IND Application Reporting: IND Safety Reports

This webpage provides an overview of investigational new drug application (IND) safety reporting requirements for sponsors set forth in 21 CFR 312.32 and additional resources, including FDA guidances, related to these requirements. This webpage is intended to help IND sponsors (including sponsor-investigators) and other interested parties understand what must be reported in an IND safety report, timeframes for reporting, and how to submit IND safety reports to FDA. For the complete IND safety reporting requirements, refer to the regulations at section 312.32 and related requirements (including requirements for the electronic submission of IND safety reports under section 745A(a) of the Federal Food, Drug, and Cosmetic Act and, as applicable, postmarketing safety reporting requirements).

IND sponsors must notify FDA and all participating investigators in an IND safety report of potential serious risks, from clinical trials or any other source, within the applicable reporting timeframe after the sponsor determines that the information qualifies for reporting under section 312.32(c)(1)(i) through (iv):

Any suspected adverse reaction that is both serious and unexpected. The sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the drug and the adverse event, such as:
- 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 (e.g., known consequences of the underlying disease or condition; events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group.
Any findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported under 21 CFR 312.32(c)(1)(i)), whether or not conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug.
Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human exposure.
Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

In each IND safety report, sponsors must reference all similar previously submitted reports and analyze the significance of each suspected adverse reaction in light of previous similar reports and any other relevant information. See 21 CFR 312.32(c)(1).

Key Terms

Key Terms (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.

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. A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse reaction, which means any adverse event caused by the drug.

Serious adverse event or serious suspected adverse reaction refers to an adverse event or suspected adverse reaction that, in the view of either the investigator or sponsor, results in any of the following outcomes:

death,
a life-threatening adverse event,
in-patient 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 or birth

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.

Life-threatening adverse event or life-threatening suspected adverse reaction refers to an adverse event or suspected adverse reaction that, in the view of either the investigator or sponsor, 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.

Unexpected adverse event or unexpected suspected adverse reaction refers to an adverse event or suspected adverse reaction that is not listed in the investigator’s brochure or is not listed at the specificity or severity that has been observed; or, if an investigator’s brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current IND application.

Reporting Timeframes

Initial reporting:

For potential serious risks that qualify for reporting under 21 CFR 312.32(c)(1)(i) through (iv): Sponsors must notify FDA and all participating investigators as soon as possible but no later than 15 calendar days after the sponsor’s determination that the information qualifies for reporting. See 21 CFR 312.32(c)(1).
- Participating investigators are all investigators to whom the sponsor is providing the drug under its INDs or under any investigator’s IND.
For unexpected fatal or life-threatening suspected adverse reactions: Sponsors must notify FDA as soon as possible but no later than 7 calendar days after the sponsor’s initial receipt of the information. See 21 CFR 312.32(c)(2).

Follow-up reporting:

The sponsor must promptly investigate all safety information it receives. See 21 CFR 312.32(d)(1).
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 as soon as the information is available. See 21 CFR 312.32(d)(2).
If the results of a sponsor's investigation show that an adverse event not initially determined to be reportable under section 312.32(c) is reportable, the sponsor must report such suspected adverse reaction in an IND safety report as soon as possible but no later than 15 calendar days after the determination is made. See 21 CFR 312.32(d)(3).

IND Safety Reporting Decision Tree

Decision Tree for IND Safety Reporting to FDA and Investigators *

Has the sponsor or investigator assessed the adverse event as serious?
Yes: The event is a serious adverse event (SAE). Proceed to Question 2.
No: The event is not reportable as an IND safety report. Include in the IND annual report (see 21 CFR 312.33) or an information amendment (see 21 CFR 312.31) as appropriate.

Has the sponsor determined the SAE is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed? (If an investigator brochure is not required or available, has the sponsor determined the SAE is not consistent with the risk information described in the general investigational plan or elsewhere in the current IND application)?
Yes: The SAE is unexpected. Proceed to Question 3.
No: Proceed to Question 4.

Has the sponsor determined there is a reasonable possibility the drug caused the SAE? For example, has the sponsor identified:
- A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure?
- 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?
- Based on aggregate analysis, an event anticipated to occur in the study population independent of drug therapy is occurring more frequently in the drug treatment group than in a concurrent or historical control group?
Yes: The event is a serious and unexpected suspected adverse reaction that must be reported in an IND safety report according to section 312.32(c)(1)(i). Submit an IND Safety Report.
No: The event is not reportable in an IND safety report. Include in an annual report (see 21 CFR 312.33) or an information amendment to the IND (see 21 CFR 312.31) as appropriate.

Has the sponsor determined the SAE indicates a clinically important increased rate of occurrence of a serious suspected adverse reaction over that listed in the protocol or investigator brochure?
Yes: The increased rate of occurrence of the serious suspected adverse reaction must be reported in an IND safety report according to section 312.32(c)(1)(iv). Submit an IND Safety Report.
No: The event is not reportable in an IND safety report. Include in an annual report (see 21 CFR 312.33) or an information amendment to the IND (see 21 CFR 312.31) as appropriate.

For Other Findings

An IND Safety Report also is required when the sponsor identifies:

Any finding from other studies or analyses, whether or not conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug.
Any finding from animal or in vitro testing (e.g., carcinogenicity, mutagenicity, teratogenicity, or significant organ toxicity at or near expected human exposure) suggesting a significant risk in humans exposed to the drug.

Such findings ordinarily would 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. See 21 CFR 312.32(c)(1)(ii) and (iii).

* This decision tree is intended as a helpful tool for determining whether adverse events and other safety information must be submitted to FDA and participating investigators in an IND safety report. It does not cover all the IND safety reporting requirements set forth in 21 CFR 312.32. Sponsors are responsible for complying with 21 CFR 312.32 and related requirements (including requirements for the electronic submission of IND safety reports under section 745A(a) of the Federal Food, Drug, and Cosmetic Act and postmarketing safety reporting requirements (see, e.g., 21 CFR 314.80 and 314.81) as applicable) and are encouraged to have a thorough understanding of applicable requirements and FDA guidance on this topic.

Submitting IND Safety Reports

Format for IND Safety Reports of Serious and Unexpected Suspected Adverse Reactions

As of April 1, 2026, submission of IND safety reports of serious and unexpected suspected adverse reactions under 21 CFR 312.32(c)(1)(i) must be submitted to FDA electronically to the FDA Adverse Event Monitoring System (AEMS) database (formerly the FDA Adverse Event Reporting System (FAERS) database) using E2B(R3) data standards via Database-to-Database Transmission or the Safety Reporting Portal.

This requirement implements the electronic submission requirements of section 745A(a) of the Federal Food, Drug, and Cosmetic Act for the electronic format of the content of IND safety reports required under 21 CFR 312.32(c)(1)(i) for serious and unexpected suspected adverse reactions. Note that noncommercial INDs (i.e., INDs for products not intended for commercial distribution, including investigator-sponsored INDs and expanded access INDs) are exempt from this requirement. For more information, see FDA’s guidance for industry Providing Regulatory Submissions in Electronic Format: IND Safety Reports.
Submission of IND safety reports to the AEMS database provides a reporting format that is consistent with the International Council for Harmonisation (ICH) E2B(R3) standards. See the Adverse Event Monitoring System (AEMS) Electronic Submissions web page for more information.

Format for Other IND Safety Reports

IND safety reports of findings from other studies (section 312.32(c)(1)(ii)), findings from animal or in vitro testing (section 312.32(c)(1)(iii)), and an increased rate of occurrence of serious suspected adverse reactions over that listed in the protocol or investigator brochure (section 312.32(c)(1)(iv)) must be submitted electronically in the electronic common technical document (eCTD) format. See FDA’s guidance for industry Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specification.

This table illustrates the submission locations described above for the different types of IND safety reports:

Type of report	Submit to AEMS	Submit to eCTD
A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (21 CFR 312.32(c)(1)(i)(A))	X
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 (21 CFR 312.32(c)(1)(i)(B))	X
An aggregate analysis of specific events observed in a clinical trial (e.g., known consequences of the underlying disease or condition under investigation, other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group (21 CFR 312.32(c)(1)(i)(C))	X
Findings from other studies (21 CFR 312.32(c)(1)(ii))		X
Findings from animal or in vitro testing (21 CFR 312.32(c)(1)(iii))		X
Increased rate of occurrence of serious suspected adverse events (21 CFR 312.32(c)(1)(iv))		X

For specifications, recommendations, and general considerations on how to submit electronic IND safety reports to FDA, see the Electronic Submission of IND Safety Reports: Technical Conformance Guide.

Resources

For more information on the IND sponsor’s responsibilities for IND safety reporting, including detailed explanations of the above definitions, requirements, and submission procedures, refer to FDA’s guidance for industry Sponsor Responsibilities—Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies. Additional topics addressed in this guidance include the sponsor’s review of safety information, including the development of safety surveillance plans; considerations for aggregate data analyses and approaches to for assessing aggregate data for IND safety reporting purposes; considerations for U.S-marketed drugs; and other safety reporting issues.

For related information on the investigator’s responsibilities for safety reporting, refer to FDA’s guidance for investigators, industry, and institutional review boards Investigator Responsibilities – Safety Reporting for Investigational Drugs and Devices.

For information on investigator-initiated INDs, see Investigator-Initiated IND Applications.

Select ICH Guidances: