IND Safety Report

An IND Safety Report is the expedited notification that a sponsor holding an active Investigational New Drug (IND) application must send to FDA and to every participating investigator under 21 CFR 312.32, whenever the sponsor determines there is a reasonable possibility that the investigational drug caused a serious and unexpected adverse event. In practice, research teams often refer to the underlying event as a SUSAR (Suspected Unexpected Serious Adverse Reaction), a term defined in ICH E2A clinical safety data management — the report itself is the regulatory instrument that discloses a SUSAR once the sponsor has assessed it. This is a distinct, fundamental obligation of holding an IND, separate from routine adverse-event documentation, from the IND annual report, and from post-marketing adverse-event reporting under 21 CFR 314.80, which only applies once a drug is FDA-approved.

What triggers an IND Safety Report

21 CFR 312.32 requires expedited reporting only when an adverse event meets all three of the following criteria at once:

• Serious — the event results in death, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is judged by the sponsor or investigator to require medical or surgical intervention to prevent one of those outcomes.
• Unexpected — the event’s nature, severity, or frequency is not consistent with the current Investigator’s Brochure (for a marketed drug not being studied under an IND, the current package labeling serves the same reference role).
• A reasonable possibility that the drug caused the event — meaning there is evidence suggesting a causal relationship, not merely that the event occurred while the subject was taking the drug. This is a sponsor determination, made after reviewing all relevant safety information, not an automatic trigger from a single investigator’s causality guess.

An event that is serious but expected (already described in the Investigator’s Brochure), or unexpected but not serious, does not meet the bar for an expedited IND Safety Report — though it still must be tracked in the sponsor’s ongoing safety surveillance and reflected in the IND annual report.

The reporting timelines

21 CFR 312.32(c) sets two clocks, both measured from when the sponsor first receives the information, not from when the event occurred:

• 7 calendar days for any unexpected fatal or life-threatening suspected adverse reaction, reported initially by telephone or fax (or, in current practice, electronic submission through FDA’s safety reporting systems) followed by a complete written report within an additional 8 calendar days.
• 15 calendar days for other serious, unexpected suspected adverse reactions, submitted as a written IND Safety Report.

Sponsors must also submit follow-up reports promptly as significant new information becomes available, and must promptly investigate all safety information they receive. FDA may also require, and sponsors may voluntarily submit, safety reports for findings from other sources — animal or epidemiological studies, other clinical investigations, or a pooled/aggregate analysis showing a rate of a serious adverse event occurring more frequently than expected — even where no single case meets the individual-case reporting criteria.

Who must be notified

An IND Safety Report is not filed with FDA alone. Under 312.32(c), the sponsor must notify FDA and every participating investigator (in a multicenter trial, this means all investigators across all sites operating under that IND, not only the site where the event occurred). Investigators, in turn, are generally required by their institution’s IRB reporting policies — built on the broader unanticipated-problem reporting duty in 21 CFR Part 56 — to forward safety information they receive from the sponsor to their local IRB, consistent with that IRB’s written procedures.

IND Safety Report vs. related mechanisms

• vs. investigator-to-sponsor SAE reporting (21 CFR 312.64(b)): an investigator must report any serious adverse event to the sponsor immediately, regardless of the investigator’s own causality assessment. The IND Safety Report is a separate, later step — the sponsor’s own expedited notification to FDA and all investigators, made after the sponsor assesses seriousness, expectedness, and causality across the accumulating body of safety data.
• vs. the IND annual report: the annual report is a once-a-year summary of the IND’s overall status and safety experience; the IND Safety Report is event-driven and expedited, triggered only by a qualifying SUSAR.
• vs. post-marketing adverse-event reporting (21 CFR 314.80): 314.80 governs an already-approved drug and feeds FDA’s post-market surveillance database (FAERS); 312.32 applies only to investigational products still under an active trial protocol, before approval.
• vs. IRB unanticipated-problem reporting (21 CFR 56.108(b)): the IRB reporting duty is broader than SUSAR reporting — it can include non-serious findings that nonetheless represent a new or increased risk to subjects, and runs on the institution’s own procedures rather than the sponsor’s 7-/15-day clock.

For the broader picture of how adverse-event terminology and reporting obligations fit together across a trial — AE, SAE, and SUSAR definitions, investigator-to-sponsor flow, and the sponsor’s onward reporting — see CASRAI’s guide to Pharmacovigilance in Clinical Research: AE, SAE, and SUSAR Reporting.

Frequently Asked Questions

What is the difference between a SUSAR and an IND Safety Report?

A SUSAR (Suspected Unexpected Serious Adverse Reaction) is the adverse event itself, once a sponsor has assessed it as serious, unexpected, and possibly drug-related. The IND Safety Report is the separate regulatory instrument — the expedited notification the sponsor sends to FDA and every participating investigator to disclose that SUSAR under 21 CFR 312.32.

What makes an adverse event “serious” under 21 CFR 312.32?

An event is serious if it results in death, is life-threatening, requires or prolongs inpatient hospitalization, causes persistent or significant disability, results in a congenital anomaly, or is judged to require medical or surgical intervention to prevent one of those outcomes. It must also be unexpected and reasonably possibly caused by the drug before it triggers an expedited IND Safety Report.

What makes an adverse event “unexpected” under 21 CFR 312.32?

An event is unexpected if its nature, severity, or frequency is not consistent with the current Investigator’s Brochure. For a marketed drug not being studied under an IND, the current package labeling serves the same reference role.

How many days does a sponsor have to file an IND Safety Report?

21 CFR 312.32(c) sets two timelines, both measured from when the sponsor first receives the information. Fatal or life-threatening unexpected suspected adverse reactions must be reported within 7 calendar days (initially by phone, fax, or electronic submission, followed by a complete written report within 8 more days), while other serious, unexpected suspected adverse reactions must be reported in writing within 15 calendar days.

Who has to be notified when a sponsor files an IND Safety Report?

The sponsor must notify FDA and every participating investigator, not just the site where the event occurred — in a multicenter trial that means all investigators at all sites operating under that IND. Investigators are then generally required by their institution’s IRB policies to forward that information to their local IRB.

How is an IND Safety Report different from an investigator’s SAE report to the sponsor?

Under 21 CFR 312.64(b), an investigator must report any serious adverse event to the sponsor immediately, regardless of the investigator’s own view on causality. The IND Safety Report is a separate, later step: the sponsor’s own expedited notification to FDA and all investigators, made only after the sponsor has assessed seriousness, expectedness, and causality across the accumulating safety data.