Lesson 2

Adverse Event Reporting and Classification Cheat Sheet

Adverse Event Reporting and Classification

Key concepts and criteria for pharmacovigilance professionals

⚠️ Adverse Event vs. Adverse Drug Reaction

📋 Adverse Event (AE)

Definition: Any unfavorable and unintended sign, symptom, disease, or medical occurrence in a patient or clinical trial subject who has been administered a pharmaceutical product.

No causality is implied – temporal association is sufficient
Includes abnormal laboratory findings, symptoms, or diseases

Example: A patient experiences headache after taking a medication, regardless of whether the medication caused it.

🔄 Adverse Drug Reaction (ADR)

Definition: A response to a medicinal product that is noxious and unintended, where causality between the product and the occurrence is at least a reasonable possibility.

Implies at least a reasonable possibility of causal relationship
For approved products, occurs at normal doses used in humans
For investigational products, occurs at any dose

Example: A patient experiences rash due to an allergic reaction to the medication.

Aspect	Adverse Event (AE)	Adverse Drug Reaction (ADR)
Causality	Not implied, temporal association only	Causal relationship with drug is suspected
Assessment	Based on occurrence after drug exposure	Requires medical evaluation of relationship
Reporting	Collected for all clinical trials	Focus of post-marketing surveillance
Regulatory Impact	Initial collection and processing	Drives labeling changes and safety measures

Important: The distinction between AE and ADR is critical for regulatory reporting, as different requirements apply based on causality assessment.

🚨 Serious Adverse Event (SAE) Criteria

An adverse event is considered serious when it meets any of the following criteria:

Results in Death

Fatal outcome where the event caused or contributed to death
Not simply cases where a patient died while experiencing an event

Is Life-threatening

Patient was at risk of death at the time of the event
Not events that hypothetically might have caused death if more severe

Examples: Anaphylaxis, severe hemorrhage, respiratory arrest

Requires/Prolongs Hospitalization

Initial or prolonged inpatient hospitalization
Excludes pre-planned hospitalizations or those for convenience
Emergency room visits without admission generally don’t qualify

Example: Severe GI bleeding requiring hospital admission

Results in Disability/Incapacity

Substantial disruption of ability to conduct normal life functions
Considers baseline functional status

Example: Stroke leading to permanent paralysis, blindness, or severe cognitive impairment

Congenital Anomaly/Birth Defect

Structural or functional abnormality present at birth
Includes exposure during pregnancy, even if identified after birth

Example: Limb malformation in a baby exposed to a medication in utero

Medically Important Condition

Events not meeting above criteria but jeopardizing patient safety
Typically requires medical intervention to prevent one of the other outcomes
Often based on medical judgment

Examples: Bronchospasm requiring ER treatment, seizures, drug-induced hepatitis

Regulatory Impact: The classification of an event as serious has significant implications for reporting timelines and regulatory obligations. Serious AEs/ADRs typically require expedited reporting to authorities.

📝 Expectedness

Expectedness relates to whether an adverse reaction is documented in the reference safety information:

Expected (Listed) Adverse Reaction

Consistent with the nature or severity described in the applicable reference safety information
For marketed products: Company Core Data Sheet (CCDS) or Summary of Product Characteristics (SmPC)
For investigational products: Investigator’s Brochure (IB)
Listing includes the specific event, not just the class of events
May differ by country based on local labeling

Unexpected (Unlisted) Adverse Reaction

Not consistent with reference safety information
Events that differ in nature, severity, specificity, or outcome
Events occurring at higher frequency than documented
New aspects of known reactions (e.g., new risk factors)

Important Note: Expectedness assessment is independent of causality assessment. An adverse reaction can be assessed as related to a product but still be unexpected if not documented in reference safety information.

Reporting Requirements Based on Seriousness and Expectedness:

Serious, unexpected suspected adverse reactions (SUSARs) typically require expedited reporting
Serious, expected reactions may be reported in periodic reports
Non-serious reactions are typically collected in aggregate form

🔍 Causality Assessment

Causality assessment evaluates the likelihood that a drug caused an observed adverse event:

WHO-UMC Scale

Certain

Event follows reasonable temporal sequence, cannot be explained by disease or other drugs, response to withdrawal plausible, rechallenge positive

Probable/Likely

Reasonable time relationship, unlikely attributed to disease or other drugs, response to withdrawal clinically reasonable

Possible

Reasonable time relationship, could be explained by disease or other drugs

Unlikely

Temporal relationship improbable, disease or other drugs provide plausible explanations

Conditional/Unclassified

More data needed for assessment

Unassessable/Unclassifiable

Insufficient or contradictory information

Naranjo Algorithm

10-question scoring system (-4 to +13) that considers:

Previous reports of the reaction
Temporal relationship
Dechallenge/rechallenge
Alternative causes
Placebo response
Dose relationship
Drug levels in body fluids/tissues
Dose-dependent relationships
Patient’s history with similar drugs
Objective evidence of the event

Categorization:

Definite: ≥9 points
Probable: 5-8 points
Possible: 1-4 points
Doubtful: ≤0 points

Bradford Hill Criteria

Strength of association: Magnitude of the relationship between exposure and outcome
Consistency: Observation of the association in different populations and circumstances
Specificity: The extent to which the exposure is associated with a particular outcome
Temporality: The exposure precedes the outcome
Biological gradient: Dose-response relationship
Plausibility: Biological explanation for the association
Coherence: Agreement with current knowledge of disease mechanisms
Experimental evidence: Results from controlled studies
Analogy: Similar effects from similar substances

Documentation Requirements: Causality assessment requires medical expertise and careful consideration of all available information. Documentation should include the method used and rationale for the causality determination.

⏱️ Expedited Reporting Timelines

Expedited reporting ensures prompt notification of significant safety concerns:

Serious, Unexpected Suspected Adverse Reactions (SUSARs)

Most regulatory authorities require reporting within 15 calendar days
Fatal or life-threatening cases often have shorter timelines (7 days in some regions)
Initial reports may be followed by complete information within additional timeframes
Clock starts when the minimum four elements for a valid case are established

Reporting Criteria Variations by Region

EU: All serious reactions from spontaneous sources, regardless of expectedness
US FDA: 15-day reports for serious, unexpected adverse events with reasonable possibility of causal relationship
Japan PMDA: Requires reporting of both domestic and foreign cases

Reporting Process:

Case assessment and validation
Determination of reportability
Preparation of report in required format (often E2B electronic format)
Submission to relevant authorities
Documentation of submission
Follow-up information handling

Compliance Note: Compliance with expedited reporting timelines is critical and closely monitored by regulatory authorities. Failure to meet these timelines can result in regulatory actions.

📊 Periodic Reporting

Periodic reports provide comprehensive evaluation of cumulative safety data:

Periodic Safety Update Reports (PSURs)

Comprehensive analysis of benefit-risk at defined intervals
Format and content specified in regulations
Submission frequency varies by product lifecycle (6 months to 3 years)
Includes cumulative data since approval
Required in many countries globally

Periodic Benefit-Risk Evaluation Reports (PBRERs)

ICH E2C(R2) format that replaced PSURs in many regions
Enhanced focus on benefit-risk evaluation
Includes interval and cumulative data
Requires integrated analyses of risks in context of benefits

Development Safety Update Reports (DSURs)

Annual reports for investigational products
Comprehensive review of safety for ongoing clinical trials
Submitted to regulatory authorities where clinical trials are conducted

Value of Periodic Reports: Periodic reports allow evaluation of emerging patterns that might not be apparent from individual case reports and provide opportunity for comprehensive benefit-risk reassessment.

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