Finalized Guidance for Industry: Investigator Responsibilities for Safety Reporting

01/08/2026

Photo by Nick Fewings on Unsplash    

On December 15th, 2025, the US Food and Drug Administration (FDA) released the finalized guidance for industry “Investigator Responsibilities — Safety Reporting for Investigational Drugs and Devices”. Unlike most updates, this finalized guidance is replacing the FDA’s recommendations from two separate final guidance documents: “Safety Reporting Requirements for INDs and BA/BE Studies” from 2012 and “Adverse Event Reporting to IRBs—Improving Human Subject Protection” from 2009, both of which are now withdrawn. The guidance provides a framework for clinical investigators to comply with the safety reporting requirements for investigational new drug application (IND) studies and investigational device exemption (IDE) studies and highlights some of the sponsor responsibilities for timely safety reporting to the FDA, without overwhelming them with a constant influx of individual reports. The guidance also applies to SAEs related to bioavailability/ bioequivalence (BA/BE) studies that meet conditions for IND exemption under 21 CFR 320.31(d)(3).

Key terms used as found in the Code of Federal Regulations (CFR) with added emphasis follow.

Related to INDs (21 CFR 312.32(a)):

  • Adverse Event (AE) (or Adverse Experience): means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. This includes the use of the investigational product (IP), active comparator, or a placebo.

  • 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.

  • Reasonable possibility is interpreted in the guidance as there is evidence to suggest a causal relationship between the drug and the adverse event.

  • Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction:  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. (21 CFR 312.32(a))

Related to IDEs  (21 CFR 812.3(s)):

  • Unanticipated Adverse Device Effect (UADE):  Any serious adverse effect on health or safety, or any life-threatening problem or death caused by, or associated with, a device that was not previously identified or unanticipated serious problems that may impact the rights, safety, or welfare of participants.

  • Serious: An adverse effect 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. (21 CFR 812.3(s))

Investigator IND and IDE Safety Reporting

The review of IND safety reports and UADE reports from the sponsor, is considered a critical responsibility of the investigator to protect the rights, safety and welfare of participants as required under 21 CFR 312.60 (IND) and 21 CFR 812.100 (IDE). Safety reports contain information about safety events (ex. AEs, SAEs) from other investigators working under the same sponsor IND or IDE, that is often outside what was previously expected from the IP according to the investigator’s brochure and protocol. Therefore, it is essential that each investigator reads and understands these reports as they are intended to inform investigators about potential health concerns that were not previously noted.

Investigator Reporting Requirements

The following safety related reporting requirements apply for investigators.

IND Studies:

  • Immediate reporting of SAEs to the sponsor, regardless if IP-related. The guidance clarifies immediate to mean as soon as feasible after the investigator is aware the event meets criteria for SAE and recommends an interval of no longer than 1 calendar day, although this is frequently defined by the sponsor in the protocol.

  • It is noted that details the investigator includes in the report are important since they are more knowledgeable about the participant’s clinical status and therefore better suited to distinguish between a safety event being possibly related to the IP versus being related to an underlying clinical condition or concomitant medications.

  • Although the sponsor determines if an SAE is a suspected adverse reaction, the investigator’s interpretation of whether the SAE is related to the IP is important to be taken into account.

IDE studies:

  • UADEs must be reported to the sponsor and IRB as soon as possible but no later than 10 days.

  • Annual UADE progress reports are to be provided to the sponsor, monitor, and IRB. 

Sponsor Responsibilities

For IND studies, the guidance emphasizes the requirement for the sponsor to notify the FDA and all participating investigators of potential serious risks (including Serious and Unexpected Suspected Adverse Reactions, or SUSARs, and clinically important increases in the rates of serious suspected adverse reactions) within 15 calendar days. (21 CFR 312.32(c))

For IND-exempt BA/BE studies, the person conducting the study must notify the FDA and participating investigators of SAEs no later than 15 calendar days after awareness. If the information is considered fatal or life-threatening, the reporting deadline to FDA is shortened to 7 calendar days. (21 CFR 320.31(d))

In IDE studies, sponsors are required to conduct an evaluation of UADEs and report the results to the FDA, reviewing IRB, and all participating investigators within 10 working days after receiving notice of the effect. (21 CFR 812.46(b) and 812.150(b)(1)) Because devices and the way they function differ, risk information is included in the investigational plan to define what is considered a UADE, and the risk information is provided to investigators to assist in the identification of potential UADEs. (21 CFR 812.25(c) and 812.45)

The FDA believes that sponsors are generally better positioned than individual investigators to determine if an event should be considered expected or unexpected for both IND and IDE studies, as they have access to SAE and UADE reports from multiple sites and can aggregate and analyze the reports. For IND studies, it is expected for the sponsor to take into account the investigator’s assessment of causality, although ultimately the sponsor determines if an adverse event is unexpected and whether an SAE meets the definition of a serious suspected adverse reaction.

There are a couple differences between the old and new guidance. Safety reporting for bioavailability and bioequivalence studies (BA/BE) have been isolated into their own guidance document which was released at the same time and is primarily sponsor focused. Also, the new guidance is primarily focused on investigator; it more clearly describes and emphasizes the responsibilities of the investigator when reporting safety information to the sponsor where the previous guidance documents had a more split focus of both sponsor and investigator responsibilities.

The entire guidance is available on the FDA website, and those who wish to comment on the new guidance can do so any time on the docket. The information in this guidance is important to understand in regards to passing the FDAs Bioresearch Monitoring (BIMO) inspections of both investigators (see section “N” in the linked BIMO Manual) and sponsors (see section “J” in the linked BIMO Manual). If you think further clarifications about the guidance and the requirements within may be needed, consider reaching out to Clinical Pathways, we can help prepare you and your company for BIMO and other regulatory inspections.

-The Clinical Pathways Team

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