The Reference Document Decides

Part of Pharmacovigilance and Drug Safety (PV) Training: Expectedness.

About 1 minutes. Free, in your language, no account needed.

Expectedness is not about what you would expect

This is the single most counterintuitive concept in pharmacovigilance. Expectedness has nothing to do with clinical intuition, experience, or whether the event is common in the population.

An event is expected if it appears in the applicable reference document, in the right form. If it does not appear there, it is unexpected, no matter how unsurprising it is.

Which document

For an investigational product in a trial, the reference is the Reference Safety Information, normally a specific section of the Investigator's Brochure. Not the whole brochure. The section designated as the RSI.

For an authorized product, the reference is the approved product information: the Summary of Product Characteristics in the EU, the package insert in the United States, or the relevant local label.

Version matters

The RSI in force is the one approved for that trial at the time of the assessment, not the latest draft. When an updated Investigator's Brochure is approved, the RSI changes, and events that were unexpected may become expected from that date.

Getting the version wrong is a real and recurring error. Assessing against a superseded document produces submissions that are wrong in a way nothing downstream will catch.

Why the rule is mechanical on purpose

Because expectedness determines regulatory obligation, and a threshold that varied with an assessor's clinical experience would not be a threshold at all. The mechanical rule is what makes the determination reproducible.

Nausea with a chemotherapy agent is as ordinary as anything in medicine. If the RSI does not list it, it is unexpected.