Week 7 Study Guide

SECTION 1: TERMINOLOGY HIERARCHY AND DEFINITIONS

1.1 Complete Definitions Framework

The Pyramid Structure:

                 ALL EVENTS
                    ↓
        ADVERSE EVENTS (AE)
              ↙        ↘
        AE with       AE without
        Causality     Causality
            ↓              ↓
        Adverse         Non-Related
        Reactions           ↓
        (AR)         Documented but
            ↓         not as AR
        ┌───┴────┐
        ↓        ↓
     Serious  Non-Serious
     (SAE)      AR
        ↓
     Serious
     Adverse
     Reaction
     (SAR)

1.2 Key Terminology Table

Term	Causality Required?	Seriousness?	Example
AE	No	No	Nausea during trial
AR	Yes (Possible+)	No	Rash after drug dose
SAE	No	Yes	Hospitalization
SAR	Yes	Yes	Unexpected hospitalization from drug
ADR	Yes	Yes (varies)	Post-marketing term for AR
UP	Yes	Yes	Data breach

1.3 Critical Distinctions

AE vs. AR:

Causality is the distinguishing factor
Both are documented
AR is subset of AE

SAE vs. SAR:

Causality is the distinguishing factor
Both are documented
SAR is subset of SAE
SAR gets expedited FDA reporting (if unexpected)

SAE vs. Important Medical Event:

Important Medical Event is ONE OF six SAE criteria
All Important Medical Events are SAE
Not all SAE are Important Medical Events

SECTION 2: SAE CRITERIA FRAMEWORK

2.1 The Six Criteria (B-CHILD)

1. DEATH

Most straightforward
Any death during trial = SAE
Causality determines if also SAR

2. LIFE-THREATENING

Substantial risk of death AT TIME OF EVENT
Event itself was critical (not hindsight)
Examples: Anaphylaxis, septic shock, massive MI with hemodynamic instability

3. INPATIENT HOSPITALIZATION

Admission + overnight stay
Planned procedures sometimes excluded
All unplanned hospitalizations = SAE

4. DISABILITY/INCAPACITY

PERSISTENT significant functional loss
Temporary symptoms don't count
Examples: Residual stroke paralysis, hearing loss

5. CONGENITAL ANOMALY

Birth defect from fetal drug exposure
NEW anomalies (not pre-existing)
Includes structural and functional defects

6. IMPORTANT MEDICAL EVENT

Clinically significant
Requires medical intervention
"Catch-all" for serious diagnoses
Examples: Cancer, MI (even if mild), serious infection diagnosis

2.2 Application Scenarios

Scenario: Severe Symptom, No SAE Criterion

Patient: Severe (9/10) headache
Duration: 2 hours at home
Outcome: Full recovery
Classification: NOT SAE (no criterion met)
Key Point: Severity ≠ Seriousness

Scenario: Mild Symptom, Meets SAE Criterion

Patient: Mild fever and malaise
Outcome: Admitted for monitoring overnight
Classification: SAE (hospitalization)
Key Point: Outcome-based, not symptom-based

SECTION 3: SERIOUS VS. SEVERE DISTINCTION

3.1 Definition and Framework

SERIOUS:

Based on: OUTCOME/CONSEQUENCE
Determined by: Meeting one of six SAE criteria
Independency: Can be serious without severe
Examples:
- Any hospitalization (even if mild symptoms)
- Cancer diagnosis (even if asymptomatic)
- Mild hospitalization = SERIOUS
- Important medical event requiring intervention = SERIOUS

SEVERE:

Based on: INTENSITY/MAGNITUDE
Determined by: Grading scale (mild/moderate/severe)
Independency: Can be severe without serious
Examples:
- 9/10 pain that resolves at home = SEVERE (not serious)
- Pronounced rash in ED, discharged same day = SEVERE (not serious)
- Intense vomiting for 1 hour = SEVERE (not serious unless hospitalized)

3.2 2x2 Matrix

                SEVERE SYMPTOMS
                  YES      NO
MEETS        YES  ■ Both   ■ Serious
SAE          NO   ■ Severe ■ Neither
CRITERIA?

3.3 SOCRA Favorite Test Questions

Question Type 1: "Severe symptoms that resolve at home"

Answer: NOT serious (despite severity)

Question Type 2: "Mild symptoms requiring hospitalization"

Answer: SERIOUS (despite mild severity)

Question Type 3: "Important medical event with minimal symptoms"

Answer: SERIOUS (diagnosis/intervention required)

SECTION 4: IND SAFETY REPORTING REQUIREMENTS (21 CFR 312.32)

4.1 The Three Report Categories

7-DAY REPORTS (Most Urgent)

Criteria (ALL THREE required):

Fatal OR Life-threatening (outcome)
AND Unexpected (vs. IB)
AND Suspected adverse reaction (reasonable possibility of causation)

Format:

PHONE: Within 7 calendar days
WRITTEN: Within 15 calendar days (follow-up)
BOTH required

Rationale: Most serious, unexpected events

15-DAY REPORTS

Criteria (ALL THREE required):

Serious (NOT fatal or life-threatening) (outcome)
AND Unexpected (vs. IB)
AND Suspected adverse reaction (reasonable possibility of causation)

Format:

WRITTEN only: Within 15 calendar days
No phone required

Rationale: Serious but not immediately life-threatening

NOT EXPEDITED

When to use:

Event is expected (vs. IB) — even if serious + causality
Event is not serious
Event has no reasonable possibility of causation
Event is AE only (not AR)

Reporting Method:

Documented in study records
Included in annual report
Not expedited FDA notification

4.2 Decision Tree for Report Classification

ADVERSE EVENT IDENTIFIED
        ↓
Is there reasonable possibility 
of causation (Suspected AR)?
    ├─ NO → STOP
    │       NOT EXPEDITED
    │
    └─ YES ↓
    
Is the event UNEXPECTED
(vs. Investigator's Brochure)?
    ├─ NO → STOP
    │       NOT EXPEDITED
    │
    └─ YES ↓
    
Does the event meet one 
of six SAE criteria?
    ├─ NO → STOP
    │       NOT EXPEDITED
    │
    └─ YES ↓
    
Is it FATAL or LIFE-THREATENING?
    ├─ YES → 7-DAY REPORT
    │        (Phone + Written)
    │
    └─ NO → 15-DAY REPORT
             (Written Only)

4.3 Key Regulatory Definitions

Sponsor Awareness = DAY 0

NOT event date
NOT investigator awareness date
When sponsor becomes aware through any source

Calendar Days

Includes weekends and holidays
NOT business days
Count continuously

"Reasonable Possibility of Causation"

Includes: Possible, Probable, Definite
Does NOT require: Proven causation
Threshold: Cannot reasonably exclude

SECTION 5: CAUSALITY ASSESSMENT FRAMEWORK

5.1 Five-Level Causality System

Level	Definition	AR Classification?
Unrelated	Causation clearly excluded	NO
Unlikely	Alternative explanations more likely	NO
Possible	Cannot reasonably exclude causation	YES ✓
Probable	Reasonable basis for causation	YES ✓
Definite	Causation with reasonable certainty	YES ✓

5.2 Five Assessment Factors

1. TEMPORAL RELATIONSHIP

Timing of event relative to drug
Immediate/rapid onset = supports causality
Remote timing = weakens but doesn't exclude

2. DECHALLENGE

Effect of stopping drug
Improvement on discontinuation = supports
No change = less supportive

3. RECHALLENGE

Effect of restarting drug
Recurrence = strong support
No recurrence = challenges
Rarely done for safety

4. ALTERNATIVE EXPLANATIONS

How well alternatives explain the event
Multiple plausible alternatives = weakens
No alternatives = strengthens

5. PHARMACOLOGIC PLAUSIBILITY

Known drug effect?
Mechanism plausible?
Known for drug class?
Consistent with mechanism of action?

5.3 Application Examples

Example 1: Probable Causality

Strong temporal relationship
Pharmacologically plausible
Minimal alternatives
No dechallenge data
Result: PROBABLE

Example 2: Possible Causality

Temporal relationship exists
Alternative explanations also exist
Cannot exclude drug
Result: POSSIBLE (meets AR threshold)

Example 3: Unlikely Causality

Alternative explanation more likely
Weak temporal relationship
Not pharmacologically plausible
Result: UNLIKELY (not AR)

SECTION 6: EXPECTEDNESS DETERMINATION

6.1 The Investigator's Brochure (IB) as Reference

What is Expectedness? Event that is consistent with the IB = EXPECTED Event that differs from IB = UNEXPECTED

Three Components to Check:

Event TYPE (is it listed?)
Event SEVERITY (does it match description?)
Event FREQUENCY (does rate match?)

6.2 Expectedness Scenarios

Scenario A: Type, Severity, Frequency ALL Match IB

Result: EXPECTED

Scenario B: Type Listed, but Severity EXCEEDS IB

Example: Rash listed as mild-moderate; patient has severe blistering
Result: UNEXPECTED

Scenario C: Type Listed, Frequency EXCEEDS IB Substantially

Example: IB lists event at 2%; study shows 15%
Result: UNEXPECTED

Scenario D: Event Type NOT Listed Anywhere

Result: AUTOMATICALLY UNEXPECTED

6.3 Critical Point: IB Versioning

Use IB version IN EFFECT AT TIME OF EVENT

Not post-event IB updates
Not future IB versions
Not retrospective reclassifications

SECTION 7: DECISION-MAKING FLOWCHARTS

7.1 Master Classification Flowchart

[See earlier sections for detailed flowchart]

7.2 Timeline Calculation Flowchart

SPONSOR AWARE DATE (Day 0)
        ↓
Classification
 (7-day? 15-day? Not expedited?)
        ↓
Determine Deadline
(Day 7 for phone? Day 15 for written?)
        ↓
Count CALENDAR DAYS
(Include weekends, holidays, all days)
        ↓
DEADLINE DATE

7.3 Causality Assessment Flowchart

ADVERSE EVENT IDENTIFIED
        ↓
TEMPORAL RELATIONSHIP?
(When did it occur relative to drug?)
        ↓
DECHALLENGE DATA?
(Does it improve on stopping drug?)
        ↓
ALTERNATIVE EXPLANATIONS?
(How many? How plausible?)
        ↓
PHARMACOLOGIC PLAUSIBILITY?
(Known drug effect?)
        ↓
CAUSALITY CATEGORY
(Unrelated through Definite)
        ↓
AR? (Possible, Probable, or Definite)

KEY CONCEPTS SUMMARY

Highest Yield Topics:

Timeline Calculations (30% of questions)
- Sponsor awareness as Day 0
- Calendar days (not business days)
- 7-day vs. 15-day distinction
Serious vs. Severe (20% of questions)
- Serious = outcome-based
- Severe = intensity-based
- Independent concepts
Expedited Reporting Criteria (25% of questions)
- ALL THREE required
- Expected = no expedited
- Causality threshold = "Possible" or higher
Causality Assessment (15% of questions)
- Five-level system
- Five assessment factors
- "Reasonable possibility" standard
Expectedness Determination (10% of questions)
- IB version at time of event
- Type, severity, frequency comparison

FINAL EXAM PREPARATION CHECKLIST

Before taking the actual SOCRA exam:

End of Study Guide