SUSAR (Suspected Unexpected Serious Adverse Reaction)

SUSAR is a European coinage, not an ICH one. The three-part test it names comes from ICH E2A (Current Step 4 version dated 27 October 1994), but the word appears nowhere in that guideline — E2A says “serious, unexpected adverse drug reactions” — and nowhere in US law either, where 21 CFR 312.32 spells out “serious and unexpected suspected adverse reaction” in full. A sponsor running one protocol on both sides of the Atlantic applies a single substantive standard under two vocabularies, with clocks that start on different triggers. That mismatch, not the definition, is where most classification and timing errors begin.

The three elements, and what decides each

• Serious — decided against a fixed list: results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect, plus a judgement clause for other important medical events. “Life-threatening” means the patient was at risk of death at the time of the event, not that it might have become fatal. Seriousness is not severity — see serious adverse event (SAE).
• Suspected — decided by judgement, against a deliberately low bar. E2A treats a case as an adverse drug reaction where either the reporting health care professional or the sponsor judges a reasonable suspected causal relationship, glossed as facts or arguments suggesting one. 21 CFR 312.32(a) is near-identical: a suspected adverse reaction is “any adverse event for which there is a reasonable possibility that the drug caused the adverse event,” reasonable possibility meaning “there is evidence to suggest a causal relationship.” Neither requires proven causation.
• Unexpected — decided against a document, not clinical intuition: the current Investigator’s Brochure, or approved labelling for an authorised comparator. E2A’s test is a reaction “the nature or severity of which is not consistent with the applicable product information”; 21 CFR 312.32(a) frames it as not listed, or not listed at the specificity or severity observed. Because the wordings differ, record expectedness against a named, versioned brochure.

All three must hold at once; an event failing any one is not a SUSAR, however alarming.

Who decides, and who reports

The most consequential difference between the regimes is also the one most often stated backwards. Under E2A a single investigator’s suspicion is enough to make the case an ADR; the sponsor cannot assess it away. Under 21 CFR 312.32 “the sponsor must notify FDA and all participating investigators,” and the 15-day clock runs from the point at which the sponsor determines that the information qualifies — the investigator appears there as a recipient of notifications, not the filing party. In the EU the sponsor likewise reports, to EudraVigilance under Regulation (EU) No 536/2014 (Article 42 and Annex III), while the investigator’s separate and faster duty is to report serious adverse events to the sponsor under the protocol and ICH E6. Investigator-to-sponsor and sponsor-to-regulator reporting are two different clocks; collapsing them is a recurring inspection finding.

7 days and 15 days — same durations, different start points

• ICH E2A: fatal or life-threatening unexpected ADRs, no later than 7 calendar days after first knowledge by the sponsor that a case qualifies, “followed by as complete a report as possible within 8 additional calendar days”; all other serious, unexpected ADRs, no later than 15 calendar days after first knowledge that the case meets the minimum criteria.
• 21 CFR 312.32: (c)(2) requires FDA to be notified of an unexpected fatal or life-threatening suspected adverse reaction “in no case later than 7 calendar days after the sponsor’s initial receipt of the information” — receipt, not qualification — while (c)(1)(i) sets 15 calendar days “after the sponsor determines that the information qualifies for reporting.” Applying the 15-day trigger logic to a 7-day case files it late.

E2A’s minimum criteria let an incomplete case go in on time: an identifiable patient, a suspect medicinal product, an identifiable reporting source, and an event identifiable as serious and unexpected with a reasonable suspected causal relationship. Waiting for a complete narrative is not a defence for a missed deadline. In the US the resulting filing is the IND safety report.

What is not a SUSAR — but is still reportable

Failing one element removes a case from expedited reporting, not from reporting. A serious, causally plausible event already described in the Investigator’s Brochure is expected, so it flows into routine collection and the periodic Development Safety Update Report. A serious, unexpected event with no reasonable possibility of drug causation is not a SUSAR regardless of severity. And an event flagged for close tracking is not automatically expedited: an adverse event of special interest is a sponsor-defined monitoring category that must still clear all three elements before any clock starts.

Related terms

• ICH E2A (Clinical Safety Data Management) — the source of every definition above and of the 7/15-day structure.
• Serious adverse event (SAE) — the seriousness element alone.
• Adverse event (AE) — the causality-free category cases are filtered from.
• IND safety report — the US filing a SUSAR-equivalent case becomes.
• Development Safety Update Report (DSUR) — where non-expedited safety data goes.
• Adverse event of special interest (AESI) — a monitoring designation, not a trigger.
• Good Pharmacovigilance Practices (GVP) — the EU post-authorisation equivalent.

Frequently Asked Questions

What does SUSAR stand for?

SUSAR stands for Suspected Unexpected Serious Adverse Reaction. It describes an adverse event in a clinical trial that is simultaneously serious, judged to have a reasonable suspected causal relationship to the investigational product, and unexpected relative to the current Investigator’s Brochure or approved labelling for an authorised comparator.

Does ICH E2A actually use the term “SUSAR”?

No. SUSAR is a European coinage, not an ICH one — ICH E2A refers only to “serious, unexpected adverse drug reactions,” and the word appears nowhere in US law either, where 21 CFR 312.32 spells out “serious and unexpected suspected adverse reaction” in full. The three-part test the term names does come from E2A, even though the acronym itself does not.

What’s the difference between a SUSAR and an SAE?

An SAE (serious adverse event) is any event meeting the seriousness criteria alone — death, life-threatening, hospitalisation or prolongation of hospitalisation, persistent or significant disability, or a congenital anomaly. A SUSAR is a narrower category: it must also be judged to have a reasonable suspected causal relationship to the drug and be unexpected against the current Investigator’s Brochure. Every SUSAR is serious in this sense, but not every serious adverse event is a SUSAR.

Who is responsible for reporting a SUSAR — the investigator or the sponsor?

The sponsor. Under ICH E2A, 21 CFR 312.32 in the US, and Regulation (EU) No 536/2014 in the EU, it is the sponsor who files the expedited SUSAR report to regulators, not the investigator. The investigator’s separate, faster duty is to report serious adverse events to the sponsor in the first place — under E2A, a single investigator’s suspicion is already enough to make a case reportable, and the sponsor cannot assess it away.

How long does a sponsor have to report a SUSAR?

It depends on severity. Fatal or life-threatening unexpected reactions must be reported no later than 7 calendar days after the sponsor first has the qualifying information, with a fuller follow-up report within an additional 8 days under ICH E2A. All other serious, unexpected SUSARs get 15 calendar days. The exact starting point for the clock differs between frameworks — receipt of information under 21 CFR 312.32 versus the sponsor’s determination that a case qualifies — so using the wrong trigger can make an on-time report late.