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PV Modules

MODULE 7: EXPECTEDNESS

Expectedness determines whether an adverse event (or adverse reaction) is listed in the product’s reference safety information (RSI). It answers the question: Is this adverse reaction already known (expected) for this medicine/vaccine/biologic, or is it new/unlisted (unexpected)?

  • Expected = event (by term, nature, severity, or frequency) appears in the RSI (e.g., Investigator Brochure (IB) for clinical trials; SmPC/label/Core Data Sheet/CDS for marketed products).
  • Unexpected = event is not described in the RSI (or is described but differs materially in nature or severity), and therefore is considered new safety information.

Expectedness is assessed after you have: (a) established an adverse event/reaction and (b) completed causality/suspect-drug assessment (i.e., the event is considered suspected to be related to the drug). For regulatory expedited reporting (e.g., SUSARs), the event must be serious, suspected causal, and unexpected.

Why it matters

  • Regulatory reporting: Unexpected serious suspected adverse reactions (SUSARs) often require expedited reporting to regulators and ethics committees (eg, 7-/15-day timelines in many regions).
  • Labeling & risk management: Unexpected events can trigger label updates, risk minimization measures, or safety signal investigations.
  • Signal detection: Unexpectedness helps prioritize cases for signal review and aggregate evaluations.
  • Audit & compliance: Expectedness assessments must be defensible and well-documented.

Reference Safety Information (RSI) — where to compare

  • Clinical trials: Investigator Brochure (IB) — usually the core RSI. For marketed products studied in trials, the SmPC (or local label) may be used if agreed in the protocol/SOP.
  • Post-marketing: SmPC / Package Insert / Product Label or Core Data Sheet (CDS).
  • Vaccines / biologicals: Product label + specific vaccine safety guidance; for novel products, the IB or manufacturer’s Investigator Safety Information.
  • Combination products / generics / off-label use: use the RSI agreed for that study or region (e.g., sponsor CDS, not an unrelated label).

Always use the most current approved RSI version applicable to the jurisdiction and trial/protocol.

Principles for Expectedness Assessment

  1. Compare the adverse reaction (PT / LLT) against the RSI — exactness matters. Use MedDRA Preferred Term (PT) mapping.
  2. Severity and nature: an AE may be listed in RSI, but the severity or specific presentation may be more serious than the RSI description — that can make it “unexpected” (e.g., “mild rash” listed vs “Stevens-Johnson syndrome” observed).
  3. Causality prerequisite: expectedness usually applies only if the event is suspected to be related to the drug. If causality is ‘unlikely’, expectedness is irrelevant for SUSAR logic.
  4. New clinically important information: even if a PT is listed, a new frequency, unusual presentation, or new severity may be considered unexpected in regulatory terms.
  5. Source of truth: RSI documents are the authoritative source. If multiple RSIs exist (IB vs SmPC), follow the protocol/SOP on which to use. Document the chosen RSI and version/date.

Step-by-step workflow (operational)

1) Prepare the case for expectedness check

  • Confirm coding of the AE(s) using MedDRA PTs (and LLTs if needed).
  • Confirm causality assessment: is the event classified as suspect (related) to the medicinal product?

2) Select the correct RSI

  • For trials: IB (include version/date). If protocol mandated SmPC, use that.
  • For marketed cases: current SmPC/label/CDS for the country/region or the sponsor’s global CDS as per SOP.
  • Record RSI version/date in the case.

3) Search RSI for the PT and synonyms

  • Search for the PT and likely synonyms; check SOC/HLT if RSI uses broad language.
  • Use MedDRA mapping: does an LLT/PT in the case map to a PT phrasing included in the RSI?

4) Assess match quality

  • Direct match: PT appears verbatim or as an explicit expected reaction → Expected.
  • Close match: PT is similar or within a broader term listed (e.g., ‘peripheral neuropathy’ listed, case is ‘sensory neuropathy’) → treat as Expected if medically encompassed.
  • Not listed: PT or clinical presentation not present or not encompassed by RSI → Unexpected.

5) Consider severity & clinical character

  • If PT is listed but the severity or clinical pattern is materially different (e.g., listed as mild, observed as life-threatening), consider it Unexpected for reporting. Document rationale.

6) Document decision & rationale

  • Capture: RSI source (name + version + date), MedDRA PT/LLT used, search evidence, final expectedness decision, assessor name/date, and rationale (short factual sentence).
  • If decision affects reporting (SUSAR), trigger the regulatory reporting workflow immediately.

Examples (practical)

Example A — Clinical trial

  • Case: MedDRA PT Anaphylactic shock after dose.
  • RSI: IB lists Anaphylaxis as a known, rare risk.
  • Outcome: Expected (term present). If serious and related → SUSAR? No for unexpectedness, but still report as serious AE per procedures (may or may not be expedited depending on causality).

Example B — Clinical trial

  • Case: Acute liver failure (life-threatening).
  • RSI: IB lists transaminitis and asymptomatic ALT elevation but not acute liver failure.
  • Outcome: Unexpected (severity/presentation not covered). If related → SUSAR → expedited reporting.

Example C — Post-marketing

  • Case: Deep vein thrombosis (DVT) reported for a contraceptive. SmPC lists thromboembolic events generally.
  • Outcome: Expected (if DVT falls within “thromboembolic events”); rationale should note where in SmPC it’s referenced.

Example D — New clinical pattern

  • Case: Peripheral neuropathy presenting with small-fiber neuropathy (autonomic features). RSI lists “peripheral neuropathy” historically as sensory neuropathy only.
  • Outcome: potentially Unexpected (new clinical pattern). Document justification and consider regulatory notification.

Regulatory implications & timelines (high-level)

  • Clinical trials: Serious, suspected, unexpected adverse reaction (SUSAR) → expedited reporting to Competent Authorities and Ethics Committees per regional timelines (examples commonly used: 7 days for fatal/life-threatening SUSARs with 8 days follow-up, 15 days for other SUSARs). (Check your local regulations and protocol; SOP should state the applicable timelines and references.)
  • Post-marketing: Unexpected serious ADRs generally must be reported to regulators according to the country’s pharmacovigilance regulations and in periodic safety reports (PSUR/PBRER). Unexpected non-serious ADRs are handled per local rules (often via periodic aggregate reporting).
  • Label updates: Accumulation of unexpected events may trigger safety signal procedures and label/PI updates.

Note: Because country/regional specifics vary, always reference the local regulatory requirement in your SOP (and record date/version of the rule used).

Documentation template (fields to capture)

You can paste this into your database or case form:

  • Case ID:
  • AE MedDRA LLT / PT:
  • Verbatim term:
  • Date of onset:
  • Suspect product(s): (name, batch if relevant)
  • Causality: (method + category)
  • RSI used (document name): (e.g., IB v3.2; SmPC India v2025-01-10)
  • RSI version / date:
  • RSI excerpt / location (page/section):
  • Expectedness decision: (Expected / Unexpected)
  • Rationale: (1–2 sentence factual rationale)
  • Assessor name & designation:
  • Assessor date:
  • If Unexpected & Serious → Regulatory action triggered? (Yes/No; detail)
  • Follow-up required: (Yes/No; what & by when)

Sample SOP paragraph (copy-paste ready)

Expectedness Assessment — SOP except:

For each case with a suspected causal relationship to the investigational product, the designated safety assessor will determine expectedness by comparing the MedDRA-coded PT/LLT to the Reference Safety Information (RSI) identified for the study/region (e.g., Investigator Brochure v[version] dated [date] or SmPC dated [date]). The RSI version used must be recorded in the case. If the PT (or an encompassing higher-level term) and its severity/presentation are listed in the RSI, classify the event as Expected. If not listed, or if the observed clinical presentation/severity materially exceeds the RSI description, classify as Unexpected. The assessor will document the rationale, their name and date. For serious + suspected + unexpected events, the expedited reporting workflow must be initiated immediately per regulatory timelines.

Example wording for the expectedness justification

  • “Expected — PT ‘Dizziness’ appears under ‘Nervous System Disorders’ in IB v2.1 (page 38); RSI lists ‘dizziness’ as an adverse reaction. Assessed by Dr. X on 2025-11-27.”
  • “Unexpected — PT ‘Acute hepatic failure’ not present in IB v4.0 (most recent), which lists mild transaminase elevations only. Clinical course and labs consistent with acute hepatic failure. Assessed by Dr. X on 2025-11-27. Regulatory reporting initiated.”

Special scenarios & nuance

  • Multiple RSIs available: follow protocol/SOP on precedence (e.g., trial protocol may require SmPC for marketed comparators). Document which RSI you used.
  • Class effects: If RSI for a drug class includes a reaction, but the specific product ‘s RSI does not, discuss with medical lead/legal/regulatory—could be treated as unexpected for that product.
  • Combination products: check RSI for each active ingredient and the combination product.
  • Off-label use / overdose / medication error: expectedness is judged against RSI for the exposure actually used (dose/route). An overdose reaction could be unexpected compared with labelled therapeutic use.
  • Limited RSI (e.g., new biologic, early phase): IB may be sparse—assess conservatively and consult sponsor medical lead if unsure.
  • Non-drug causes with suspected relation: If causality strong but RSI absence is due to different cause, document clearly.

Common pitfalls & how to avoid them

  • Pitfall: Using an outdated RSI.
    Fix: Always capture RSI version/date; SOP to check for latest approved RSI.
  • Pitfall: Basing expectedness only on free-text search (miss synonyms).
    Fix: Use MedDRA mapping; search for synonyms and HLT/SOC terms.
  • Pitfall: Ignoring severity/pattern differences.
    Fix: Include severity in assessment decision and document why a listed PT may still be unexpected.
  • Pitfall: Expectedness decided before causality.
    Fix: Only determine expectedness for events judged as suspected (related).
  • Pitfall: Poor documentation of rationale.
    Fix: Use the template wording above and include page/section of RSI.

Quick checklist to copy into your process

  1. Has the AE been coded to MedDRA PT?
  2. Is the event judged as suspected (causality not ‘unlikely’)?
  3. Which RSI is applicable? (document name/version/date)
  4. Does the PT (or encompassing term) appear in the RSI? (Yes/No)
  5. Does the observed severity/pattern differ materially from RSI? (Yes/No)
  6. Final expectedness: Expected / Unexpected.
  7. Rationale recorded (1–2 lines).
  8. Assessor name & date saved.
  9. If Serious + Suspected + Unexpected → trigger expedited reporting.
  10. Update case record and file RSI excerpt.