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The FDA’s CDER and CBER recently issued a revision of the Small Entity Compliance Guide: Safety Reporting Requirements for INDs and BA/BE Studies.
It’s a short Q&A guide meant to help small businesses comply with FDA’s expedited safety reporting regulations. Those cover drugs and biologics studied under an IND, and bioavailability (BA) or bioequivalence (BE) studies that are exempt from the IND requirements.
The revision might have been easy to miss since the FDA handled it under Level 2 guidance procedures, and the guidance history notes that no new notice of availability was issued for the October 2026 revision.
Here’s what the revision does, what the guide says, and what teams should check as a result.
What changed in Revision 1
According to the guidance history, the changes here are limited to three things:
Updating Section II to reflect the current history of guidance on this topic
Replacing outdated guidance references
Minor editorial changes
The requirements the guide explains come from a final rule the FDA published on September 29, 2010. That rule revised the IND safety reporting requirements in 21 CFR part 312 and added safety reporting requirements for BA/BE studies in 21 CFR part 320. The guide first appeared in December 2012.
So this revision changes no requirements. It updates the references.
The reference change is the part you might need to act on
The guide was first issued alongside FDA’s 2012 final guidance, Safety Reporting Requirements for INDs and BA/BE Studies. That guidance is gone, along with one other. In December 2025, the FDA issued two final guidances that replaced them.
For sponsors: Sponsor Responsibilities — Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies. Per the revised guide, it incorporated content from the 2012 guidance and replaced it with respect to sponsors’ safety reporting responsibilities for INDs and BA/BE studies. (Federal Register notice)
For investigators, industry, and IRBs: Investigator Responsibilities — Safety Reporting for Investigational Drugs and Devices. This covers investigator responsibilities for reporting adverse events to sponsors and IRBs. It replaced the corresponding recommendations for investigators in both the 2012 guidance and the January 2009 guidance Adverse Event Reporting to IRBs — Improving Human Subject Protection. (Federal Register notice)
To be clear, the FDA withdrew both the 2012 and 2009 guidance. The revised guide now points readers to the two 2025 guidances as the current guidance on this topic.
One nuance matters if you’re updating documents on your end. The guide says the sponsor guidance incorporated content from the 2012 guidance. It doesn’t say the content carried over unchanged.
Repointing an SOP’s citation without reading the 2025 guidance isn’t a real update!
What the Q&As say at a glance
The guide answers eight questions. Some carry legal obligations and some carry recommendations. The distinction there is important, so here’s each one with the key piece you need to know.
Q1. Small entities aren’t exempt. Small entities are required to follow the IND safety reporting regulations at 21 CFR 312.32 and 312.64(b), and the BA/BE safety reporting regulation at 21 CFR 320.31(d)(3).
Q2. Sponsor-investigators carry both sets of obligations. The guide quotes the 21 CFR 312.3 definition: a sponsor-investigator is an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The requirements that apply to a sponsor-investigator include those for both an investigator and a sponsor. The IND safety reporting requirements at 312.32 and 312.64(b) therefore apply to a study run by a sponsor-investigator, often called an investigator-initiated study.
Q3. You’re responsible for the safety information you have, and you should go looking for more. FDA recognizes that a sponsor or sponsor-investigator running one trial may not have access to the complete safety data a commercial sponsor holds. The requirement is to evaluate all safety information available to them to determine whether it qualifies for reporting under 312.32.
On top of that requirement, FDA recommends two things. Sponsors and sponsor-investigators should examine reports in the scientific literature and run literature searches to actively seek new safety information about the drug. And entities that provide a drug to, or receive a drug from, other entities should share safety information with each other.
Q4. Aggregate reporting needs a plan and a cross-study view. The regulation at 312.32(c)(1)(i)(C) requires an IND safety report when an aggregate analysis of specific events in a trial indicates those events occur more frequently in the drug treatment group than in a control group. To comply, FDA recommends that sponsors:
have a predefined safety monitoring plan, with processes and procedures for reviewing, evaluating, and managing safety information
run aggregate analyses of specific events both for individual studies and across all studies, including across INDs of the drug, to determine whether the events meet the criteria at 312.32(c)(1)(i)(C) or 312.32(c)(1)(iv)
As in Q3, those analyses are run on the data available to the sponsor.
Q5. The 2010 safety-reporting rule didn’t change the IND annual report requirements. The revised safety reporting requirements made no changes to the IND annual report requirements at 21 CFR 312.33.
Q6. The 2010 safety-reporting rule didn’t change what investigators report to IRBs.
Q7. For current guidance, go to the two 2025 guidances.
Q8. Know who to ask. For questions on IND safety reporting, contact the CDER or CBER review division responsible for the IND. For BA/BE safety reporting, contact OGD-PremarketSafetyReports@fda.hhs.gov.
A quick refresher on the reporting clocks
The guide cites the regulations but doesn’t restate their timelines. These come from the regulations themselves, summarized here so you can check your procedures against them.