used to
refer to human drugs and to human biological products that are regulated under section 351 of the Public Health
Service Act.

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Reporting (December 2015) (the 2015 draft guidance).3 This guidance includes revised
recommendations initially described in the 2015 draft guidance and June 2021 draft guidance on
the following topics: (1) planned unblinding of safety data and implications for trial integrity
(see section VI); (2) increased flexibility regarding the party reviewing aggregate safety
information for IND safety reporting purposes (see section VI.B); (3) clarification regarding the
scope and methodology of aggregate analyses (see section VI.C); and (4) clarification regarding
the plan for safety surveillance, including what elements should be included in the plan (see
section V.A).
With respect to the content from the 2012 final guidance that was incorporated into this
guidance, a considerable amount remains unchanged. However, this guidance includes updated
recommendations on submissions of IND safety reports and replaces the 2012 final guidance in
terms of sponsors’ responsibilities for safety reporting requirements for INDs and BA/BE
studies. This guidance does not incorporate content on investigator reporting (§ 312.64(b)) from
the 2012 final guidance. Concurrent with the publication of this guidance, FDA issued the
guidance for investigators, industry, and institutional review boards Investigator Responsibilities
— Safety Reporting for Investigational Drugs and Devices (December 2025) on investigator
responsibilities for adverse event reporting that replaces the corresponding recommendations for
investigators in the 2012 final guidance. Accordingly, the 2012 final guidance was withdrawn
upon the publication of these two guidances.
This guidance addresses reporting of serious adverse events (SAEs) in the setting of a clinical
investigation conducted under an IND. Drugs used in such clinical investigations may be
unapproved drugs or those that are already marketed or approved in the United States. For drugs
already marketed or approved, additional reporting requirements for safety information from
clinical studies are specified by the relevant postmarketing safety reporting requirements (e.g.,
under 21 CFR 314.80, 329.100, 600.80, or 606.170; see also § 312.32(c)(4)). This guidance does
not address those obligations.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.
II. 	BACKGROUND
On September 29, 2010, FDA published a final rule (75 FR 59935) amending the IND safety
reporting requirements under 21 CFR 312.32 and adding safety reporting requirements for
persons conducting IND-exempt BA and BE studies under § 320.31. The IND safety reporting
regulations distinguish between circumstances in which it is appropriate to submit IND safety
3 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. The 2015 draft guidance was
withdrawn upon the publication of the June 2021 draft guidance.

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reports based on individual cases (§ 312.32(c)(1)(i)(A) and (B)) and circumstances in which an
IND safety report would need to be based on an aggregate analysis of SAEs to determine
whether the events occur more frequently in the drug treatment group (§ 312.32(c)(1)(i)(C)).
Compliance with these requirements increases the likelihood that submitted information will be
interpretable and will meaningfully contribute to the developing safety profile of the
investigational drug and improve the overall quality of safety reporting.
Timely reporting of the required safety information allows FDA to consider whether any changes
in study conduct should be made beyond those initiated by the sponsor and allows investigators
to make any changes that are needed to protect participants.4 An effective systematic approach
by sponsors to safety surveillance, coupled with limiting the scope of IND safety reports to FDA
and participating investigators (and subsequent reporting to involved institutional review boards)
to suspected adverse reactions that are both serious and unexpected, allows all parties to
focus on important safety issues and take actions needed to minimize the risks of participation in
a clinical trial.5
The 2010 final rule also requires sponsors to report findings from other studies
(§ 312.32(c)(1)(ii)) and findings from animal6 or in vitro testing (§ 312.32(c)(1)(iii)) that suggest
a significant risk to humans exposed to the drug and to report an increased occurrence of serious
suspected adverse reactions over those listed in the protocol or investigator brochure
(§ 312.32(c)(1)(iv)).
III. 	DEFINITIONS
A. 	Adverse Event (§ 312.32(a))
Adverse event means “any untoward medical occurrence associated with the use of a drug in
humans, whether or not considered drug related” (§ 312.32(a)).
FDA considers an adverse event (also referred to as an adverse experience) to include any
unfavorable sign (e.g., an abnormal laboratory finding), symptom, or clinical outcome
temporally associated with the use of an investigational drug, an active control, or a placebo,
regardless of whether the event is thought to be related to the drug. An adverse event can arise
during any use of a drug (e.g., use for a purpose other than the FDA-approved indication or in
combination with another drug) and with any route of administration, formulation, or dose,
including an overdose.
4 FDA’s regulations under 21 CFR parts 312 and 320 use the terms subject or human subject; however, in this
guidance, we use the term participant except when directly quoting the regulations.
5 In most cases, such events will lead to an update to the investigator brochure and/or informed consent.
6 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.

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B. 	Adverse Reaction7 and Suspected Adverse Reaction (§ 312.32(a))
Adverse reaction means any adverse event caused by a drug.
Suspected adverse reaction means —
any adverse event for which there is a reasonable possibility that the drug caused the
adverse event. For the purposes of IND safety reporting, “reasonable possibility”
means there is evidence to suggest a causal relationship between the drug and the
adverse event. Suspected adverse reaction implies a lesser degree of certainty about
causality than adverse reaction[.] (§ 312.32(a)) (emphasis added)
Both an adverse reaction and a suspected adverse reaction require evidence of a causal
relationship between the drug and the adverse event. Therefore, if no drug has been
administered, an adverse event is not reportable under IND safety reporting regulations.8
The following examples are also provided in the IND safety reporting regulation
(§ 312.32(c)(1)(i)) and illustrate the meaning of reasonable possibility with respect to a
determination that there may be a causal relationship between the drug and the adverse event:
• 	A single occurrence of an event that is uncommon and known to be strongly associated
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome).
• 	One or more occurrences of an event that is not commonly associated with drug exposure
but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture).
• 	An aggregate analysis of specific events observed in a clinical trial that indicates those
events occur more frequently in the drug treatment group than in a concurrent or
historical control group. Examples of such events are known consequences of the
underlying disease or condition or events that commonly occur in the study population
independent of drug therapy.
7 For the purposes of prescription drug labeling that complies with the content and format requirements of 21 CFR
201.56(d) and 201.57 (established by what is commonly referred to as the Physician Labeling Rule (71 FR 3922,
January 24, 2006)), 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 § 201.57(c)(7)). For the purposes of prescription drug labeling that complies with the
content and format requirements of §§ 201.56(e) and 201.80, the term adverse reaction is defined to mean “an
undesirable effect, reasonably associated with the use of the drug, that may occur as part of the pharmacological
action of the drug or may be unpredictable in its occurrence” (see § 201.80(g)).
8 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 drug is not administered.

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For aggregate analysis under § 312.32(c)(1)(i)(C), such events could also be associated with
treatment or therapy that is standard of care for the disease or condition.
To determine whether an adverse event should be classified as a suspected adverse reaction, or as
an adverse reaction, the sponsor must promptly evaluate the available evidence (§ 312.32(b)) and
make a judgment about the likelihood that the drug caused the adverse event. For an adverse
event to be considered a suspected adverse reaction, the sponsor should conclude that there is a
reasonable possibility that the drug caused the adverse event. FDA considers the application of
the reasonable possibility causality standard to be consistent with the discussion about causality
in the International Council for Harmonisation (ICH) guidance for industry E2A Clinical Safety
Data Management: Definitions and Standards for Expedited Reporting (March 1995) (the ICH
E2A guidance). However, FDA notes there is a difference between the IND safety reporting
regulation under § 312.32 and the ICH E2A guidance with respect to who is responsible for
making a judgment about whether there is evidence to suggest a causal relationship between the
drug and the adverse event for reporting purposes. Although the ICH E2A guidance9
recommends reporting the adverse event as a suspected adverse reaction if either the investigator
or the sponsor makes a judgment that there is a reasonable suspected causal relationship, under
§ 312.32, the sponsor is responsible for making this judgment.
C. 	Unexpected (§ 312.32(a))
An adverse event or suspected adverse reaction is considered unexpected if (1) it is not listed in
the investigator brochure10 or it is not listed at the specificity or severity that has been observed
in the study population; or (2) if the investigator brochure is not required or available, it is not
consistent with the risk information described in the general investigational plan. For example, if
the listed term in the investigator brochure is erythema, a reported event of Stevens-Johnson
Syndrome is both more specific and more severe than the term in the investigator brochure and
would therefore be considered unexpected. In addition, if the event occurs at a rate that is
meaningfully higher than listed in the investigator brochure,11 that rate would be considered to
make the event more specific or severe than that listed in the investigator brochure, and it would
also be considered unexpected. Events must be listed in the investigator brochure, when one is
required, if they have been observed with the particular drug under investigation and a causal
relationship with the drug is suspected or confirmed (see §§ 312.23(a)(5) and 312.55).12
9 See the ICH E2A guidance, pages 6–7.
10 For an FDA-approved drug, an unexpected adverse event would include adverse events not listed in the FDA-
approved labeling.
11 Not all adverse events listed in an investigator brochure will have incidence estimates. To the extent that
incidence estimates of adverse events are provided early in a development program, they may be an overestimation
based on small numbers.
12 The investigator 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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When new adverse event information is received, it is the sponsor’s responsibility to determine
whether the event is unexpected for IND safety reporting purposes.
For example, under this definition of unexpected, if the investigator brochure referred only to
elevated hepatic enzymes or hepatitis, an event of hepatic necrosis would be unexpected (by
virtue of greater severity). Similarly, intracerebral hemorrhage and cerebral vasculitis would be
unexpected (by virtue of greater specificity) if the investigator brochure only listed cerebral
vascular accidents. Unexpected also refers to adverse events or suspected adverse reactions that
are mentioned in the investigator brochure as occurring with a class of drugs or as predicted to
occur from the pharmacological properties of the drug but are not specifically mentioned as
occurring with the particular drug under investigation. For example, although angioedema is
known to occur in some individuals exposed to drugs in the angiotensin-converting enzyme
(ACE) inhibitor class and therefore would be described in the investigator brochure as a class
effect, a case of angioedema observed with the drug under investigation should be considered
unexpected for reporting purposes until angioedema is included in the investigator brochure as
occurring with the drug under investigation. Likewise, safety-related findings from animal
studies that have not been observed with the drug under investigation in humans would also be
considered unexpected until such an event occurs in humans and is listed in the investigator
brochure as an adverse or suspected adverse reaction.
There has been some confusion about the terms expected and anticipated as used for the
purposes of IND safety reporting. The terms have distinct meanings:
• 	Expected refers to adverse or suspected adverse reactions to the drug that are listed in the
investigator brochure or, if an investigator brochure is not required or available, that are
consistent with the risk information described in the general investigational plan. Events
that are listed in the investigator brochure are considered expected because they have
been observed with the particular drug under investigation and a causal relationship with
the drug is suspected or confirmed.
• 	Anticipated refers to adverse events that are likely to occur in the study population
because the adverse events (1) reflect consequences of participants’ underlying disease or
factors such as age and (2) are events that may occur in the study population unrelated to
an effect of a drug (e.g., cancer-related deaths in a cancer trial, strokes or acute
myocardial infarctions in an older population).
The term expected has been incorrectly used to describe adverse events that are anticipated in
individuals with the disease being treated or population being studied but are not listed in the
investigator brochure as adverse or suspected adverse reactions. For reporting purposes, events
that are anticipated for the disease being treated or the population being studied would be
considered unexpected if the events are not listed in the investigator brochure (i.e., the
investigational drug is not suspected or known to cause the events).
To summarize, an adverse event that is anticipated in the population being studied refers to an
event that would be seen in this population independent of investigational drug exposure. An
expected adverse or suspected adverse reaction refers to an adverse event that is known or

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suspected to be caused by the investigational drug and is listed in the description of the adverse
or suspected adverse drug reactions in the investigator brochure or, if an investigator brochure is
not required or available, as consistent with the risk information described in the general
investigational plan.
D. 	Serious (§ 312.32(a))
An adverse event, adverse reaction, or suspected adverse reaction is considered serious —
if, in the view of either the investigator or sponsor, it results in any of the following
outcomes: Death, a life-threatening adverse event, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant incapacity or
substantial disruption of the ability to conduct normal life functions, or a congenital
anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon
appropriate medical judgment, they may jeopardize the patient or subject and may require
medical or surgical intervention to prevent one of the outcomes listed in this definition.
Examples of such medical events include allergic bronchospasm requiring intensive
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not
result in inpatient hospitalization, or the development of drug dependency or drug abuse.
(§ 312.32(a))
The sponsor and the investigator must evaluate whether an event meets the definition of serious
(see §§ 312.32(a), 312.32(c)(1)(i), and 312.64(b)). Because identifying SAEs is critically
important for the evaluation of potential significant safety problems, it is important that the
sponsor consider the investigator’s assessment. Therefore, if the sponsor or investigator believes
that the event is serious, the event must be considered serious and must be evaluated by the
sponsor for expedited reporting (§ 312.32(a) and (c)(1)).
E. 	Life-Threatening (§ 312.32(a))
An adverse event or suspected adverse reaction is considered life-threatening —
if, in the view of either the investigator or sponsor, its occurrence places the patient or
subject at immediate risk of death. It does not include an adverse event or suspected
adverse reaction that, had it occurred in a more severe form, might have caused death.
(§ 312.32(a))
For example, not all seizures are considered life-threatening, although the most severe form,
status epilepticus, is a life-threatening medical emergency.
As with the definition of serious, the determination of whether an adverse event is life-
threatening can be based on the opinion of either the investigator or sponsor. Thus, if either
believes that the adverse event meets the definition of life-threatening, it must be considered life-
threatening for reporting purposes (§ 312.32(a)).

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IV. 	OVERVIEW OF IND SAFETY REPORTING REQUIREMENTS
Under § 312.32(c), the sponsor is required to notify FDA and all participating investigators
through an IND safety report of potential serious risks from clinical trials or any other source as
soon as possible but no later than 15 calendar days after the sponsor determines that the
information qualifies for reporting in an IND safety report. Participating investigators include all
investigators, at U.S. and non-U.S. sites, to whom the sponsor is providing the drug under any of
its INDs or under any investigator’s IND (§ 312.32(c)(1)).13 For unexpected fatal or life-
threatening suspected adverse reaction reports, the sponsor must notify FDA as soon as possible
but in no case later than 7 calendar days after the sponsor’s initial receipt of the information (§
312.32(c)(2)). (See the Appendix for a flowchart to help determine whether an adverse event
meets the criteria for IND safety reporting to FDA. See section VIII.E of this guidance for a
discussion of IND safety reporting time frames.)
In each IND safety report, the sponsor must identify all IND safety reports previously submitted
to FDA concerning a similar suspected adverse reaction and must analyze the significance of the
suspected adverse reaction in light of previous, similar reports or any other relevant information
known to the sponsor (i.e., conduct an analysis of similar events including, for example, similar
IND safety reports from all INDs for the same drug held by the sponsor and related reports or
adverse events available from pre- and postmarketing studies) (see § 312.32(c)(1)). For
example, if the sponsor plans to submit an IND safety report for pulmonary embolus, the sponsor
should look to see if IND safety reports were previously submitted for other thrombotic events
(e.g., deep vein thrombosis) to analyze the occurrence of medically related adverse events.
Similarly, for an IND safety report for fracture, the sponsor should consider whether IND safety
reports previously submitted for falls are relevant to the analysis of the significance of the event.
Sponsor-investigators, as defined in § 312.3(b), are required to comply with both the sponsor and
the investigator responsibilities under 21 CFR part 312. FDA recognizes that a sponsor-
investigator may need to rely on the investigational drug supplier for updated safety information
in order to meet their obligations under the IND safety reporting regulations (see § 312.32(b)).
To protect participants, FDA recommends that entities that provide a drug to or receive a drug
from other entities share safety information with each other.
13 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 participant safety.

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A. 	Serious and Unexpected Suspected Adverse Reaction (§ 312.32(c)(1)(i) and
(c)(1)(iv)14)
The sponsor must report in an IND safety report any suspected adverse reaction to the study
treatment that is both serious and unexpected (§ 312.32(c)(1)(i)).15 Before submitting an IND
safety report, the sponsor needs to ensure that the event meets three criteria: (1) it is serious; (2)
it is unexpected (i.e., is not listed in the investigator brochure or is not listed at the specificity or
severity that has been observed) or, if an investigator brochure is not required or available, is not
consistent with the risk information described in the general investigational plan; and (3) there is
evidence to suggest a causal relationship between the drug and the adverse event (i.e., it is a
suspected adverse reaction). If the adverse event does not meet all three criteria, it should
not be submitted as an IND safety report.16
Deciding whether the SAE meets the definition of a suspected adverse reaction is usually the
most difficult determination, but this decision is critical to avoiding the submission of
uninformative IND safety reports. Once the adverse event is determined to be serious and
unexpected, the sponsor must evaluate the available information and decide whether there is a
reasonable possibility that the drug caused the adverse event and, therefore, that the event also
meets the definition of a suspected adverse reaction (§ 312.32(c)(1)(i)). Serious and unexpected
suspected adverse reactions must be reported in an IND safety report (§ 312.32(c)(1)(i)).
Under § 312.64(b), investigators are required to provide a causality assessment for each SAE
reported to the sponsor. The sponsor should consider the investigator’s assessment but must
submit an IND safety report only for those events for which the sponsor determines there is a
reasonable possibility that the drug caused the event (§ 312.32(c)(1)(i)). Thus:
• 	The sponsor should not report events for which the investigator’s assessment is positive
for causality but the sponsor’s evaluation did not find evidence to suggest a causal
relationship between the drug and the event.
14 FDA considers a clinically important increase in the rate of occurrence of expected serious suspected adverse
reactions over that listed in the protocol or investigator brochure to be unexpected. In this guidance, “expected
serious suspected adverse reactions” refer to serious suspected adverse reactions listed in the investigator brochure
or, if an investigator brochure is not required or available, that are consistent with the risk information described in
the general investigational plan.
15 For study treatments that are marketed or approved in the United States, postmarketing safety reporting
requirements (§§ 314.80 and 600.80) apply to the application holder. As a result, unless the IND sponsor and
application holder are the same, or the application 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. FDA also recommends that if the sponsor is not the application holder, the sponsor
should also forward the report to the application holder of the marketed drug.
16 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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• 	The sponsor must report events for which the investigator’s assessment is negative for
causality but the sponsor’s evaluation found evidence to suggest a causal relationship
between the drug and the event (§ 312.32(c)(1)(i)).
The investigator’s assessment of causality must be included in the report submitted to the
sponsor (see § 312.64(b)). If the investigator fails to provide a causality assessment or assesses
the causality as unknown, the sponsor will need to evaluate the event without the investigator’s
assessment (see § 312.32(b) and (c)).
Serious and unexpected suspected adverse reactions reported in an IND safety report can be
divided into four categories depending on the type of event. As discussed below in sections
IV.A.1.a and b, the first two categories (§ 312.32(c)(1)(i)(A) and (B)) can generally be assessed
on the basis of an individual or a small number of events. Aggregate analyses are needed for
(1) anticipated SAEs for which it is difficult or impossible to make a causal determination based
on a single case or a small number of cases (see § 312.32(c)(1)(i)(C)); or (2) expected serious
suspected adverse reactions that must be reported if there is a clinically important increase in the
rate over that described in the protocol or investigator brochure (§ 312.32(c)(1)(iv)). For the first
of the two situations, an aggregate analysis comparing the rate of such SAEs in the intervention
arm compared to a control is needed. For the second of the two situations, an aggregate analysis
is needed to determine the rate in the investigational arm compared to the known rate from the
investigator brochure or labeling.
If the study under an IND uses a control drug that is approved or marketed in the United States,
serious and unexpected adverse events in the control group that can be assessed as suspected
adverse reactions based on an individual or small number of events must be reported by the IND
sponsor in a safety report as individual events as described in § 312.32(c)(1)(i)(A) and (B). If
the sponsor is not the application holder17 of the control drug, the sponsor should also forward
the report to the application holder. If the sponsor is also the application holder for the control
drug, the serious and unexpected suspected adverse reaction must also be submitted as required
under postmarketing regulations. See § 312.32(c)(4); see also §§ 310.305, 314.80, and 600.80.
An aggregate analysis to determine whether there is an increase in anticipated SAEs in the group
receiving the investigational drug (that would need to be reported under § 312.32(c)(1)(i)(C))
may demonstrate that the rate of the anticipated adverse event is higher in the control arm than in
the investigational drug arm. This is not likely to be a frequent occurrence, and FDA recognizes
that additional context may be needed to interpret such aggregate analysis results if the sponsor
is not the application holder for the control drug (e.g., if the aggregate event rate is higher in the
active control group than in the investigational drug group, it could be that the investigational
drug is protective rather than that the control drug is causing an increased rate of the adverse
event). For an imbalance suggesting a substantially higher rate of an anticipated SAE in the
control group not explained by a protective effect of the investigational drug, FDA recommends
17 We note that the postmarketing reporting requirements concerning the submission of postmarketing 15-day Alert
reports (§ 314.80(c)(1)(i) and (ii)) apply not only to the application 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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that the sponsor report such an imbalance to the application holder, who is in a better position to
assess the event and determine if reporting is necessary. If the sponsor does not share it with the
application holder, then it should be reported to FDA. FDA acknowledges that a small number
of events in a single trial may not inform the known safety profile of a well-characterized
approved control drug; thus the reporting threshold (i.e., the threshold at which the sponsor
determines that there is a reasonable possibility that the drug caused the anticipated SAE) for a
well-characterized approved control drug could be higher than for the investigational drug. The
sponsor should also consider sharing with the application holder the events that suggest a higher
rate in the active control group even if the events do not rise to the level of IND safety reporting.
1. 	Events That Do Not Require Aggregate Analyses
a. 	Individual occurrences (§ 312.32(c)(1)(i)(A))
Certain SAEs are informative as single cases because they are “uncommon and known to be
strongly associated with drug exposure” (§ 312.32(c)(1)(i)(A)). Some examples include
angioedema, certain blood dyscrasias (e.g., agranulocytosis), rhabdomyolysis, hepatic injury,
anaphylaxis, and Stevens-Johnson Syndrome. The occurrence of even one case of such an SAE,
where another cause has not been established, would meet the definition of suspected adverse
reaction (i.e., there is a reasonable possibility that the drug caused the event) and therefore must
be reported in an IND safety report (§ 312.32(c)(1)(i)(A)).
The blind should ordinarily be broken for these types of IND safety reports that are submitted to
FDA and all participating investigators. Knowledge of the treatment received is necessary to
interpret the event and determine whether it is a suspected adverse reaction. Further, such
knowledge may be essential for the medical management of the participant and may provide
critical safety information about a drug that could have implications for the ongoing conduct of
the trial (e.g., monitoring, informed consent). Because these cases are expected to occur
infrequently, FDA does not anticipate that unblinding single or small numbers of serious and
unexpected adverse event cases will compromise trial integrity. For example, a single case of
liver injury would be unblinded but would have no effect on overall study integrity. Moreover,
when a study participant experiences this type of SAE that is individually reportable, it is
unlikely that the participant will continue receiving the drug treatment. The challenges arising
from unblinding safety data for aggregate data analyses are discussed in sections VI.B through D
of this guidance.
If the blind is broken and a participant with an adverse event that would meet the criteria for
reporting as a single event was receiving a placebo, the event should not be reported in an IND
safety report. If the blind is broken and the participant was receiving drug treatment
(investigational drug or active comparator), it must be reported in an IND safety report
(§ 312.32(c)(1)(i)(A)).
b. 	One or more occurrences (§ 312.32(c)(1)(i)(B))
One or more occurrences of an SAE “that is not commonly associated with drug exposure but is
otherwise uncommon in the population exposed to the drug” meets the definition of a suspected

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adverse reaction and therefore must be reported in an IND safety report (§ 312.32(c)(1)(i)(B)). If
the event occurs in association with other factors strongly suggesting causation (e.g., strong
temporal association, event recurs on rechallenge), a single case may be sufficiently persuasive
to report in an IND safety report. Often, more than one occurrence from one or multiple studies
would be needed before the sponsor could determine that there is a reasonable possibility that
the drug caused the event. Examples include tendon rupture or heart valve lesions in young
adults or intussusception in healthy infants. For reasons similar to those given above in section
IV.A.1.a regarding individual occurrences, such events should be unblinded.
2. 	Events That Require Aggregate Analyses
a. 	Events anticipated to occur in the study population, independent of drug
exposure (§ 312.32(c)(1)(i)(C))
Certain SAEs can be anticipated to occur in the study population independent of investigational
drug exposure. Such events include:
• 	Events common in the study population, such as:
- 	Events related to the underlying disease or condition under investigation (e.g., death
due to progressive disease in an oncology trial, pneumonia in participants with
chronic obstructive lung disease, diabetic ketoacidosis in a trial of type 1 diabetes
management, hospitalization for gait disturbance reported in a multiple sclerosis trial)
- 	Events that are common in a population regardless of the underlying condition being
studied (e.g., cardiovascular events or hip fracture in an older adult population)
• 	Events known to occur with drugs administered as part of a background regimen (e.g.,
neutropenia with a myelosuppressive chemotherapeutic agent, intracerebral hemorrhage
with an anticoagulant, cytomegalovirus colitis with an immunosuppressive regimen)
Although these anticipated SAEs would meet the definition of unexpected in § 312.32(a) if they
are not listed in the investigator brochure (see section III.C of this guidance), they do not warrant
expedited IND safety reporting as individual cases or even when there are a number of such
events where the incidence is consistent with background rates in the study population. Such
anticipated SAEs will occur even if the investigational drug does not cause them, and their
occurrence alone will generally not support a conclusion that there is a reasonable possibility that
the drug caused the events. To assess whether the drug could have caused or contributed to the
SAE that is anticipated in the population, the sponsor should perform an aggregate analysis that
will enable an assessment of whether there is a greater occurrence of the anticipated adverse
event in a population exposed to the drug as compared to the rate of the same SAE in a similar
population not exposed. (See section VI of this guidance for details on conducting an aggregate
analysis.)
An anticipated SAE must be reported to FDA in an IND safety report if an aggregate analysis
reveals there is an imbalance between study arms that is sufficient to conclude that there is a

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reasonable possibility that the drug caused the increased incidence of the SAE
(§ 312.32(c)(1)(i)(C)). The sponsor should consider all relevant drug development data (in
addition to the clinical trial data) when determining whether there is a reasonable possibility that
the drug caused the SAE. (See section IV.B.1 of this guidance for factors to consider when
interpreting imbalances in aggregate data and section V of this guidance for a list of sources of
safety information that must be evaluated.)
b. 	Increased occurrence of an expected serious suspected adverse reaction
(§ 312.32(c)(1)(iv))
The sponsor must report any clinically important increase in the rate of an expected serious
suspected adverse reaction over that listed in the protocol or investigator brochure or that is
otherwise evident from the risk information described in the general investigational plan
(§ 312.32(c)(1)(iv)). The sponsor should perform an aggregate analysis to compare the rate of a
serious suspected adverse reaction seen in the study to the rate listed in the protocol or
investigator brochure or otherwise estimated.
The sponsor’s determination of whether the increase in the rate of an expected serious suspected
adverse reaction is clinically important and is thus required to be reported under
§ 312.32(c)(1)(iv) is a matter of judgment based on a variety of factors, including the study
population, the nature and seriousness of the reaction, and the magnitude of the observed
increase in the incidence rate. Monitoring the rate of these events in a blinded trial requires a
systematic safety surveillance process that will protect the integrity of the trial; this is discussed
in section VI of this guidance.
B. 	IND Safety Reporting Criteria for Aggregate Data
Determining when the aggregate safety data provide evidence suggesting (1) a causal
relationship between the drug and an SAE (e.g., myocardial ischemia) or (2) that there has been a
clinically important increase in the rate of an expected serious suspected adverse reaction (i.e.,
determining whether the reporting threshold has been met) is a complex judgment. It is almost
never a simple application of a planned statistical analysis, and the determination may change as
data accumulate. FDA recognizes that these determinations can be difficult and require
judgment. It may be helpful for sponsors to document in internal records all aggregate analyses
of SAEs, including those that are determined not to meet the reporting threshold. In the event of
a disagreement regarding a causality assessment between the sponsor and an entity designated to
evaluate aggregate safety data, detailed documentation of the justification for submitting or not
submitting an IND safety report is recommended. Documentation of such justification and of the
aggregate analysis is important because FDA will focus primarily on the robustness of the
sponsor’s process and the reasoning underlying the sponsor’s decision if, during FDA’s review
of trial safety data, FDA reaches a different conclusion about whether an IND safety report was
warranted. The sponsor may also prespecify reporting thresholds in its safety surveillance plan
that, if exceeded, would lead to submission of an IND safety report.

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1. 	Serious and Unexpected Suspected Adverse Reactions (§ 312.32(c)(1)(i)(C))
As noted previously, for the purposes of IND safety reporting, a suspected adverse reaction
means there is a reasonable possibility that the drug caused the event (i.e., evidence to suggest a
causal relationship between the drug and the adverse event) (§ 312.32(a)). When interpreting
imbalances in aggregate data between study arms, both clinical and statistical (if applicable)
expertise will usually be needed to determine whether that reasonable possibility exists, based on
the totality of available information.
Factors to consider when determining whether the reasonable possibility threshold has been met:
• 	Extent of the increase in incidence seen in the test group compared to the control group(s)
and the uncertainty around that difference
• 	Evidence of a dose response
• 	Temporal relationship (for example, early increase post-drug initiation, such as drug-
induced liver injury occurring in the usual 1- to 6-month window, or malignancy events
occurring after a lag period between the dates of exposure and date of event onset)
• 	Consistency of the increase in multiple trials
• 	Presence of a plausible mechanism of action
• 	Nonclinical evidence (from toxicology or pharmacology animal studies, genetic studies
such as knock-out or knock-in mouse models, or human genetic data) to support the
finding
• 	Pharmacology of the drug (including results from receptor, transporter, or enzyme
binding or activation studies, and animal models) and known class effects
• 	Pattern across the study population (for example, the event is observed more frequently in
individuals likely to be susceptible to it (e.g., acute kidney injury in individuals with prior
chronic kidney disease, myocardial infarctions in older individuals or those with existing
coronary heart disease, hyperkalemia in individuals on ACE inhibitors))
• 	Occurrence of other potentially related adverse events (for example, occurrence of both
strokes and transient ischemic attacks, unexpectedly large increase in creatine kinase and
events of rhabdomyolysis)
2. 	Increased Rate of Occurrence of Expected Serious Suspected Adverse Reactions
(§ 312.32(c)(1)(iv))
For previously recognized serious suspected adverse reactions, clinical judgment is needed to
determine whether a suspected adverse reaction to the investigational drug is occurring at a
clinically important increased rate relative to the rate provided in the investigator brochure or

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otherwise estimated based on data or analysis in the investigator brochure. Factors to consider
when making the judgment may include (1) the magnitude of the increase in rate of occurrence
for the investigational drug treatment group over the rate listed in the investigator brochure or
elsewhere in the current IND application, or otherwise estimated, and (2) the consistency of the
increase over time and across multiple trials, if applicable.
C. 	Other Reporting Requirements
1. 	Findings From Other Sources (§ 312.32(c)(1)(ii) and (iii))
The sponsor must also report any findings from clinical, epidemiological, or pooled analyses of
multiple studies and any findings from animal or in vitro testing that suggest a significant risk in
humans exposed to the drug, regardless of whether they are conducted under the IND or by the
sponsor (§ 312.32(c)(1)(ii) and (iii)). A finding that suggests a significant risk would “ordinarily
. . . result in a safety-related change in the protocol, informed consent, investigator brochure
(excluding routine updates of these documents), or other aspects of the overall conduct of the
clinical investigation” (§ 312.32(c)(1)(ii) and (iii)). For example, actions often taken in response
to a significant risk finding include (1) an immediate revision of the informed consent, (2) an
intensification of participant monitoring, (3) a revision to the eligibility criteria or screening
procedures, (4) an enrollment hold, or (5) a consideration of discontinuation of the trial. The
sponsor is also required to submit protocol amendments that describe certain changes to the
protocol (§ 312.30(b)) in addition to the IND safety report.
a. 	Findings from other studies (§ 312.32(c)(1)(ii))
Findings that suggest a significant risk generally arise from ongoing or completed clinical
studies, pooled data from multiple studies, and epidemiological studies. Findings from clinical
studies that are subject to this requirement are those that have not already been reported under
§ 312.32(c)(1)(i). For example, any significant risk finding from a drug interaction study, a
study evaluating changes in the QT interval on an electrocardiogram, or a study of a marketed
drug would be reported under this provision. An example of such a finding would be a
significant prolongation of the QT interval in participants receiving the investigational drug.
b. 	Findings from animal or in vitro testing (§ 312.32(c)(1)(iii))
Before reporting a finding from animal or in vitro testing to FDA, the sponsor should use
judgment to decide whether the finding suggests a significant risk in humans or is too
preliminary to interpret without replication or further investigation. Findings from animal
studies, such as carcinogenicity, mutagenicity, teratogenicity, or reports of significant organ
toxicity, are examples of the types of findings that suggest a significant risk, especially when the
exposure to the investigational drug is at or near human exposures. Even if the findings from
animal studies arise from exposures at a margin above clinical exposure, they may raise
important risks to human use of the drug and should be reported. For example, if the no
observed adverse effect level (NOAEL) is determined to be marginally above clinical exposure,
findings from animal studies involving exposures at such NOAEL should be reported. Also,

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certain findings, for example, carcinogenicity, even if seen at levels markedly above clinical
exposures, may suggest an important risk that warrants reporting.18
2. 	IND Safety Reports for Study Endpoints (§ 312.32(c)(5))
Generally, study endpoints refer to outcomes that sponsors are measuring to evaluate efficacy.
For trials designed to evaluate the effect of a drug on disease-related mortality or major
morbidity, endpoint information should be collected, tracked, and monitored, usually by a data
monitoring committee (DMC), during the course of the trial.19 The study endpoints must be
reported according to the protocol and are not ordinarily reported in IND safety reports, except
when there is evidence of a causal relationship between the drug and the event (§ 312.32(c)(5)).
For example, a death ordinarily would not be reported as an individual case in an expedited
report from a trial designed to compare all-cause mortality in participants receiving either an
investigational drug or a placebo. If, however, the death occurred as a result of an anaphylactic
reaction that coincided with initial exposure to the drug or was the result of fatal hepatic
necrosis, the death must be reported as an individual case in an IND safety report because of the
evidence suggesting a causal relationship between the drug and the event (§ 312.32(c)(5)). This
is analogous to a single uncommon event required to be reported under § 312.32(c)(1)(i)(A).
In addition to the study endpoints described above, some trials also evaluate the effect of the
drug on several other pre-identified specific adverse events, often called safety endpoints or
adverse events of special interest. These safety endpoints should be identified in the protocol
and monitored and reported by the sponsor as specified in the protocol.
V. 	SYSTEMATIC APPROACH FOR REVIEW OF SAFETY INFORMATION
(§ 312.32(b))
Sponsors should have a systematic approach to safety surveillance20 to comply with the IND
safety reporting requirements and to improve the overall quality of safety reporting. Such an
approach should include a process for promptly reviewing, evaluating, and managing both
individually reported SAEs and accumulating data on all SAEs from the entire drug development
program that are obtained or otherwise received from domestic or foreign sources.
18 See the guidance for industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for
Therapeutics in Adult Healthy Volunteers (July 2005).
19 See the guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data Monitoring
Committees (March 2006) and the draft guidance for industry Use of Data Monitoring Committees in Clinical Trials
(February 2024) (when final, this guidance will represent FDA’s current thinking on this topic).
20 For more discussion of this subject, see the guidance for clinical trial sponsors Establishment and Operation of
Clinical Trial Data Monitoring Committees, the draft guidance for industry Use of Data Monitoring Committees in
Clinical Trials (when final, this guidance will represent FDA’s current thinking on this topic), and the guidance for
industry Premarketing Risk Assessment (March 2005).

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During the course of drug development, investigators who conduct clinical trials generally report
adverse event information to the sponsor; however, a sponsor may become aware of new safety
information from a variety of sources, both domestic and foreign.
The sponsor must review and evaluate safety information from any source, regardless of whether
the data came from studies conducted under the IND (§ 312.32(c)(1)(ii) and (iii)), to determine if
there is a newly identified significant risk to trial participants.21 Sources include but are not
limited to:
• 	Animal or in vitro studies
• 	Clinical or epidemiological investigations
• 	Reports in the scientific literature, including unpublished reports of which the sponsor
becomes aware
• 	Information presented at professional or scientific meetings (e.g., abstracts)
• 	Reports from foreign regulatory authorities
• 	Reports from commercial marketing experience, including outside the United States
The sponsor’s review should include examining data from all sources and deciding whether the
information meets the criteria for expedited reporting (see section IV of this guidance), as well as
evaluating all accumulating data at regular intervals to update safety information and to identify
new safety signals. Monitoring the progress of investigations is necessary to identify previously
undetected potential serious risks (§ 312.56(a)); to update investigator brochures, protocols, and
consent forms with new information on adverse events; and, when necessary, to take steps to
protect participants (e.g., modifying dosing, participant selection, or monitoring) that will allow
an investigational drug to be safely developed despite potential risks or to discontinue
investigations for drugs with unreasonable and significant risks (§ 312.56(d)).
A. 	Prospective Development of a Plan for Safety Surveillance
The prospective development of a plan for assessing all SAEs — particularly those SAEs that are
only interpretable in the aggregate — and other important safety information is an important
component of IND safety reporting. The plan should describe processes and procedures for
assessing SAEs and other important safety information in a drug development program.
A plan for safety surveillance should include descriptions of the following elements:
21 Although sponsors must examine all information relevant to the safety of the drug obtained or otherwise received
by the sponsor (§ 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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• 	Clearly defined roles and responsibilities of the entities and participating individuals that
have responsibility for any or all of following: reviewing, analyzing, and making
decisions regarding IND safety reporting. The positions and names of individuals and/or
entities who have access to unblinded individual safety data and/or unblinded aggregate
data should be specified in the safety plan.
• 	A plan for regular review of all SAEs and other important safety information, including
related AEs and relevant safety information from the sources listed above, with
unblinding if necessary for interpretation.
• 	A process for aggregate safety reviews (see section VI of this guidance for considerations
for aggregate data analysis), including:
− 	A list of anticipated SAEs for the study population (see section IV.A.2.a of this
guidance for more information about identifying anticipated SAEs) that the sponsor
does not plan to report individually, regardless of the investigator’s assessment of
causality. The preferred terms (PTs) for such events should be specified in a
standardized coding convention or dictionary such as MedDRA (Medical Dictionary
for Regulatory Activities). The events should each reflect a cohesive medical concept
and not necessarily a single PT: the medical concept associated with an SAE may be
reflected by a number of different PTs. For example, the medical concept of
myocardial infarction may be reflected by the PTs of myocardial infarction or acute
myocardial infarction (see section VII.B of this guidance). Sponsors may
communicate with the applicable FDA review division during protocol development
and prior to trial initiation, as appropriate, about how anticipated SAEs will be
handled. It is not expected that the prespecified list of anticipated SAEs will cover all
clinical events that may be considered to be anticipated for the population. For
complex programs that include multiple indications, the anticipated SAEs may differ
by the population(s) in the trial(s) under the same development program. The failure
to identify an anticipated SAE up front does not mean that it necessarily requires IND
safety reporting as a single event. Rather, such non-prespecified but anticipated
SAEs should be carefully reviewed to determine if they meet the criteria for IND
safety reporting when such a determination cannot be made based on a single case.
(See section VI of this guidance.)
− 	A plan to monitor the incidences of SAEs that require aggregate reporting. These
include anticipated SAEs (both prespecified and those not on the anticipated SAE list
but reviewed and assessed as consistent with an anticipated SAE and hence not
immediately reported) and expected serious suspected adverse reactions (those listed
in the package insert or investigator brochure).
− 	For studies that use a trigger approach (see section VI.C.1.b of this guidance) to
decide when such SAEs should be unblinded, the predicted rates of anticipated SAEs
and the basis for the predicted rates should be specified.

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− 	The frequency and approach with which aggregate reviews of safety data will be
performed (see section VI.C.1 of this guidance).
− 	Pre-planned assessments of the trial and program safety database when trials within
the program are completed and unblinded, when safety information from trials of
other drugs in the same class are reported, or when any information relevant to safety
is presented (e.g., pharmacology, toxicology, genetic).
− 	Methods that may be used to evaluate events, including graphical, tabular, or
statistical approaches.
− 	Unblinding practices and controls and processes for maintaining trial integrity (see
section VI.D of this guidance).
The sponsor should evaluate the safety surveillance plan as the development program progresses
and the safety profile of the product evolves to determine whether the plan should be updated.
The plan should be maintained by the sponsor and must be available for FDA inspection as
required for all sponsor records and reports of an investigation under § 312.58(a).
VI. 	CONSIDERATIONS FOR AGGREGATE DATA ANALYSES FOR IND SAFETY
REPORTING
Analyses of aggregate data to identify imbalances in the types of SAEs discussed in
§§ 312.32(c)(1)(i)(C) or 312.32(c)(1)(iv) generally will become more informative as drug
development progresses and data accumulate. Unless differences are large, detection of a
clinically meaningful imbalance often requires a database of significant size. Clinical judgment
is important because imbalances of events between arms may result from chance, even with
larger databases. Interpreting imbalances may be particularly challenging for smaller programs
where the number of events is small (for additional considerations regarding aggregate analyses
for small programs, see section VI.C.3 of this guidance). Reporting should not rely solely on a
statistical assessment because even imbalances that have marginally small p-values or
confidence intervals (CI) that do not or that minimally exclude the null (for between-group
difference) may be relevant, and interpretation requires a broader evaluation including detailed
assessment of trial data such as time to event, detailed case assessments, and reliance on
information outside of the trial, such as the pharmacology of the drug, class effects, and
nonclinical findings. Waiting for a smaller p-value (i.e., p <0.05) or a CI that has a greater
separation from a null difference when other evidence points to a potential causal association
may unduly delay reporting SAEs of concern. It is particularly difficult to detect differences in
rates of SAEs that may be anticipated in the population being studied but that are not expected to
be common during the trial (e.g., prostate cancer in middle-aged men). Recognizing the
complexity of the judgments, FDA will focus primarily on the sponsor’s process and the
reasoning underlying the sponsor’s decision in the event FDA and the sponsor reach different
conclusions regarding whether SAEs evaluated by analyses of aggregate data meet IND safety
reporting criteria.

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A. 	Identify Serious Adverse Events Anticipated to Occur in the Study
Population
As discussed in section V of this guidance, regarding the safety surveillance plan, the first step in
preparing for an aggregate analysis of anticipated SAEs is developing a list of these events in the
plan for safety surveillance and documenting a plan for monitoring these events. This will
enable the safety assessment team to identify SAEs that should not be assessed for IND safety
reporting on the basis of an individual or a small number of events, even if they are assessed by
the investigator as drug-related. As discussed in section V.A above, an SAE that occurs during a
trial can be classified and managed as an anticipated SAE if the SAE is determined to be an
event that could occur in the population in the absence of exposure to the drug. While
prespecifying such events is the goal, an SAE that was not included in the prespecified list of
anticipated SAEs can be treated as such for the purposes of IND safety reporting if it meets the
criteria of an anticipated event. Clinical judgment should be used to determine whether the event
could occur in the population even in the absence of exposure to the drug.
Reported SAEs should be based on prospectively grouped adverse event terms that represent
closely related medical concepts (see section VII.B of this guidance for information about the
importance of standardized coding).
B. 	Entities That Review Aggregate Data for IND Safety Reporting
Under § 312.32, sponsors are responsible for promptly reviewing all information relevant to the
safety of the drug, determining whether safety information meets the IND safety reporting
criteria, notifying FDA and all participating investigators in an IND safety report of potential
serious risks, and promptly investigating all follow-up safety information they receive. Sponsors
may choose to designate an entity (an individual or group of individuals) to review the unblinded
accumulating safety information in a drug development program (e.g., over time in a late-stage
clinical trial, across trials, across INDs for the same drug) and to make a recommendation to the
sponsor regarding whether the safety information must be reported under § 312.32. Sponsors
have flexibility in determining which entity, entities, and/or sponsor personnel should perform
this function. There does not need to be a single entity to evaluate all SAEs; for example, there
could be one entity used to assess individual occurrences or a small number of adverse events
that are not anticipated in the population (reported under § 312.32(c)(1)(i)(A) and (B)), and there
may be a different entity assessing aggregate adverse events reported under § 312.32(c)(1)(i)(C),
or there could be some combination thereof. It is essential that roles are clearly defined in study
plans and that firewall procedures are in place to ensure that individuals whose roles do not
include access to unblinded aggregate data are insulated from knowledge of any unblinded
aggregate data (see section VI.D of this guidance).
1. 	Features and Composition of the Entity
The entity or entities reviewing aggregate safety information should include an individual or
individuals with knowledge about the investigational drug; the disease being treated, including
the epidemiology of the disease; and the characteristics of the study population (e.g., natural
history of the disease being treated, background rates of anticipated adverse events). Such

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individual(s) should be qualified by training and experience to make clinical judgments about the
safety of the drug. Identification of a new type of clinical safety concern (e.g., ocular toxicity,
renal toxicity) may warrant adding additional expertise to the entity reviewing safety data.
The positions, roles, and responsibilities of each individual or group of individuals in the entity
should be clearly defined in the plan for safety surveillance (see section V.A of this guidance).
2. 	Identifying the Entities That Review Safety Information
If a DMC is in place, the DMC may be used to conduct aggregate analyses of safety information
to help the sponsor assess whether the reporting criteria in § 312.32(c)(1)(i)(C) and (c)(1)(iv)
have been met. An advantage of having a DMC conduct this review is that the DMC could
access unblinded data and can utilize existing controls for maintaining trial integrity. FDA
recognizes that analyzing these data for the purpose of providing a recommendation to the
sponsor regarding whether the IND safety reporting criteria have been met would be a new role
for most DMCs, distinct from their role in monitoring risks and benefits to make
recommendations for trial continuation or modification. If this role is allocated to the DMC, the
DMC charter should reflect this new role.
If the sponsor does not use a DMC for the purpose of reviewing safety analyses to detect events
meeting the criteria for IND safety reporting, the sponsor should identify an entity within or
outside the sponsor’s organization for this purpose. If the entity consists of more than one
individual, it may have sponsor representation and/or external representation. It is important that
no unblinded data, including references to masked treatment group assignments (e.g., treatment
groups A, B, or C), be revealed to internal or external personnel participating in the conduct or
analysis of an ongoing clinical trial program. Only DMC members and any firewalled personnel
designated to conduct unblinded analyses of safety data should have access to such data. (See
section VI.D of this guidance for information regarding maintaining trial integrity when
reviewing aggregate data.)
C. Aggregate Analyses of Safety Data
1. 	Approach to Aggregate Analyses
For anticipated SAEs and expected serious suspected adverse reactions, an aggregate analysis of
the data is necessary to determine whether these events meet the criteria for reporting under
§ 312.32(c)(1)(i)(C) and (c)(1)(iv), respectively. The unblinding of participant treatment for
anticipated SAEs or expected serious suspected adverse reactions that may be necessary for
aggregate analyses requires scrupulous, thoroughly planned, and well-documented efforts to
protect trial integrity, ensuring that the entity or persons carrying out the review are completely
firewalled from the staff conducting the trial and assessing blinded data (see section VI.D of this
guidance).

Contains Nonbinding Recommendations
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a. 	Aggregate analyses by a DMC
If a DMC (or other firewalled external entity)22 is responsible for assessing accumulating
unblinded safety data for the purpose of IND safety reporting, the DMC should review unblinded
safety data on a periodic basis to assess the incidence of anticipated SAEs and expected serious
suspected adverse reactions by treatment arm. The DMC should be given access to
accumulating information from the drug development program, not just the specific trial, and
should be aware of preclinical and early clinical data that bears on safety issues.
If the DMC identifies either an imbalance between study arms of an anticipated SAE suggesting
a causal relationship between the investigational drug and the SAE or an increased rate of an
expected serious suspected adverse reaction in the treatment arm above what is expected
according to the available safety information for the investigational drug, the DMC would be
expected to make a recommendation23 to the sponsor regarding whether the safety information
should be reported under § 312.32. Such recommendations should be made to the sponsor
personnel who are specifically assigned the responsibility to review unblinded data (and who are
not involved in the conduct or analysis of the study) to determine if an IND safety report is
appropriate (see section VI.C.2 of this guidance).
The cadence for review of unblinded data by the DMC for purposes for expedited IND safety
reporting should be specified in the charter. If the DMC is reviewing safety information for the
purposes of IND safety reporting as well as their usual role of assessing the ongoing benefit-risk
ratio of the trial, in the absence of a specific concern, an aggregate analysis by the DMC should
occur at regular intervals (e.g., every 6 months, or more or less frequently as appropriate).
However, it is also reasonable for the DMC to conduct the aggregate analyses at intervals based
on volume of safety data collected or based on participant accrual into the trial (e.g., as each 25
percent of the recruitment target is reached) or on event rates (e.g., that might be higher in a
study population with more severe illness and/or greater comorbidities). The frequency may be
modified, as needed, if safety concerns arise that require follow-up (e.g., an imbalance might be
determined not to require an IND safety report but could lead to more frequent monitoring). In
addition, in determining the appropriate frequency of aggregate reviews, the sponsor should
consider factors such as experience with the drug, the condition being treated, the study
population, and enrollment rates. The frequency of review and the rationale behind it should be
described in the plan for safety surveillance (see section V.A of this guidance).
b. 	Unblinding trigger approach
In this approach, a predicted rate of an anticipated SAE or expected serious suspected adverse
reaction across the study population is determined such that if the rate is exceeded to a
potentially meaningful extent, an unblinded analysis by treatment group is then performed to
22 While a sponsor could establish an external entity that is appropriately firewalled like a DMC to periodically
review all unblinded safety data, likely in the absence of a DMC, the unblinding trigger approach as discussed in this
guidance would be the preferred approach.
23 Though the DMC may make a recommendation regarding whether the safety information should be reported
under § 312.32, this determination is ultimately the sponsor’s responsibility under § 312.32.

Contains Nonbinding Recommendations
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evaluate whether the anticipated SAE or expected serious suspected adverse reaction meets the
criteria for IND safety reporting. In the case where there is no external entity responsible for
conducting periodic unblinded reviews of safety data, FDA recommends the use of this approach
for aggregate analysis.
• 	Anticipated SAEs
For anticipated SAEs, the predicted rate for the SAE across the population should be specified
based on information that is applicable to the specific study population (e.g., based on age,
comorbidities, concomitant treatments). Sponsors should use all available data, including
placebo databases, historical data, literature, external epidemiological databases, electronic
health records, and disease-specific registries, to determine predicted rates of SAEs anticipated to
occur in the study population. When data are available such that accurate population-based rates
can be calculated for the study population, a precise trigger for unblinding can be used.
Utilizing the predicted SAE rates, sponsors should specify unblinding criteria based on a
comparison of the predicted rate of the SAE with the observed blinded SAE rate.24 If the results
of the overall blinded analyses demonstrate that the rate of events in the pooled treatment groups
is notably higher (i.e., exceeding the predicted rate by more than a minor difference and meeting
the unblinding criteria), the next step would be to examine the rates by treatment group using an
unblinded analysis and compare the numbers of events for the specific SAE in each arm to
determine whether the IND safety reporting criteria in § 312.32(c)(1)(i)(C) have been met. Note
that clinical judgment should be incorporated into any assessment because there may be
circumstances that mitigate the need for unblinding even if a trigger rate is exceeded. For
example, in the setting of a known seasonally higher rate of pneumonia in a community, such
information should be taken into account before unblinding based on a trigger rate for
pneumonia that was established before the seasonal information was known.
FDA recognizes that in some cases, the data necessary to establish a predicted rate of some
anticipated SAEs in the specific study population may be limited or unavailable, for example:
• 	When the rate of the anticipated SAE is low in the study population and it is difficult to
determine an accurate rate
• 	In drug development programs for rare diseases or other small programs
• 	For the specific study population
- 	For example, although it may be possible to find data on the rates of cardiovascular
events in the general population aged 40 to 70 years, data specific to a similarly aged
population with a specific condition may not be available.
24 Generally, the comparison of the predicted SAE rate to the observed blinded SAE rate should account for
uncertainty in the comparison rather than relying on a simple comparison of one value to another. Methods for
comparisons should be provided in the plan for safety surveillance.

Contains Nonbinding Recommendations
24
For anticipated SAEs with limited or no available data regarding rates for the study population,
the trigger for unblinding may be based on factors including statistical probability and clinical
judgment. For example, unblinding should be done if there are more than a few SAEs of a
certain type such that if the majority occurred in the investigational arm, it would lead one to
suspect that the investigational drug may have a causal role. Such a trigger should be set based
on review of blinded data for anticipated events that do not occur frequently in the population
and have not been prespecified.
For anticipated SAEs that are prespecified in the plan for safety surveillance, the predicted rates
also should be included in the plan (see section V.A of this guidance). It is not expected that all
anticipated SAEs, particularly for less common anticipated SAEs, would be prespecified in the
safety surveillance plan. For SAEs that are classified as anticipated during the trial (i.e., not
prespecified as anticipated in the safety surveillance plan), the unblinding trigger should be set as
described in this section during the trial, with appropriate documentation.
• 	Expected Serious Suspected Adverse Reactions
For expected serious suspected adverse reactions, the trigger to unblind is based on rates listed in
the protocol or investigator brochure and takes into account whether the events being monitored
could occur in the control group. Sponsors should have processes for comparing the rates of
expected serious suspected adverse reactions to the rates listed in the protocol or investigator
brochure in order to determine whether there is a clinically important increased rate of
occurrence that must be reported under § 312.32(c)(1)(iv).
2. 	Considerations for Small Programs/Rare Diseases
In drug development programs for rare diseases or other small programs that are not using an
external entity such as a DMC for aggregate analyses, external data sources used to predict
anticipated SAE rates are often limited, and thus the trigger for unblinding would likely be based
on clinical judgment and probability (see section VI.C.1.b of this guidance). Additionally, for
small programs where the number of SAEs is expected to be small, the trigger for unblinding
may be lower given the size of the population.
When unblinding of treatment is necessary for the evaluation of an anticipated SAE or expected
serious suspected adverse reaction, interpreting imbalances between treatment arms may be
particularly challenging for smaller programs because the number of events is small.
Furthermore, the clinical trial to support effectiveness in these programs may be an open-label,
single-arm trial (i.e., a trial with no concurrent comparator group). These settings are especially
challenging, and sponsors should use judgment in determining whether there is a reasonable
possibility that the drug caused the event.
3. 	Considerations When Evaluating Aggregate Data Across a Development
Program
Aggregate analyses should generally be performed across multiple studies under the IND and, as
appropriate, across all INDs for the drug held by the sponsor, including both completed and

Contains Nonbinding Recommendations
25
ongoing trials. Clinical and statistical judgment is needed to evaluate the totality of the
information related to a specific anticipated SAE or expected serious suspected adverse reaction,
including information from trials in different populations, particularly when the trials have
different study designs (e.g., different dosing schedules, varying durations of follow-up, different
indications). FDA recognizes that these differences between studies may make it difficult to
compare event rates across trials; therefore, documentation of this clinical assessment is
recommended. The draft guidance for industry Meta-Analyses of Randomized Controlled
Clinical Trials to Evaluate the Safety of Human Drugs or Biological Products (November
2018)25 provides recommendations regarding combining data and comparative analyses of data
from multiple trials.
4. 	Updating Safety Information
For aggregate analysis, after an anticipated SAE is reported under § 312.32(c)(1)(i)(C) or the
increased rate of occurrence of an expected serious suspected adverse reaction is reported under
§ 312.32(c)(1)(iv), the investigator brochure, the protocol, informed consent, and other safety-
related information should be updated as appropriate and as soon as possible during the conduct
of the ongoing clinical trial. After the anticipated event is listed in the investigator brochure, the
event should no longer be reported in IND safety reports because it would then be considered
expected, unless there is a clinically important increase in the event rate (§ 312.32(c)(1)(iv)).
Similarly, the increased rate of occurrence of an expected serious suspected adverse reaction
reported under § 312.32(c)(1)(iv) should no longer be reported in IND safety reports after the
investigator brochure, the protocol, and other safety-related information have been updated to
reflect the updated rate of occurrence, unless a further increase in occurrence is observed and
meets the reporting criteria.
The IND sponsor should in some circumstances develop, in consultation with the FDA review
division and other safety oversight bodies (e.g., a DMC), an approach for reporting, in an IND
safety report, subsequent occurrences of certain events that the sponsor has added, as expected
events, to the investigator brochure, the protocol, and other safety-related information. Although
IND safety reporting of a particular SAE is no longer required after that SAE is listed in the
investigator brochure, ongoing reporting of subsequent events may still be appropriate. For
example, for certain events that are infrequent with immediate health implications or an event
that is uncommon in a specific study population (e.g., stroke in young adults), prompt
notification of subsequent events after the first IND safety report may be warranted to ensure that
the benefit-risk ratio remains acceptable to continue the trial (see § 312.56(d)). A plan for
reporting should be developed in consultation with the FDA review division and other safety
oversight bodies (e.g., a DMC). For an event that is known to occur independent of drug
exposure in the study population, the sponsor may specifically describe an approach for reporting
to FDA and all participating investigators (e.g., an updated aggregate narrative summary report
once a certain number of additional cases are identified or after a specified period of time, as
appropriate). Additionally, the sponsor must submit to FDA any additional data or information
that FDA deems necessary as soon as possible but in no case later than 15 calendar days after
receiving the request (§ 312.32(c)(1)(v)).
25 When final, this guidance will represent FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
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D. 	Maintaining Trial Integrity When Reviewing Aggregate Data
Recommended steps to protect trial integrity include ensuring that:
• 	Internal personnel conducting unblinded safety reviews do not participate in the conduct
or analysis of the trial or trials.
• 	Appropriate procedural controls and processes are prospectively specified in the safety
surveillance plan to prevent sponsor personnel involved with the conduct or analysis of
the trial(s) from being unblinded to participants’ treatment. If a firewalled external entity
other than the DMC is set up to look at aggregate data, it should have access only to the
unblinded analyses necessary to conduct the safety review. For example, it may be
necessary to unblind the treatment of participants who experienced an SAE, or it may be
necessary to unblind additional data that is relevant to interpreting the observed
imbalance (e.g., related adverse events). Study endpoints, efficacy data, and other data
collected for the trial that do not pertain to the adverse event should not be unblinded.
FDA acknowledges that serious suspected adverse reactions may be unblinded at the site level if
knowledge of the treatment received is assessed as necessary for the medical management of the
participant.
To address sponsor concerns about unblinding large numbers of participants’ treatment to
investigators when submitting aggregate reports, FDA recommends sending only the narrative
summary portion of the IND safety report to all participating investigators, without the individual
unblinded case safety reports that are summarized in the narrative summary report, to meet the
requirement of § 312.32(c)(1) for a sponsor to notify all participating investigators in an IND
safety report of potential serious risks (see section VIII.D of this guidance for information about
narrative summary reports for IND safety reports of aggregate analyses).
VII. 	OTHER SAFETY REPORTING ISSUES
A. 	Alternative Reporting Arrangements (§ 312.32(c)(3))
The requirement in § 312.32(c)(1) specifies the format and time frame for reporting potential
serious risks in an IND safety report (see section VIII of this guidance). Sponsors may request
and adopt different reporting formats or frequencies if agreed to in advance by the director of the
FDA review division responsible for reviewing the IND (§ 312.32(c)(3)). In addition, FDA may
require a sponsor to submit IND safety reports in a different format or at a different frequency
than required under § 312.32(c)(1) (see § 312.32(c)(3)). FDA may require a sponsor to continue
to report expeditiously a medically significant suspected adverse reaction that is listed in the
investigator brochure as observed with the drug (i.e., expected) so that its rate can be carefully
monitored (§ 312.32(c)(1)(v)). For example, if a single occurrence of Stevens-Johnson
Syndrome was observed in a participant receiving the investigational drug (and hence listed in
the investigator brochure), FDA may nonetheless require expedited reporting of additional cases

Contains Nonbinding Recommendations
27
of rash of a lesser severity. FDA may also require an alternative format or frequency for
reporting suspected adverse reactions. For example, once a drug has been identified as posing a
potential or previously unforeseen risk to participants in a clinical trial, FDA may require
expedited reporting of specific suspected adverse reactions for monitoring purposes.
B. 	Importance of Standardized Coding
As part of the sponsor’s responsibility to promptly review all SAEs under § 312.32(b), sponsors
should review the verbatim (reported) term and how it was coded to a MedDRA PT to ensure
that coding was appropriate. To define these medical concepts, sponsors should plan to
prospectively group adverse event terms that represent closely related medical concepts (e.g., for
the medical concept of renal failure, appropriate PTs might include PTs of renal failure, renal
failure acute, renal failure chronic, renal impairment, acute prerenal failure, azotemia, urine
output decreased, postoperative renal failure, and other relevant terms). Varying approaches are
available, such as Standardized MedDRA Queries (SMQs) or Higher Level Terms (HLTs) that
sponsors should consider as appropriate. See the guidance for industry Premarketing Risk
Assessment (March 2005) for additional discussion of coding.
C. 	Investigations of Marketed Drugs (§ 312.32(c)(4))
According to § 312.32(c)(4), a sponsor of a clinical study of a drug marketed or approved in the
United States that is conducted under an IND must submit IND safety reports for suspected
adverse reactions that meet reporting criteria under § 312.32 and are observed in the study at
domestic or foreign sites. If the sponsor is not the application holder,26 the sponsor should also
forward the report to the application holder of the marketed drug. If the sponsor is also the
application holder, the sponsor must also submit safety information from the clinical study as
prescribed by the relevant postmarketing safety reporting requirements (e.g., under §§ 314.80 or
600.80).
In addition, under § 312.32(c)(1)(ii), a sponsor must report findings from other studies, including
clinical studies that are not conducted under an IND or by the sponsor, that suggest a significant
risk in humans exposed to the drug. Generally, such a finding would result in a safety-related
change in the protocol, informed consent, investigator brochure, or other aspect of study conduct.
Therefore, as long as the sponsor maintains an open IND for a marketed or approved drug, safety
information from foreign and domestic studies, including non-IND studies, must be reported to
the IND. If the sponsor is also the application holder, such safety information must be reported
in accordance with the postmarketing requirements if it also meets the criteria for reporting,
regardless of whether there is an ongoing clinical study under the IND.
If the IND sponsor (who may also be the application holder) for a drug approved in the United
States becomes aware of a spontaneous report of an adverse event from U.S. or foreign
commercial marketing experience for the drug that is under investigation (i.e., an experience
occurring outside of a clinical trial), the report would be submitted based on required
26 See footnote 17.

Contains Nonbinding Recommendations
28
postmarketing reporting and does not also need to be submitted as an IND safety report, even if it
meets the criteria for being a serious and unexpected suspected adverse reaction.
If a drug is not approved and not marketed in the United States but is approved outside the
United States, a sponsor conducting a study under an IND must submit an IND safety report for
serious adverse reactions received through foreign commercial marketing experience if the event
meets reporting criteria for IND safety reports (§ 312.32(c)(1)). If there is no approved drug
product in the United States that has the same active moiety, such reports would not come to
FDA as a postmarketing report. Therefore, the only way for FDA to receive such safety
information is through the IND for the investigational drug.
D. 	Duration of Safety Reporting
The purpose of sending IND safety reports to investigators is to provide investigators with the
information they need to protect clinical trial participants. Once investigators are no longer
enrolling or monitoring participants and the site is officially closed, this information is no longer
necessary. Cutoff dates for sending IND safety reports to investigators may be described in the
protocol. If no cutoff dates are specified, once a site has been officially closed out, the sponsor
usually does not need to continue sending IND safety reports to that site, and an investigator
does not need to receive or review them (see generally § 312.32(c)(1)).
In unusual cases, safety information related to delayed toxicity may be reported after a site is
officially closed out. For example, if a late toxicity is discovered that would affect participants
who received the investigational drug, the investigator should be notified so participants can be
followed up with if necessary (e.g., serious unexpected suspected adverse reactions that are
detected and reported during the long-term follow-up for gene therapy products).
VIII. 	SUBMITTING AN IND SAFETY REPORT (§ 312.32(c)(1)(v))27
The guidance for industry Providing Regulatory Submissions in Electronic Format: IND Safety
Reports (April 2024) implements the electronic submission requirements of section 745A(a) of
the FD&C Act for the electronic format of the content submitted for IND safety reports that are
required under § 312.32(c)(1)(i) for serious and unexpected suspected adverse reactions.28 As
discussed in the guidance, IND safety report types required under § 312.32(c)(1)(i)(A), (B), and
(C) contain individual data from one or more participants and should be submitted as individual
case safety reports (ICSRs) to the FDA Adverse Event Reporting System (FAERS). Other types
of required IND safety reports under § 312.32(c)(1)(ii), (iii), and (iv) are reports of overall
27 Under section 745A(a) of the FD&C Act (21 U.S.C. 379k-1(a)), 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 guidance for
industry Providing Regulatory Submissions in Electronic Format: IND Safety Reports.
28 See the guidance for industry Providing Regulatory Submissions in Electronic Format: IND Safety Reports,
which describes the format required for the electronic submission of IND safety reports for serious and unexpected
suspected adverse reactions that are required under § 312.32(c)(1)(i).

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29
findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or
clinical studies and reports of increased rates of occurrences of expected serious suspected
adverse reactions. The sponsor should submit these other types of reports in a narrative format
in electronic common technical document (eCTD) format and should not submit these reports to
FAERS.
Submission of safety information to FAERS as structured data elements will improve FDA’s
ability to review and track potential safety signals that occur during the conduct of clinical trials
and will provide sponsors with a reporting format that is consistent with the ICH guidance for
industry E2B(R3) Electronic Transmission of Individual Case Safety Reports Implementation
Guide — Data Elements and Message Specification; and Appendix to the Implementation Guide
— Backwards and Forwards Compatibility guidelines and reporting requirements to other
regulatory agencies.
Until the electronic submission requirements specified in the guidance for industry Providing
Regulatory Submissions in Electronic Format: IND Safety Reports become effective on April 1,
2026, the most recent effective version of the eCTD guidance29 will continue to apply to
sponsors electronically submitting IND safety reports for serious and unexpected suspected
adverse reactions. FDA will also accept IND safety reports to FAERS as part of an
implementation period of the electronic submission program. During the implementation period
of electronic submission, if sponsors choose to submit IND safety reports to FAERS using the
ICH E2B(R3) data standards, they should no longer submit those IND safety reports in eCTD
format. Sponsors must use either the Electronic Submission Gateway Next Generation (ESG
NextGen) or the Safety Reporting Portal (SRP) when submitting IND safety reports to FAERS.
See the FAERS Electronic Submissions web page30 for more information on the electronic
submission process during the implementation period.
IND safety reports must be submitted to all of the sponsor’s INDs under which the drug is being
administered (§ 312.32(c)(1)). When submitting IND safety reports to the FAERS database,
sponsors should refer to the Electronic Submission of IND Safety Reports — Technical
Conformance Guide (Technical Conformance Guide)31 for information on appropriate IND
number data fields, including cross-reporting.
A. 	Method of Submission for IND Safety Reports to FAERS
The Technical Conformance Guide discusses general information and the format for the
submission of IND safety reports required under § 312.32(c)(1)(i) to FAERS and provides
29 See the guidance for industry Providing Regulatory Submissions in Electronic Format — Certain Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (September 2024).
30 The FAERS Electronic Submissions web page is available at https://www.fda.gov/drugs/fda-adverse-event-
reporting-system-faers/fda-adverse-event-reporting-system-faers-electronic-submissions.
31 The Electronic Submission of IND Safety Reports — Technical Conformance Guide is available at
https://www.fda.gov/media/132078/download. Technical conformance guides are also available on the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.

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recommendations to sponsors who elect to submit such reports to FAERS before the requirement
for submission to FAERS is in effect for applicable INDs.32
B. 	Method of Submission for IND Safety Reports in eCTD Format33
IND safety reports are required to be submitted electronically in eCTD format for findings from
other studies (§ 312.32(c)(1)(ii)), findings from animal or in vitro testing (§ 312.32(c)(1)(iii)),
and findings of an increased rate of occurrence of expected serious suspected adverse reactions
(§ 312.32(c)(1)(iv)).34 If the findings are published, in full or in abstract form, the sponsor
should include a copy of the publication. The sponsor should submit these other types of reports
in a narrative report in eCTD format and should not submit the reports to FAERS.35 Complete
information on eCTD specifications and guidance can be found on the FDA eCTD website,36
and sponsors may contact ESUB@fda.hhs.gov for assistance.
C. 	INDs That Are Exempted From Electronic Submission Requirements
FDA has exempted all submissions regarding noncommercial INDs from the electronic
submission requirements under section 745A(a) of the FD&C Act.37 For the purposes of the
section 745A(a) exemption, the term noncommercial IND refers to an IND for a product that is
not intended for commercial distribution and includes investigator-sponsored INDs and
expanded access INDs (e.g., emergency use INDs and treatment INDs).38 Although
noncommercial INDs (and their associated IND safety reports) are exempt from the requirements
of section 745A(a) of the FD&C Act, FDA encourages the electronic submission of IND safety
reports from sponsors of noncommercial INDs as per sections VIII.A and VIII.B of this
guidance.39
Sponsors with INDs that are exempted from the electronic submission requirement under section
745A(a) and who are not submitting IND safety reports required under § 312.32(c)(1)(i)(A), (B),
32 See the Electronic Submission of IND Safety Reports — Technical Conformance Guide.
33 See the guidance for industry Providing Regulatory Submissions in Electronic Format — Certain Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.
34 Ibid.
35 See the Electronic Submission of IND Safety Reports — Technical Conformance Guide.
36 See the Electronic Common Technical Document (eCTD) web page, available at
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-
ectd.
37 See the guidance for industry Providing Regulatory Submissions in Electronic Format — Submissions Under
Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (December 2014).
38 Ibid.
39 See the guidance for industry Providing Regulatory Submissions in Electronic Format: IND Safety Reports.

Contains Nonbinding Recommendations
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and (C) to FAERS or IND safety reports required under § 312.32(c)(1)(ii), (iii), and (iv) in eCTD
format should submit IND safety reports according to the following options:
1. 	Alternate Electronic Format
FDA has provided guidance to sponsors of INDs exempted from the 745A(a) electronic
reporting requirements describing an alternate electronic format sponsors should use for
submissions covered under such exemption.40 An IND safety report containing individual data
from one or more participants required under § 312.32(c)(1)(i) should be submitted to FDA
using Form FDA 3500A and should be submitted electronically as a portable document format
(PDF) submission in the alternate electronic format according to the guidance for industry
Providing Regulatory Submissions in Alternate Electronic Format (June 2022).
Other types of IND safety reports required under § 312.32(c)(1)(ii), (iii), and (iv), which do not
contain individual data from one or more participants, are reports of overall findings or pooled
analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies
and reports of increased rates of occurrences of serious suspected adverse reactions. The sponsor
should submit these other types of reports to FDA using a narrative format and should submit
these other types of reports electronically as a PDF submission in the alternate electronic
format.41
This recommendation is consistent with the efforts of Federal Agencies to transition their
business processes and recordkeeping to a fully electronic environment.42
2. 	Other Means of Rapid Communication
If the IND safety report is not submitted to FAERS, in eCTD format, or in an alternate electronic
format, a safety report may be submitted on a Form FDA 3500A via other means of rapid
communication (e.g., telephone, fax, email). The sponsor should complete all sections of Form
FDA 3500A that apply to IND safety report submissions.43 If the sponsor intends to submit IND
safety reports by fax or email, the sponsor should address the submissions to the Regulatory
Project Manager and the Chief, Project Management Staff in the FDA review division that has
responsibility for review of the IND. In addition, if the sponsor intends to submit IND safety
reports by email, FDA recommends that the sponsor obtain a secure email account with FDA.44
40 See the guidance for industry Providing Regulatory Submissions in Alternate Electronic Format.
41 Ibid.
42 Ibid.
43 For instructions for completing Form FDA 3500A, see https://www.fda.gov/safety/medical-product-safety-
information/medwatch-forms-fda-safety-reporting.
44 For details on obtaining a secure email account with FDA, visit https://www.fda.gov/drugs/forms-submission-
requirements/electronic-regulatory-submission-and-review.

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D. 	Submitting IND Safety Reports Based on Aggregate Analyses
IND safety reports required for submission based on aggregate analyses should include a
narrative summary report that provides a summary of the cases and the analysis the sponsor
conducted and should identify all individual cases that contributed to the analysis. The narrative
summary report should include a summary of the analysis of the individual cases that are
reportable because of aggregate analysis findings. Sponsors should use judgment in deciding
what to include in the summary of the analysis. Generally, this summary should include:
1. 	A description of the suspected adverse reaction, along with a brief overall summary of
the cases. This summary could include demographic factors, symptoms, comorbid
conditions, medical history, pertinent test results, concomitant medications, and timing of
events relative to drug exposure.
2. 	A description of the characteristics and results of the analysis, including a description of
the safety data sources, how the conclusion was reached, who reviewed the analysis, any
planned changes in monitoring or to study documents (e.g., informed consent,
investigator brochure), and any additional analyses planned.
Additionally, the narrative summary report must identify any previously submitted IND safety
reports concerning a similar suspected adverse reaction, and the sponsor must analyze the
significance of the suspected adverse reaction in light of previous, similar reports or any other
relevant information, as required for all IND safety reports (§ 312.32(c)(1)).
Before submission to FDA, each individual case that comprises an IND safety report of an
aggregate analysis should be unblinded to include data that is necessary for FDA to evaluate the
event. (See section VI.D of this guidance for reporting aggregate analyses to participating
investigators.)
When submitting IND safety reports that are a result of aggregate analysis of anticipated SAEs
under § 312.32(c)(1)(i)(C), the sponsor should submit each ICSR that contributed to the
aggregate analysis to FAERS. For such reports that occurred under multiple INDs, sponsors
should reference the technical specifications document FDA Regional Implementation Guide for
E2B(R3) Electronic Transmission of Individual Case Safety Reports for Drug and Biological
Products for instructions on the appropriate data elements to include in IND safety reports from
aggregate analyses as per § 312.32(c)(1)(i)(C); on how to link all supporting IND safety reports
to the narrative summary report; and on where to include the narrative summary report. This
information may also be applicable for IND safety reports submitted as per § 312.32(c)(1)(i)(B)
that include more than one case and where a narrative summary report is provided.45
45 See the technical specifications document FDA Regional Implementation Guide for E2B(R3) Electronic
Transmission of Individual Case Safety Reports for Drug and Biological Products, available on the FAERS
Electronic Submissions website at https://www.fda.gov/drugs/fda-adverse-event-reporting-system-faers/fda-adverse-
event-reporting-system-faers-electronic-submissions, and the Electronic Submission of IND Safety Reports —
Technical Conformance Guide, available at https://www.fda.gov/media/132078/download.

Contains Nonbinding Recommendations
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IND safety reports required under § 312.32(c)(1)(iv) should be submitted in eCTD format. (See
section VIII.B of this guidance.)
E. 	Reporting Time Frame
The time frame for submitting an IND safety report to FDA and all participating investigators is
as soon as possible but no later than 15 calendar days after the sponsor determines that the
suspected adverse reaction or other information qualifies for reporting (§ 312.32(c)(1)). The
IND safety reporting regulations were modified describing the reporting time frame applicable to
IND safety reports of more than one event (e.g., reports of events qualifying for reporting under
§ 312.32(c)(1)(i)(B) and (C) and increases in rates of occurrence of serious suspected adverse
reactions (§ 312.32(c)(1)(iv)), because these events generally require more than one occurrence
to make the determination that the event meets the criteria for reporting. Thus, the date of initial
receipt of the first event would likely be well before it was determined that the information must
be reported.
FDA expects that events that are interpretable as single cases (i.e., uncommon and known to be
strongly associated with drug exposure (§ 312.32(c)(1)(i)(A)) will be reported to FDA within 15
calendar days from sponsor’s initial receipt of the information because it will be immediately
apparent that such events meet the reporting criteria (§ 312.32(c)(1)). For events that require
more than one occurrence to assess causality and events evaluated in the aggregate, the time
clock starts from whatever date the sponsor determines that the events qualify for expedited
reporting. This means that, for example, incomplete cases must be promptly followed up for
additional information so that a determination can be made about whether the event is reportable
as an IND safety report (§ 312.32(d)).
Under § 312.32(d)(3) —
If the results of a sponsor’s investigation show that an adverse event not initially
determined to be reportable under paragraph (c) of this section is . . . [determined to be]
reportable, the sponsor must report such [a] suspected adverse reaction in an IND safety
report as soon as possible but in no case later than 15 calendar days after the
determination is made.
This applies to reporting of single and aggregate events and to events that would individually or
in the aggregate qualify for either 7- or 15-day reporting. FDA expects that any entity
responsible for making recommendations to the sponsor regarding submitting an IND safety
report based on aggregate data will promptly provide the recommendation to the sponsor so that
the sponsor can meet its obligations under § 312.32. The sponsor must promptly review the
information to determine whether the IND safety reporting criteria have been met (§ 312.32(b)).
Unexpected fatal or life-threatening suspected adverse reactions represent especially important
safety information and must be reported more rapidly to FDA (§ 312.32(c)(2)). The requirement
for reporting any unexpected fatal or life-threatening suspected adverse reaction to FDA is as
soon as possible but no later than 7 calendar days after the sponsor’s initial receipt of the
information (§ 312.32(c)(2)).

Contains Nonbinding Recommendations
34
Day zero for 7- and 15-day reports is considered as (1) the day the sponsor initially receives
information for a case that is interpretable as a single case or (2) the day the sponsor determines
that multiple cases qualify for expedited reporting.
If FDA requests any additional data or information, the sponsor must submit it to FDA as soon as
possible but no later than 15 calendar days after receiving the request (§ 312.32(c)(1)(v)).
Additionally, the sponsor must submit relevant follow-up information to a 7- or 15-day IND
safety report as soon as the information is available (§ 312.32(d)(2)). (See section IX of this
guidance.)
Day zero for the 7- and 15-day reporting time frames and the date of the adverse event may not
be the same. FDA considers the date of an adverse event to be the actual or best estimate of the
date of first onset of the adverse event.46 FDA interprets the date of first onset of the adverse
event to be the date that the participant first experienced the symptoms that were related to the
adverse event. FDA recognizes that this determination is not always straightforward and
requires clinical judgment to relate the prodromal symptoms to the adverse event.
IX. 	FOLLOW-UP INFORMATION (§ 312.32(d))
Most IND safety reports are derived from observations from clinical trials. In the setting of a
clinical trial, information is usually collected in a controlled environment so that the information
needed to evaluate the suspected adverse reaction (e.g., as an IND safety report submitted to the
FAERS database47) is generally readily available. If any information necessary to evaluate the
suspected adverse reaction is missing or unknown, the sponsor should actively seek such
information from the source of the report. In the event that the participant withdraws consent
from participating in a clinical trial, FDA recognizes that the sponsor cannot continue to provide
SAE reports related to that participant once the consent is withdrawn unless those reports are
associated with publicly available records.
Any relevant additional information obtained by the sponsor that pertains to a previously
submitted IND safety report must be submitted as a Follow-up IND Safety Report to the FAERS
database using the same unique case identification number/manufacturer control number as the
initial IND safety report without delay, as soon as the information is available (§ 312.32(d)(2)),
but should be submitted no later than 15 calendar days after the sponsor receives the information.
The sponsor should maintain records of its efforts to obtain additional information.
For example, if information on concomitant medications is obtained after the initial IND safety
report is submitted and such information is relevant to evaluating the suspected adverse reaction,
a sponsor must submit a Follow-up IND Safety Report as soon as the information is available
(§ 312.32(d)(2)). However, if the sponsor obtains other information that is not relevant to
46 See Form FDA 3500A Supplement (4/16) — Form Instructions, available at
https://www.fda.gov/media/82655/download.
47 See the guidance for industry Electronic Submission of IND Safety Reports Technical Conformance Guide (April
2022).

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evaluating the suspected adverse reaction, records of such information should be maintained by
the sponsor and, if applicable, submitted in an information amendment (§ 312.31) or in an IND
annual report (§ 312.33).
To help sponsors determine whether follow-up information is relevant to an IND safety report,
FDA provides in this section additional guidance on the types of information that generally
would require a follow-up IND safety report.
For an individual case that was submitted as an IND safety report under § 312.32(c)(1)(i)(A) and
(B), examples of the types of information that trigger the follow-up IND safety reporting
requirements include (1) a change in diagnosis of the adverse event, (2) an important change in
outcome of the adverse event (e.g., death), (3) autopsy findings, and (4) other new information
that significantly impacts the assessment of causality.
For aggregate data that were submitted as an IND safety report under § 312.32(c)(1)(i)(C) and
(c)(1)(iv), examples of the type of information that would trigger follow-up IND safety reporting
requirements include (1) additional occurrences of the adverse event that, in the aggregate,
suggest a significant change in the rate of occurrence from the initial aggregate report and
(2) information about individual events that comprise the aggregate report that significantly
impacts the assessment of causality such that there is no longer a reasonable possibility that the
drug caused the event or strengthens the causal relationship between the adverse event and the
drug. The sponsor should evaluate whether additional occurrences of the adverse event represent
a clinically important increase in the rate of a serious suspected adverse reaction over that listed
in the protocol or investigator brochure, which must be reported under § 312.32(c)(1)(iv).
X. 	SAFETY REPORTING REQUIREMENTS FOR BA AND BE STUDIES
The IND safety reporting requirements under § 312.32 apply to BA and BE studies that are
conducted under an IND. BA and BE studies that meet the conditions for IND exemption under
§ 320.31(d) are not conducted under an IND and are not subject to the IND safety reporting
requirements. Earlier iterations of § 320.31(d) that also exempted certain in vivo BA and BE
studies in humans from the requirements of part 312, including the IND safety reporting
requirements under § 312.32, did not establish separate safety reporting requirements for these
studies. As FDA stated in its preamble to the final rule updating § 320.31(d) in 2010, the
Agency determined that “the occurrence of a serious adverse event is very unusual in a [BA or
BE] study because the number of participants enrolled in the study is small, the participants are
usually healthy volunteers, and drug exposure is typically brief.”48 However, for these same
reasons, “the occurrence of any serious adverse event [in a BA or BE study] is of interest.”
Therefore, FDA revised § 320.31(d) to require reporting of SAEs as one of the conditions under
which certain BA and BE studies are exempt from the requirements of part 312, including from
the IND safety reporting requirements in § 312.32 (see § 320.31(d)(3)).
48 Final Rule, “Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products
and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans” (75 FR 59953),
published September 29, 2010.

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36
Timely review of this safety information is critical to ensuring the safety of BA/BE study
participants, whether they are healthy volunteers or individuals with the specified medical
condition and whether the trial has a single-dose or steady-state design.
A. 	BA/BE Study Safety Reporting Requirements (§ 320.31(d)(3))
The person conducting an IND-exempt BA or BE study, including any contract research
organization, must notify FDA and all participating investigators of any SAE observed for the
test or reference drug during conduct of the study, regardless of whether the event is considered
drug-related, as soon as possible but in no case later than 15 calendar days after becoming aware
of its occurrence (§ 320.31(d)(3)). This includes, for example, SAEs listed in the reference listed
product’s approved labeling, the investigator brochure, and the protocol.
If any information necessary to evaluate the SAE is missing or unknown, the company
conducting the study should actively seek such information and maintain records of efforts to
obtain additional information. Any relevant additional information obtained that pertains to a
previously submitted safety report must be submitted as a Follow-up
Bioavailability/Bioequivalence Safety Report as soon as the information is available
(§ 320.31(d)(3)) but should be submitted no later than 15 calendar days after the company
receives the information. In addition, upon request from FDA, the company conducting the
study must submit to FDA any additional data or information that FDA deems necessary as soon
as possible but in no case later than 15 calendar days after receiving the request (e.g., hospital
record, autopsy report) (§ 320.31(d)(3)). Study drug exposure for the participant who
experienced the SAE should be unblinded.
If the adverse event is fatal or life-threatening, the company conducting the study must also
notify the Director in CDER’s Office of Generic Drugs as soon as possible but in no case later
than 7 calendar days after becoming aware of its occurrence (§ 320.31(d)(3)). In doing so, the
company should also notify the appropriate review division in CDER’s Office of New Drugs or
the Division of Clinical Safety and Surveillance in CDER’s Office of Generic Drugs.
The requirements under § 320.31(d)(3) do not apply to human BA and BE studies that are
exempt from IND requirements and conducted outside the United States. However, as part of
the information required to establish that the proposed drug product can be expected to have the
same therapeutic effect as the reference listed drug, adverse event information from foreign
clinical studies must be included in the NDA submission or the abbreviated new drug application
(ANDA) submission as appropriate, based on the purpose of the BA/BE study.49
49 See § 314.50(d)(5)(iv) and 75 FR 59935 at 59954 (interpreting § 314.97(a)(7) to require adverse event reports that
occurred in foreign clinical studies to be included in the ANDA submission).

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B. 	How and Where to Submit a Report (§ 320.31(d)(3))
For an IND-exempt BA/BE study conducted to support changes to an already approved NDA or
ANDA, SAE reports must be submitted to FDA and should be submitted to FAERS.
For a BA/BE study conducted to support a new ANDA for a generic drug product, the entity
conducting or sponsoring the study should request a pre-assigned application number at
https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/requesting-pre-
assigned-application-number. FDA recommends requesting this application number prior to
starting the BA/BE study to avoid delays in expedited reporting. As stated on the website, it can
take up to 3 business days following the online request to receive the pre-assigned application
number.
The entity should use this application number for the following:
1. 	Submission of all adverse event reports from BA/BE studies
2. 	Submission of the ANDA for the test drug, when complete
FDA encourages electronic submission of IND-exempt BA/BE safety reports to FAERS.50 FDA
provides two methods for electronically submitting safety reports from BA/BE studies conducted
to support the approval of generic drugs:
1. 	Database-to-Database (E2B) Transmission via the ESG NextGen
• 	For more information about adverse event reporting via E2B submission, visit
https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/fda-adverse-
event-reporting-system-faers-electronic-submissions.
2. 	SRP submission, available at
https://www.safetyreporting.hhs.gov/SRP2/en/Home.aspx?sid=9c063e08-5d1f-4c6d-
aedd-03b018c54cc0.
• 	The portal requires entering the six-digit pre-application ANDA number for
submission of an adverse event report.
For fatal or life-threatening adverse events that require 7-day expedited reporting, FAERS will
automatically route submissions to the appropriate group in the Office of Generic Drugs for
review for notifications generally submitted through the ESG NextGen or SRP.
In situations when the ESG NextGen and SRP routes of submission are unavailable, sponsors
should submit expedited reports of SAEs from IND-exempt BA/BE studies via email to OGD-
PremarketSafetyReports@fda.hhs.gov. Such reports should be submitted to FDA via email
50 See the guidance for industry Electronic Submission of Expedited Safety Reports from IND-Exempt BA/BE Studies
(April 2024).

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using Form FDA 3500A and completed with all the available information, including a brief
narrative describing the SAE, an assessment of causality, and any other relevant information
(§ 320.31(d)(3)). If applicable, the narrative should also include identification of other similar
reports and an analysis of the significance of the SAE. A summary of the study protocol should
be submitted with the report.
Each report must prominently identify its contents (§ 320.31(d)(3)). Reports should be labeled
as follows:
• 	“Bioavailability/Bioequivalence Safety Report” for 15-day reports
• 	“Follow-up Bioavailability/Bioequivalence Safety Report” for follow-up information
• 	“7-day Bioavailability/Bioequivalence Safety Report” for unexpected fatal or life-
threatening adverse reaction reports
Box G4 of Form FDA 3500A should include the pre-application ANDA number, and the “Pre-
ANDA” box should be checked.51 The type of report should be checked in box G6 on Form
FDA 3500A. The report can also be identified in box B5 or in a cover letter, or both, submitted
with Form FDA 3500A.
Each field in the “C” subsection of Form FDA 3500A should be completed appropriately. For
example, in box C1, the study drug or drugs to which the participant was exposed prior to onset
of the SAE should be listed (this may include active drug, placebo, and/or vehicle depending on
the study). In box C2, the participant’s concomitant medications should be listed. If the SAE
began prior to administration of a study drug but after study enrollment, this event should not be
submitted, because it is unassociated with study drug exposure. In box B5, the timeline of drug
exposures as they relate to the SAE or SAEs should be clearly described.
51 See Form FDA 3500A Supplement (4/16) – Form Instructions, available at
https://www.fda.gov/media/82655/download.

Contains Nonbinding Recommendations
1
APPENDIX: FLOWCHART FOR DETERMINING WHETHER AN ADVERSE EVENT MEETS
THE CRITERIA FOR IND SAFETY REPORTING TO FDA AND INVESTIGATORS
YES
Refer to section III.D of the
guidance and 21 CFR 312.32(a)
for the definition of “serious.”
NO	YES
Refer to section III.C of the
guidance and 21 CFR 312.32(a)
for the definition of “unexpected.”
Refer to section
III.B of the
guidance and 21
CFR 312.32(a)
for the definition
of “suspected
adverse
reaction” and
section III.B of
the guidance
and 21 CFR
312.32(c)(1)(i)
for examples of
evidence that
suggest a causal
relationship
between the
drug and the
SAE.
NO	YES
NO	YES
NO
Is there a reasonable possibility that the
drug caused the SAE (as assessed by the
sponsor)?
Examples of evidence suggesting a causal
relationship between the drug and the SAE
include:
• A single occurrence of an event that is
uncommon and known to be strongly
associated with drug exposure (e.g.,
angioedema, hepatic injury, Stevens-
Johnson Syndrome)
• One or more occurrences of an event that
is not commonly associated with drug
exposure but is otherwise uncommon in
the population exposed to the drug (e.g.,
tendon rupture)
• An aggregate analysis of specific events
observed in a clinical trial (such as known
consequences of the underlying disease or
condition under investigation or other
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
Include the AE in an
annual report (see 21
CFR 312.33) or an
information
amendment to the
IND (see 21 CFR
312.31), as
appropriate.
Is the adverse event (AE) serious (as
assessed by either the investigator or
sponsor)?
Is the serious adverse event (SAE)
unexpected according to 21 CFR
312.32(a) (as assessed by the sponsor)?
Does the SAE indicate a clinically
important increase in the rate of a
serious suspected adverse reaction
over that listed in the protocol or
investigator brochure?
Include the
SAE in an
annual report
(see 21 CFR
312.33) or an
information
amendment
to the IND
(see 21 CFR
312.31), as
appropriate.
Submit IND
Safety Report
Include the SAE in an annual
report (see 21 CFR 312.33) or
an information amendment to
the IND (see 21 CFR 312.31),
as appropriate.
Submit IND
Safety Report