In December 2025, the U.S. Food and Drug Administration released two final guidance documents focused on safety reporting in clinical research: Investigator Responsibilities Safety Reporting for Investigational Drugs and Devicesand Sponsor Responsibilities: Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies.
Together, the guidances describe FDA’s current thinking on how investigators and sponsors can meet safety reporting expectations in studies conducted under an investigational new drug application, in investigational device exemption studies, and in certain bioavailability/bioequivalence studies that meet conditions for IND exemption.
Why FDA Updated These Documents?
FDA frames the updates as part of a broader effort to improve the overall quality of safety reporting so that regulators, investigators, and institutional review boards can better focus on safety information most relevant to participant protection. The Federal Register notice for the sponsor guidance reiterates that compliance with the IND safety reporting framework is intended to increase the likelihood that submitted information is interpretable and meaningfully contributes to an investigational drug’s developing safety profile.
The investigator guidance also explains that it incorporates and clarifies concepts from earlier FDA guidance documents on safety reporting responsibilities and replaces prior recommendations contained in earlier guidances that addressed these topics.
Investigator Responsibilities: Safety Reporting for Investigational Drugs and Devices
The investigator guidance is intended to help clinical investigators comply with safety reporting requirements for IND studies under 21 CFR 312.64(b) and 312.66 and for IDE studies under 21 CFR 812.150. It also provides relevant information related to serious adverse event reporting in IND-exempt BA/BE studies that meet conditions under 21 CFR 320.31(d)(3).
A key emphasis is that investigators should review safety reports received from sponsors as part of their responsibility to protect the rights, safety, and welfare of trial participants. This includes review of IND safety reports and, where applicable, safety information received from IND-exempt BA/BE studies, as well as review of unanticipated adverse device effect reports in IDE studies.
Within IND studies, FDA describes expectations for investigators to report serious adverse events to sponsors. The guidance explains that investigators must immediately report any serious adverse event to the sponsor, even if it is not considered drug-related, and may submit follow-up information after the initial report. FDA interprets “immediately” as “as soon as feasible” after the investigator recognizes the event as serious and has relevant information for the sponsor, and notes that protocols should specify a timeframe that will generally not exceed one calendar day for initial submission.
The guidance also addresses investigator reporting to institutional review boards in IND studies. Investigators must promptly report to the IRB unanticipated problems involving risk to participants or others, and FDA notes that IND safety reports and reports of serious adverse events from IND-exempt BA/BE studies may represent such unanticipated problems requiring IRB reporting.
For IDE studies, FDA highlights the established timeline for reporting unanticipated adverse device effects. Investigators are required to report a UADE to both the sponsor and the reviewing IRB as soon as possible, and no later than ten working days after first learning of the effect.
Sponsor Responsibilities: Safety Reporting Requirements and Safety Assessment for IND and BA/BE Studies
The sponsor guidance provides recommendations for sponsors and sponsor-investigators to comply with IND safety reporting requirements and safety reporting obligations for IND-exempt BA/BE studies. FDA’s guidance page summarizes that the document interprets key terms used for safety reporting, makes recommendations on when and how to submit a safety report, and addresses additional safety reporting issues raised by sponsors, including recommendations related to IND safety reporting provisions that require assessment of aggregate data.
In the Federal Register notice announcing availability of the final sponsor guidance, FDA states that the guidance finalizes the June 2021 draft and identifies updates made during finalization. These include revisions to recommended approaches for aggregate analyses intended to reduce the need for unblinding to evaluate safety data, additional considerations for small programs and rare diseases, updated information for electronic submission of IND safety reports, and editorial changes for clarity.
The sponsor guidance also reiterates the timing framework used in expedited IND safety reporting. It describes that the timeframe for submitting an IND safety report to FDA and participating investigators is as soon as possible, and no later than fifteen calendar days after the sponsor determines the information qualifies for reporting under 21 CFR 312.32(c)(1). It further specifies that unexpected fatal or life-threatening suspected adverse reactions must be reported as soon as possible, and no later than seven calendar days after the sponsor’s initial receipt of the information, consistent with 21 CFR 312.32(c)(2).
For IND-exempt BA/BE studies, the sponsor guidance describes that the entity conducting the study, including any contract research organization, must notify FDA and all participating investigators of any serious adverse event observed during conduct of the study as soon as possible, and no later than fifteen calendar days after becoming aware of its occurrence.
Relationship to Prior Guidances
FDA explains that the two December 2025 guidances are designed to operate together, with one focused primarily on investigator responsibilities and the other focused on sponsor responsibilities and safety assessment. The sponsor guidance notes that it replaces the prior 2012 final guidance in the areas addressing sponsor responsibilities, and that, concurrent with publication of these two guidances, the earlier guidance was withdrawn.
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Written by Nare Hovhannisyan, MD