Expectedness and the Reference Safety Information
Part of Principal Investigator (PI) Training: Adverse Event Assessment.
About 4 minutes. Free, in your language, no account needed.
Why this matters
Expectedness is the third of the three assessments, and it is the one investigators most often assume is somebody else's job. It is not a clinical impression of whether an event is surprising. It is a comparison against a specific document, and getting it wrong in either direction has consequences: an unexpected reaction wrongly called expected is a safety report that never happens.
The definition
An unexpected adverse drug reaction is one whose nature or severity is not consistent with the applicable product information — for an investigational product, the current Investigator's Brochure, or the specific section of it designated as the reference safety information.
Three parts of that sentence do work.
"Nature or severity." Either is enough. Hepatitis in a product whose Brochure describes transient transaminase elevation is unexpected by nature. Fatal hepatic failure where the Brochure describes mild reversible hepatotoxicity is unexpected by severity, even though liver injury is listed. Severity escalation beyond what is described makes an otherwise-listed event unexpected — this is the limb most often missed.
"Not consistent with." Not "absent from". An event described in a different population, at a different dose, or with a different mechanism may still be inconsistent with what the document says.
"Applicable product information." A specific, versioned document. Which one is a question with an answer, and you should know it for your trial.
Which document, and which version
Ask your sponsor at start-up, in writing:
- Which document is the reference safety information for expectedness — the Investigator's Brochure as a whole, or a designated section of it?
- Which version is current, and how will you be told when it changes?
- Where an approved product is used as a comparator, is expectedness for that arm judged against its approved labeling instead?
Then keep the current version somewhere you will actually open it, and read updates when they arrive. A Brochure update can convert an event you have been calling unexpected into an expected one, and vice versa. Section 2.1's requirement to be familiar with the appropriate use of the investigational product is a continuing one, not a start-up one.
Where the three assessments combine
Seriousness, causality and expectedness are independent, and the combination determines the reporting route.
| Serious | Related | Unexpected | What it is |
|---|---|---|---|
| No | Either | Either | Adverse event; routine reporting |
| Yes | No | Either | Serious adverse event; report per protocol |
| Yes | Yes | No | Serious suspected reaction, expected |
| Yes | Yes | Yes | Suspected unexpected serious adverse reaction |
The last row is the one with an expedited regulatory route. Note that the sponsor, not the site, makes the regulatory submission — but the sponsor's assessment is built on yours, and where you and the sponsor disagree, both assessments are generally retained rather than reconciled.
Two practical habits
Do not defer. "The sponsor will decide expectedness" is a common answer and, where the protocol asks the investigator for the assessment, it is not an available one. Make the call, record it, and let the sponsor make theirs.
Tell the ethics committee what they need to know. Section 2.4 requires prompt communication to the IRB or IEC of adverse new information — including new safety information affecting the conduct of the trial or the participants. Committees differ in what they want and how fast; ask yours at start-up rather than guessing during a weekend.
Key takeaways
- Unexpected means the nature or severity is inconsistent with the applicable product information — usually the Investigator's Brochure or its designated reference safety information section.
- Severity beyond what is described makes a listed event unexpected; this limb is the one most often missed.
- Establish at start-up which document and version governs, and read updates as they arrive.
- Serious + related + unexpected is the combination with an expedited route; make your own assessment rather than deferring it to the sponsor.