Investigator Responsibilities – Safety Reporting for Investigational Drugs and Devices: Guidance for Industry

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

51798224fnl
Investigator Responsibilities —
Safety Reporting for
Investigational Drugs and
Devices
Guidance for Investigators,
Industry, and Institutional Review
Boards
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)
Center for Devices and Radiological Health (CDRH)
Oncology Center of Excellence (OCE)
December 2025
Drug Safety

Investigator Responsibilities —
Safety Reporting for Investigational
Drugs and Devices
Guidance for Investigators, Industry, and
Institutional Review Boards
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/guidance-compliance-regulatory-information/guidances-drugs
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
and/or
Office of Policy
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 66, Room 5441
Silver Spring, MD 20993-0002
Email: CDRHClinicalEvidence@fda.hhs.gov
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-medical-devices-
and-radiation-emitting-products
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)
Center for Devices and Radiological Health (CDRH)
Oncology Center of Excellence (OCE)
December 2025
Drug Safety

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	DEFINITIONS .................................................................................................................. 3
A. 	Drugs ............................................................................................................................................... 3
1. Adverse Event (21 CFR 312.32(a)) .................................................................................................. 3
2. Adverse Reaction and Suspected Adverse Reaction (21 CFR 312.32(a)) ........................................ 3
3. Serious Adverse Event or Serious Suspected Adverse Reaction (21 CFR 312.32(a)) ..................... 5
B. 	Devices............................................................................................................................................. 5
1. Unanticipated Adverse Device Effect (21 CFR 812.3(s)) ................................................................ 5
2. Serious ............................................................................................................................................. 5
IV. 	INVESTIGATOR RESPONSIBILITY FOR REVIEWING SAFETY REPORTS ... 6
V. 	INVESTIGATOR REPORTING TO SPONSORS FOR IND STUDIES, ................... 6
A. 	Serious Adverse Event Reporting................................................................................................. 6
B. 	Timing of Serious Adverse Event Reporting ............................................................................... 7
C. 	Study Endpoint Reporting ............................................................................................................ 8
D. 	Nonserious Adverse Event Reporting .......................................................................................... 8
VI. 	INVESTIGATOR REPORTING TO INSTITUTIONAL REVIEW BOARDS FOR
IND STUDIES ............................................................................................................................... 8
VII. 	INVESTIGATOR REPORTING TO SPONSORS AND INSTITUTIONAL
REVIEW BOARDS FOR IDE STUDIES................................................................................... 9
VIII. 	SPONSOR RESPONSIBILITIES ................................................................................. 10

Contains Nonbinding Recommendations
1
Investigator Responsibilities —
Safety Reporting for Investigational Drugs and Devices
Guidance for Investigators, Industry, and
Institutional Review Boards1
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 is intended to help clinical investigators (investigators) comply with the following
safety reporting requirements:
• 	Investigational new drug application (IND) studies2 under § 312.64(b) (21 CFR
312.64(b)) and § 312.66 (21 CFR 312.66)
• 	Investigational device exemption (IDE) studies under § 812.150 (21 CFR 812.150)
Recommendations are provided to help investigators identify the following:
1. 	For drugs3
• 	Serious adverse events (SAEs) that must be immediately reported to the sponsor
under § 312.64(b)
• 	Safety information that is considered an unanticipated problem involving risk to
human participants4 or others and, therefore, requires prompt reporting to institutional
review boards (IRBs) under § 312.66
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research
in cooperation with the Center for Biologics Evaluation and Research, the Center for Devices and Radiological
Health, and the Oncology Center of Excellence at the Food and Drug Administration.
2 This guidance also provides relevant information for persons reporting serious adverse events (SAEs) for
bioavailability/bioequivalence (BA/BE) studies that meet conditions for IND exemption under 21 CFR 320.31(d)(3)
(IND-exempt BA/BE studies).
3 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.
4 FDA’s regulations under 21 CFR parts 312, 320, and 812 use the terms subject or human subject; however, in this
guidance, we use the term participant instead except when directly quoting the regulations.

Contains Nonbinding Recommendations
2
2. 	For devices
• 	Safety information that meets the requirements for reporting unanticipated adverse
device effects (UADEs) to sponsors and IRBs under § 812.150(a)(1)
This guidance also provides information on investigator review of IND safety reports received
from sponsors, reports of safety information from IND-exempt BA/BE studies received from
persons conducting the studies, and UADE reports received from sponsors.
This guidance, in conjunction with the guidance for industry Sponsor Responsibilities—Safety
Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence
Studies (issued concurrently with this guidance), replaces corresponding recommendations
previously provided in the final guidance documents Safety Reporting Requirements for INDs
and BA/BE Studies (December 2012) (the 2012 final guidance) and Adverse Event Reporting to
IRBs—Improving Human Subject Protection (January 2009) (the 2009 procedural final
guidance), which focus on sponsor and investigator responsibilities for safety reporting for
investigational medical products. These final guidance documents were withdrawn concurrently
with the issuance of this guidance and the guidance for industry Sponsor Responsibilities—Safety
Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence
Studies (December 2025).
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
FDA issued the 2009 procedural final guidance in response to concerns raised by the IRB
community that increasingly large volumes of individual adverse event reports were inhibiting,
rather than enhancing, the ability of IRBs to adequately protect human participants. The
following year, FDA published a final rule (2010 IND Safety Reporting Rule)5 amending the
IND safety reporting requirements under § 312.32 (21 CFR 312.32) and adding safety reporting
requirements for persons conducting IND-exempt bioavailability (BA) and bioequivalence (BE)
studies under § 320.31(d) (21 CFR 320.31(d)). Subsequently, FDA issued the 2012 final
guidance to help sponsors and investigators comply with safety reporting requirements for INDs
and for BA/BE studies that meet the conditions for IND exemption under § 320.31(d)(3).
5 75 FR 59935, September 29, 2010. The 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,” published in the Federal Register of September 29, 2010 (21 CFR parts 312 and 320).

Contains Nonbinding Recommendations
3
To further improve the overall quality of safety reporting, this guidance incorporates and clarifies
the concepts in FDA’s previously published guidance documents on safety reporting
responsibilities for investigators of investigational drugs6 and investigational devices. This
guidance replaces the 2009 procedural final guidance and the 2012 final guidance.
This guidance focuses primarily on safety reporting responsibilities of investigators and thus
includes only limited information regarding sponsor responsibilities for safety reporting of
investigational drugs, including biological products (see section VIII); that topic is the focus of
the guidance for industry Sponsor Responsibilities—Safety Reporting Requirements and Safety
Assessment for IND and Bioavailability/Bioequivalence Studies.
III. 	DEFINITIONS
A. 	Drugs
For ease of reference, the following definitions from the 2010 IND Safety Reporting Rule
(§ 312.32(a)) are included in this guidance, along with explanations and examples.7
1. 	Adverse Event (21 CFR 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, active control, or 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 FDA-approved indication or in
combination with another drug) and with any route of administration, formulation, or dose,
including an overdose.
2. 	Adverse Reaction8 and Suspected Adverse Reaction (21 CFR 312.32(a))
An adverse reaction means any adverse event caused by a drug.
6 The IND safety reporting requirements in § 312.32 apply to sponsors and sponsor-investigators, as defined in
§ 312.3. For more information on sponsor responsibilities for IND safety reporting of investigational drugs, see the
guidance for industry Sponsor Responsibilities—Safety Reporting Requirements and Safety Assessment for IND and
Bioavailability/Bioequivalence Studies (December 2025).
7 Although the terms defined in § 312.32 refer to sponsor IND safety reporting responsibilities, FDA is using these
terms consistently for the purposes of the investigator reporting requirements for drugs discussed in this guidance.
8 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

Contains Nonbinding Recommendations
4
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 (§ 312.32(a)). Therefore, if no drug has
been administered, an adverse event is not reportable under IND safety reporting regulations.9,10
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.
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
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)).
9 However, for clinical trials that involve an invasive procedure that would not occur other than due to participation
in the trial (e.g., intrahepatic artery administration or a kidney biopsy), FDA may request that sponsors also report
SAEs associated with such a procedure, even if the investigational product is not administered.
10 Investigator reporting requirements under §§ 312.64(b) and 312.66 may still apply even where no drug has been
administered.

Contains Nonbinding Recommendations
5
make a judgment about the likelihood that the drug caused the adverse event. See section VIII
below.
3. 	Serious Adverse Event or Serious Suspected Adverse Reaction (21 CFR
312.32(a))
An adverse event, adverse reaction, or suspected adverse reaction is considered serious —
if, in the view of either the investigator or the 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)).
B. 	Devices
1. 	Unanticipated Adverse Device Effect (21 CFR 812.3(s))
An unanticipated adverse device effect (UADE) means —
any serious adverse effect on health or safety or any life-threatening problem or death
caused by, or associated with, a device, if that effect, problem, or death was not
previously identified in nature, severity, or degree of incidence in the investigational plan
or application (including a supplementary plan or application), or any other unanticipated
serious problem associated with a device that relates to the rights, safety, or welfare of
subjects. (§ 812.3(s))
2. 	Serious
What qualifies as a serious adverse effect, as that term is used in the definition of UADE, would
be specific to the device and the study in which it is being used or tested. Generally, a serious
adverse effect is one that is determined by the investigator or sponsor to be life-threatening,
require hospitalization, result in disability or permanent damage, result in a congenital anomaly
or birth defect, or require an intervention to prevent permanent impairment or damage.

Contains Nonbinding Recommendations
6
Examples of adverse effects that could be considered serious include organ perforation and
thrombus formation inside an aortic endovascular graft. The investigator should consult the
protocol for information on adverse effects to help the investigator determine what would qualify
as a serious adverse effect.
IV. 	INVESTIGATOR RESPONSIBILITY FOR REVIEWING SAFETY REPORTS
The investigator should review all IND safety reports received from sponsors as a part of the
investigator’s responsibility to protect the rights, safety, and welfare of trial participants (see
§ 312.60). The investigator should similarly review all reports of safety information from IND-
exempt BA/BE studies. IND safety reports and reports of SAEs from IND-exempt BA/BE
studies provide participating investigators with important information relevant to the safety of
human participants receiving the investigational drug.11 FDA considers the review of these
reports critical to fulfilling the investigator’s responsibility under § 312.60 to protect the rights,
safety, and welfare of participants under their care.
Similarly, investigators of IDE studies should review UADE reports received from sponsors as
part of their responsibility to protect the rights, safety, and welfare of participants according to §
812.100.
V. 	INVESTIGATOR REPORTING TO SPONSORS FOR IND STUDIES12,13
Most of the information about the safety of a drug prior to marketing comes from clinical trials.
Adverse event reports from investigators are, therefore, critically important, given that it is the
investigator who observes a participant’s response to an investigational drug.
A. 	Serious Adverse Event Reporting
The investigator must immediately report to the sponsor any serious adverse event, whether or
not considered drug-related, including those listed in the protocol or investigator brochure, as
well as an assessment of whether there is a reasonable possibility that the drug caused the event
(§ 312.64(b)).
11 See also the guidance for industry Sponsor Responsibilities—Safety Reporting Requirements and Safety
Assessment for IND and Bioavailability/Bioequivalence Studies (December 2025).
12 Guidance provided in this section may be applicable for persons conducting IND-exempt BA/BE studies to
comply with § 320.31(d)(3).
13 For combination products as defined in 21 CFR 3.2(e), IND or IDE safety reporting by the investigator should
include a complete discussion of the event with respect to the combination product as a whole, including each
constituent part of the product, as appropriate, based on the available information. For questions related to safety
reporting for an investigational product, please contact the sponsor for the IND or IDE. FDA’s Office of
Combination Products is also available for further assistance at combination@fda.gov.

Contains Nonbinding Recommendations
7
• 	The investigator, who monitors the participant’s response to the drug, is
knowledgeable about the participant’s clinical state (e.g., medical history,
concomitant medications, symptoms, pertinent test results, timing of events relative to
drug exposure). Therefore, the investigator may be sensitive to distinctions between
events that may be related to study drug exposure versus those caused by the
underlying disease process and/or concomitant therapies.
• 	The report should generally include information about the trial participant (such as
sex, age, other demographic characteristics), a description (as detailed as possible) of
the event (including any diagnostic testing results, interventions, outcomes), and the
reporting source (if not the investigator).
• 	Although the sponsor is ultimately responsible for determining whether an SAE
should be classified as a serious suspected adverse reaction (see section VIII), the
investigator’s view is important for the sponsor to carefully consider when assessing
the safety of the drug, including whether there is a reasonable possibility that the drug
caused the event, and determining whether the event is one that is required to be
reported to FDA according to § 312.32.
• 	For the purposes of § 312.64(b), FDA interprets reasonable possibility to mean there
is evidence to suggest a causal relationship between the drug and the adverse event.
This interpretation is consistent with the definition of suspected adverse reaction in
§ 312.32(a).
− 	Factors that should be considered when making a causality assessment include,
but are not limited to, temporal relationship of the event to drug administration;
biologic plausibility; the mechanism of action of the drug or similar drugs in the
same class; nonclinical evidence; and dechallenge-rechallenge information.
B. 	Timing of Serious Adverse Event Reporting
The investigator must immediately report to the sponsor any serious adverse event
(§ 312.64(b)), although more data may be collected and submitted after submitting the initial
report.
• 	For the purposes of this guidance, the Agency interprets immediately to be as soon as
feasible after the investigator recognizes an event is an SAE and obtains relevant
information for the sponsor.
• 	FDA recommends that this time frame for submitting such initial information also be
specified in the protocol and anticipates that the time frame for submission of initial
information will generally not exceed 1 calendar day.

Contains Nonbinding Recommendations
8
C. 	Study Endpoint Reporting
1. 	The investigator must immediately report to the sponsor all study endpoints that are
SAEs (e.g., all-cause mortality) when there is evidence suggesting a causal relationship
between the drug and the event (e.g., death from anaphylaxis after exposure)
(§ 312.64(b)).
2. 	When there is no evidence suggesting a causal relationship between the drug and the
event, the investigator must report study endpoints that are SAEs in accordance with the
protocol (§ 312.64(b)).
D. 	Nonserious Adverse Event Reporting
The investigator must record nonserious adverse events and report them to the sponsor
according to the timetable for reporting specified in the protocol (§ 312.64(b)).
• 	Often, nonserious events are recorded and submitted to the sponsor and reviewed at
regular intervals throughout the course of the investigation.
• 	The investigator is not required to assess causality of nonserious adverse events under
§ 312.64(b), although many sponsors may require it in the protocol.
VI. 	INVESTIGATOR REPORTING TO INSTITUTIONAL REVIEW BOARDS FOR
IND STUDIES14
The investigator must promptly report to the IRB all unanticipated problems involving risk to
human participants or others (§ 312.66),15,16 and the investigator should be familiar with and
adhere to the IRB’s written procedures for reporting these unanticipated problems to the IRB (21
CFR 56.108(b)(1)).17
• 	IND safety reports and reports of SAEs from IND-exempt BA/BE studies received
from the sponsor describe important safety information representing unanticipated
problems involving risk to human participants or others.
14 Guidance provided in this section may be applicable for persons conducting IND-exempt BA/BE studies to
comply with § 320.31(d)(3).
15 We note that IND-exempt BA/BE studies are not subject to the requirements in § 312.66. However, they must
still be conducted in compliance with the requirements for review by IRBs as established in 21 CFR part 56 (see
§ 320.31(d)(2)). Section 56.108(b)(1) provides that an IRB’s written procedures must ensure the prompt reporting
to the IRB of “any unanticipated problems involving risks to human subjects or others.” FDA interprets this
language in a manner consistent with the interpretation of § 312.66 laid out in this guidance.
16 Sponsors may require investigators to report to them such unanticipated problems as part of the sponsor’s clinical
trial monitoring responsibility (see, e.g., § 312.50).
17 A non-U.S. IRB/Ethics Committee in a multinational study may have additional reporting requirements.

Contains Nonbinding Recommendations
9
− 	The investigator must submit IND safety reports18 to the IRB (§ 312.66) because
FDA considers safety information that meets the IND safety reporting criteria
under § 312.32(c) to be an unanticipated problem involving risk to human
participants or others.
− 	FDA considers the occurrence of any SAE in an IND-exempt BA/BE study to be
an unanticipated problem involving risk to human participants or others that
must be reported to the IRB (§ 56.108(b)(1)). Reporting SAEs in a BA/BE study
is important for human participant protection because the occurrence of SAEs in
BA/BE studies is unusual: the number of participants enrolled is small, the
participants are usually healthy volunteers, and drug exposure is typically brief,
although often at the highest available dosage.
• 	Certain events may not meet the criteria for reporting in an IND safety report or as a
BA/BE study premarket SAE, but still must be reported to the IRB because they
represent unanticipated problems involving risk to human participants or others.
− 	Such events may occur at the participant, site, and/or study level and may
include serious and unexpected adverse events that occur prior to test article
administration, during a washout period, or that are attributable to a screening
procedure.
− 	Other examples may include reports of medication errors (such as receipt of
wrong dose or contaminated study medication), breach of privacy/confidentiality
(such as disclosure of personally identifiable information), untimely destruction
of study records, and other scenarios.
• 	The IRB may have written procedures or institutional policies that require the
investigator to submit to them other events, in addition to those that qualify for
reporting under § 312.66.
VII. 	INVESTIGATOR REPORTING TO SPONSORS AND INSTITUTIONAL
REVIEW BOARDS FOR IDE STUDIES
The IDE regulations require the investigator to report UADEs to both the sponsor and the IRB
(see § 812.150(a)(1)). The investigator is required to submit a report of a UADE to the sponsor
and the reviewing IRB as soon as possible, but in no event later than 10 working days after the
investigator first learns of the effect (§ 812.150(a)(1)). In addition to reporting UADEs, the
18 Many study protocols specify that the sponsor will submit IND safety reports to the IRB on the investigator’s
behalf. In these situations, where the investigator receives confirmation that the sponsor has sent the report to the
IRB, FDA would not expect an investigator to provide the IRB with a duplicate copy of the report. Such an
agreement should be documented.

Contains Nonbinding Recommendations
10
investigator is to provide progress reports to the sponsor, the monitor, and the IRB19 at regular
intervals and no less than yearly (§ 812.150(a)(3)). Such reports should provide information
about both anticipated and unanticipated adverse device effects.
VIII. 	SPONSOR RESPONSIBILITIES
While the focus of this guidance is on investigator responsibilities, this guidance discusses some
of the sponsor responsibilities20 given the close relationship between investigators and sponsors
in the IND and IDE safety reporting process.
The regulations in § 312.32(c)(1) require the sponsor to notify FDA and all participating
investigators (i.e., all investigators to whom the sponsor is providing the drug under the
sponsor’s INDs or under any sponsor-investigator’s IND) in an IND safety report21 of potential
serious risks identified from clinical trials or any other source as soon as possible but in no case
later than 15 calendar days after the sponsor determines that the information qualifies for
reporting under § 312.32(c)(1)(i) through (iv), which includes any of the following:
• 	Serious and unexpected suspected adverse reactions22
• 	Findings from epidemiological studies, pooled analyses of multiple studies, or clinical
studies that suggest a significant risk in humans exposed to the drug
• 	Findings from animal or in vitro testing that suggest a significant risk in humans exposed
to the drug
• 	Any clinically important increase in the rate of a serious suspected adverse reaction over
that listed in the protocol or investigator brochure
For IND-exempt BA/BE studies, § 320.31(d)(3) states that “[t]he person conducting the study,
including any contract research organization, must notify FDA and all participating investigators
of any serious adverse event [SAE], as defined in § 312.32(a), observed during the conduct of
the study as soon as possible but in no case later than 15 calendar days after becoming aware of
19 The terms sponsor, monitor, and IRB for purposes of the IDE regulations are defined in § 812.3.
20 For an in-depth discussion of sponsor responsibilities, see the guidance for industry Sponsor Responsibilities—
Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies
(December 2025).
21 For more information on electronic submission of IND safety reports, see the guidance for industry Providing
Regulatory Submissions in Electronic Format: IND Safety Reports (April 2024) and the guidance for industry FDA
Regional Implementation Guide for E2B(R3) Electronic Transmission of Individual Case Safety Reports for Drug
and Biological Products (April 2024).
22 Note that if the unexpected suspected adverse reaction is fatal or life-threatening, the requirement is to notify FDA
as soon as possible but no later than 7 calendar days after the sponsor’s initial receipt of the information (see
§ 312.32(c)(2)). As with all serious and unexpected suspected adverse reactions, sponsors must report unexpected
fatal or life-threatening suspected adverse reactions to all participating investigators (see § 312.32(c)(1)).

Contains Nonbinding Recommendations
11
its occurrence.” Section 320.31(d)(3) also requires the person conducting the study (including
any contract research organization) to notify FDA of any “fatal or life-threatening adverse event
from the study as soon as possible but in no case later than 7 calendar days after becoming aware
of its occurrence.” However, the regulation does not require all investigators to be notified of
such events within that time frame.
FDA believes that the sponsor is generally better positioned than the individual investigator to
determine whether an SAE should be classified as a serious suspected adverse reaction. This is
especially true for events that may warrant analysis of more than a single event to determine if
any are possibly related to the drug, because the sponsor may have access to SAE reports from
multiple study sites and multiple studies and would be able to aggregate and analyze these
reports. Moreover, the sponsor is likely to be more familiar with the drug’s mechanism of
action, class effects, and other information. The sponsor should carefully consider the
investigator’s assessment of causality; however, it is ultimately the sponsor’s responsibility to
determine whether an SAE meets the definition of a serious suspected adverse reaction (see
section III.A.2 and section V.A). It is also the sponsor’s responsibility to determine whether an
adverse event is unexpected (§ 312.32(a) and (c)(1)(i)).
For IDE studies, FDA also believes that the sponsor is generally better positioned than the
individual investigator to assess UADEs and their impact on the investigation, given that the
sponsor may have access to UADE reports from multiple study sites and multiple studies and is
able to aggregate and analyze these reports. Therefore, review of UADE reports by sponsors is
critical to the protection of participant safety, and the IDE regulations require not only timely
reporting for investigators but also timely evaluation by sponsors. For device studies under an
IDE, the regulations in 21 CFR 812.46(b) and 812.150(b)(1) require sponsors to conduct an
evaluation of any UADE immediately and to report the results to FDA, all reviewing IRBs, and
all participating investigators within 10 working days after the sponsor first receives notice of the
effect. What qualifies as a UADE is expected to vary depending on the specific device and the
way the device is used within the study. Therefore, sponsors are required to include risk
information in the investigational plan, and to provide copies of the investigational plan to all
investigators participating in the investigation, which may help investigators identify and assess
potential UADEs (§§ 812.25(c) and 812.45).