Chapter 2

The Mechanics of Expectedness: Listedness vs. Labeling

Reference Safety Information (RSI) Hierarchy

Hover each document for additional context

Global / Internal

CCSI — Company Core Safety Information

Internal global safety position, housed within the CCDS (Company Core Data Sheet)

Determines: "Listedness" globally
If an event is not in the CCSI, it is considered "unlisted" and may trigger expedited reporting obligations across all jurisdictions.
EU

SmPC — Summary of Product Characteristics

Regulator-approved labeling in the EU

Determines: "Labeling" in the EU
If an event is not listed in the SmPC, it is considered "unlabeled" for the EU jurisdiction.
US

USPI — US Package Insert

Regulator-approved labeling in the US

Determines: "Expectedness" in the US
If an event is not in the USPI, it is "unexpected" — triggering 15-day expedited reporting to the FDA.
Clinical Trials

IB — Investigator's Brochure

For unapproved products, the IB is the sole RSI for determining expectedness

Determines: Expectedness during development
The IB is the only reference safety document available for investigational drugs. All SUSARs in trials are assessed against the IB.

Expectedness Decision Flow

New Safety Event Reported Is the event in the RSI? YES Is it the same severity & specificity? YES EXPECTED Routine reporting NO UNEXPECTED Greater severity/specificity NO UNEXPECTED Not listed in RSI at all Expedited Reporting

Specificity & Severity Rule

Greater Severity

Label: "Pneumonia" → Actual: "Fatal Pneumonia"
Unexpected — fatal outcome exceeds listed severity

Greater Specificity

Label: "Skin Rash" → Actual: "Stevens-Johnson Syndrome"
Unexpected — specific diagnosis exceeds generic term

Why This Matters

The specificity and severity rule prevents companies from hiding serious outcomes under vague or mild terminology in their product labels. It ensures that the safety profile is continuously updated as more severe or specific manifestations emerge.

Day 0 — The Regulatory Clock

Day 0
Awareness
Anyone in the company first learns of the event
Day 1–3
Triage & Coding
Validate case, assess seriousness & expectedness
Day 4–10
Medical Review
Physician causality assessment & narrative
Day 15
Regulatory Deadline
Expedited report must be submitted to authorities

Key Operational Detail

The "Day 0" clock starts when anyone in the company — including sales representatives, MSLs, or admin staff — becomes aware of the event, not when the safety department receives the formal report. This makes PV awareness training critical across all company functions.

Pharmacovigilance Manual — Causality Assessment & Signal Detection · Chapter 2