📋 Three-Part Test for Expedited Reporting

IND Safety Reporting Decision Tree | 21 CFR 312.32

Decision Flowchart

flowchart TD
    Start([Event Occurs]) --> Q1{1️⃣ Is it SERIOUS?
meets any SAE criterion}
    
    Q1 -->|YES ✓| Q2{2️⃣ Is it UNEXPECTED?
not in IB or more severe}
    Q1 -->|NO ✗| NoExp1[NO EXPEDITED REPORT
Document as AE]
    
    Q2 -->|YES ✓| Q3{3️⃣ Is it SUSPECTED?
reasonable possibility}
    Q2 -->|NO ✗| NoExp2[NO EXPEDITED REPORT
Include in annual report]
    
    Q3 -->|YES ✓| Q4{Fatal or
Life-Threatening?}
    Q3 -->|NO ✗| NoExp3[NO EXPEDITED REPORT
Include in annual report]
    
    Q4 -->|YES| SevenDay[🔴 7-DAY REPORT
Phone ≤7 days
Written ≤15 days]
    Q4 -->|NO| FifteenDay[🟡 15-DAY REPORT
Written only
≤15 days]
    
    style SevenDay fill:#C53030,color:#fff
    style FifteenDay fill:#D69E2E,color:#fff
    style NoExp1 fill:#38A169,color:#fff
    style NoExp2 fill:#38A169,color:#fff
    style NoExp3 fill:#38A169,color:#fff

Quick Reference Table

Condition	Report Type	Phone Required?	Timeline
Fatal/Life-threatening + Unexpected + Suspected	7-Day	✅ YES	Phone ≤7d, Written ≤15d
Serious (other) + Unexpected + Suspected	15-Day	❌ NO	Written ≤15d
Missing ANY criterion	None	❌ NO	Annual report

The Three Criteria

ALL THREE must be met for expedited reporting

1️⃣ SERIOUS

2️⃣ UNEXPECTED

Not listed in Investigator's Brochure
OR more severe than described in IB

3️⃣ SUSPECTED

Reasonable possibility of causal relationship
Includes: Possible, Probable, Definite
Excludes: Unrelated, Unlikely

Memory Aid: "SUS Report" Serious + Unexpected + Suspected = Expedited Report Required

SOCRA CCRP Exam Prep | Week 7: Adverse Event Reporting

🏥 SAE Criteria Quick Reference

An event is SERIOUS if it meets ANY ONE of these six criteria

The Six Criteria

1. 💀 DEATH Definition: Results in death

Note: Always serious regardless of relationship to drug

2. ⚡ LIFE-THREATENING Definition: Immediate risk of death AT THE TIME of the event

⚠️ TRAP: Cancer is NOT "life-threatening" by this criterion!

3. 🏥 HOSPITALIZATION Definition: Requires inpatient admission or prolongs existing hospitalization

⚠️ TRAP: ER visit without admission does NOT qualify!

4. ♿ DISABILITY Definition: Persistent or significant disability/incapacity

⚠️ TRAP: Temporary symptoms that resolve don't count

5. 👶 CONGENITAL ANOMALY Definition: Birth defect in offspring of a trial subject

Note: Pregnancy itself is NOT an SAE

6. ⚠️ IMPORTANT MEDICAL EVENT Definition: May jeopardize patient or require intervention to prevent serious outcome

Note: Requires medical/scientific judgment

Reference Table

#	Criterion	Definition	Common Trap
1	Death	Results in death	Even if unrelated
2	Life-Threatening	Immediate risk at TIME	Cancer ≠ life-threatening
3	Hospitalization	Inpatient admission	ER visit ≠ hospitalization
4	Disability	Persistent/significant	Temporary ≠ disability
5	Congenital Anomaly	Birth defect in offspring	Pregnancy ≠ SAE
6	Important Medical	May jeopardize patient	Requires judgment

Memory Aid

DLIHC-B Mnemonic

Death
Life-threatening
Inpatient hospitalization
Handicap (disability)
Congenital anomaly
Big medical event (important)

Hospitalization Clarification

✅ QUALIFIES as SAE

New hospitalization for medical treatment
Prolongation of existing hospitalization
Transfer to ICU/higher level of care

❌ Does NOT Qualify

ER visits without admission
Outpatient observation
Pre-planned/elective hospitalizations
Social admissions

SOCRA CCRP Exam Prep | Week 7: Adverse Event Reporting

⚠️ Serious vs. Severe

This is a highly tested concept

Side-by-Side Comparison

Characteristic	🔴 SERIOUS	🔵 SEVERE
Measures	Outcome / Consequence	Intensity / Grade
Question	"What happened?"	"How bad was it?"
Based on	Regulatory criteria (6 SAE)	Clinical grading scale
Triggers reporting?	✅ YES	❌ NO
Scale	SAE vs. Non-SAE	Mild, Moderate, Severe

Key Distinction

Core Concept

SERIOUS = What HAPPENED (outcome) → Triggers reporting obligations
SEVERE = How BAD (intensity) → Just a descriptor

Critical Understanding A "severe" event may NOT be "serious" A "serious" event may NOT be "severe"

Severity Grading Scale

Grade	Severity	Definition
1	Mild	Awareness of symptom, easily tolerated
2	Moderate	Discomfort interferes with usual activities
3	Severe	Incapacitating, unable to do usual activities
4	Life-threatening	Immediate risk of death
5	Death	Death related to event

Grade 4 and Grade 5 are always serious by definition Grades 1-3 may or may not be serious depending on other criteria

Classic Exam Scenarios

🔵 SEVERE but NOT Serious

Scenario 1: Grade 3 Headache Description: Subject has 10/10 pain headache, treats at home with OTC medication, resolves in 2 hours

Assessment	Result
Severity	SEVERE (Grade 3)
Serious	❌ NO (no SAE criteria met)
Reporting	Document as AE, no expedited report

Scenario 2: Grade 3 Nausea in ER Description: Subject has severe nausea, treated in ER for 6 hours with IV fluids, discharged home

Assessment	Result
Severity	SEVERE (Grade 3)
Serious	❌ NO (ER ≠ hospitalization)
Reporting	Document as AE, no expedited report

🔴 SERIOUS but NOT Severe

Scenario 3: Mild MI with Hospitalization Description: Subject has mild chest discomfort (Grade 1), hospitalized for observation, diagnosed with MI

Assessment	Result
Severity	Mild (Grade 1)
Serious	✅ YES (hospitalization criterion)
Reporting	SAE — may require expedited report

Scenario 4: Asymptomatic Cancer Description: Asymptomatic malignancy (Grade 1) discovered on routine scan during trial

Assessment	Result
Severity	Mild/Asymptomatic
Serious	✅ YES (important medical event)
Reporting	SAE — may require expedited report

Quick Classification Guide

flowchart LR
    A[Event Occurs] --> B{Meets SAE
Criteria?}
    B -->|YES| C[SERIOUS]
    B -->|NO| D[Not Serious]
    
    A --> E{Intensity
Grade 3+?}
    E -->|YES| F[SEVERE]
    E -->|NO| G[Not Severe]
    
    style C fill:#C53030,color:#fff
    style F fill:#3182CE,color:#fff

Common Exam Traps

Trap 1: Assuming Severe = Serious ❌ "The headache was severe, so it must be an SAE" ✅ Severity describes intensity; check SAE criteria for seriousness

Trap 2: ER Visit = Hospitalization ❌ "They went to the ER, so it's serious" ✅ Must be INPATIENT admission to meet hospitalization criterion

Trap 3: Dramatic Language ❌ Being fooled by words like "worst ever" or "unbearable" ✅ Always ask: Does it meet the regulatory SAE CRITERIA?

Memory Aid: "Outcome vs. Intensity" Serious = What HAPPENED (outcome) Severe = How BAD (intensity)

SOCRA CCRP Exam Prep | Week 7: Adverse Event Reporting

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⏱️ IND Safety Reporting Timelines

21 CFR 312.32 | All timelines are CALENDAR days from SPONSOR AWARENESS

Timeline Visual

gantt
    title IND Safety Reporting Timeline
    dateFormat  X
    axisFormat %d
    
    section Sponsor Awareness
    Day 0 (Clock Starts)    :milestone, m1, 0, 0
    
    section 7-Day Report
    Phone Notification Due  :crit, 0, 7
    
    section 15-Day Report
    Written Report Due      :active, 0, 15
    
    section Annual Report
    Annual Report Due       :60, 60

Report Types Summary

Report Type	Criteria	Phone?	Timeline
🔴 7-Day	Fatal/Life-threatening + Unexpected + Suspected	✅ YES	Phone ≤7d, Written ≤15d
🟡 15-Day	Serious (other) + Unexpected + Suspected	❌ NO	Written ≤15d
🔵 Annual	All safety data summary	❌ NO	≤60d from IND anniversary
🟢 None	Missing ANY of S+U+S	❌ NO	Document, annual report

Critical Reminder

Clock starts from SPONSOR AWARENESS — NOT when event occurs!

Detailed Report Requirements

🔴 7-Day Report (IND Safety Report - Fatal/Life-Threatening)

Fatal OR Life-Threatening + Unexpected + Suspected

Phone Notification: Within 7 calendar days of sponsor awareness Written Report: Within 15 calendar days of sponsor awareness

⚠️ BOTH are required — phone does not replace written

🟡 15-Day Report (IND Safety Report - Other Serious)

Serious (not fatal/LT) + Unexpected + Suspected

Written Report: Within 15 calendar days of sponsor awareness

ℹ️ No phone notification required

🔵 Annual Report

All IND safety data summary

Deadline: Within 60 calendar days of IND anniversary date

Includes: All AEs, SAEs, and safety analyses

🟢 No Expedited Report

Missing any criterion (S+U+S)

Document as AE per protocol
Include in annual report
No expedited reporting required

✅ Clock STARTS When:

Sponsor receives notification from investigator
Sponsor receives info from CRO
ANY sponsor employee/agent becomes aware

❌ Clock Does NOT Start When:

Event occurs (not yet reported to sponsor)
Investigator documents event (not yet reported)
Subject reports to site staff (not yet reported)

Timeline Calculation Example

Practice Scenario Event: Fatal cardiac arrest (not in IB) Event Date: June 3 Site Documents: June 4 Sponsor Notified: June 6 Causality: Probable

Step	Analysis
Serious?	✅ YES (Death)
Unexpected?	✅ YES (not in IB)
Suspected?	✅ YES (Probable)
Report Type	7-Day Report
Day 0	June 6 (sponsor awareness)
Phone Due	June 13 (Day 0 + 7)
Written Due	June 21 (Day 0 + 15)

Follow-Up Reports

Follow-Up Information

Timeline: Within 15 calendar days of receiving NEW information

Examples of new information:

Autopsy results
Additional lab findings
Change in causality assessment
Outcome update

Key Reminders

Common Mistakes

❌ Counting from event date instead of sponsor awareness
❌ Using business days instead of calendar days
❌ Forgetting that 7-day reports need BOTH phone AND written
❌ Confusing follow-up timeline (15 days from NEW info)

Memory Aid: "7-15 Phone Home"

7 days = Phone notification (fatal/life-threatening)
15 days = Written report (all expedited)
60 days = Annual report

SOCRA CCRP Exam Prep | Week 7: Adverse Event Reporting

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🧠 Week 7 Memory Aids

Key mnemonics and quick references for AE Reporting

Core Mnemonics

DLIHC-B — SAE Criteria

Death
Life-threatening
Inpatient hospitalization
Handicap (disability)
Congenital anomaly
Big medical event (important)

Only ONE criterion needed to be serious

SUS Report — Three-Part Test Serious + Unexpected + Suspected = Expedited Report

ALL THREE must be met for expedited reporting

7-15 Phone Home — Timelines

7 days = Phone (fatal/life-threatening)
15 days = Written (all expedited)
60 days = Annual report

All calendar days from SPONSOR AWARENESS

Outcome vs. Intensity

Serious = What HAPPENED (outcome)
Severe = How BAD (intensity)

They are independent concepts!

Quick Decision Tables

Expedited Reporting Decision

Serious?	Unexpected?	Suspected?	Report?
✅	✅	✅	✅ Expedited
✅	✅	❌	❌ Annual
✅	❌	✅	❌ Annual
❌	✅	✅	❌ AE only

Report Type Decision

Fatal/Life-Threatening?	Report Type
✅ YES	7-Day (Phone + Written)
❌ NO	15-Day (Written only)

Causality Quick Reference

Category	Meets "Reasonable Possibility"?
Unrelated	❌ NO
Unlikely	❌ NO
Possible	✅ YES
Probable	✅ YES
Definite	✅ YES

Threshold is LOW "Reasonable possibility" = relationship cannot be ruled out

Common Exam Traps

Trap 1: Severe = Serious ❌ WRONG: "Grade 3 pain means it's an SAE" ✅ RIGHT: Check the 6 SAE criteria, not severity grade

Trap 2: ER = Hospital ❌ WRONG: "ER visit counts as hospitalization" ✅ RIGHT: Must be INPATIENT admission

Trap 3: Cancer = Life-Threatening ❌ WRONG: "Cancer diagnosis is life-threatening SAE criterion" ✅ RIGHT: Life-threatening = immediate risk AT THE TIME

Trap 4: Timeline from Event ❌ WRONG: "Clock starts when event occurs" ✅ RIGHT: Clock starts from SPONSOR AWARENESS

Trap 5: Expected for Disease ❌ WRONG: "Common in disease = expected" ✅ RIGHT: Expectedness determined by IB only

The 5 P's of Causality

[*] Proximate (temporal relationship)
[*] Pharmacologically plausible
[*] Positive dechallenge (improved when stopped)
[*] Positive rechallenge (recurred when restarted)
[*] Pattern (no alternative explanation)

Key Definitions to Know

Term	Definition
AE	Any untoward occurrence, regardless of causality
ADR	Response with reasonable possibility of causation
Unexpected	Not in IB or more severe than described
SUSAR	Serious + Unexpected + Suspected Adverse Reaction
Dechallenge	Improvement when drug stopped
Rechallenge	Recurrence when drug restarted

Reporting Responsibilities

flowchart LR
    A[Subject] -->|Reports symptoms| B[Site/Investigator]
    B -->|24 hours for SAE| C[Sponsor]
    C -->|7 or 15 days| D[FDA]
    
    style D fill:#1A365D,color:#fff

Key Point Investigators report to Sponsors Sponsors report to FDA

Timeline Calculation Checklist

Identify sponsor awareness date (Day 0)
Apply three-part test (S + U + S)
Determine if fatal/life-threatening
Calculate deadline (Day 0 + 7 or 15)
Remember: CALENDAR days, not business days

SOCRA CCRP Exam Prep | Week 7: Adverse Event Reporting

📋 Three-Part Test for Expedited Reporting

Decision Flowchart

Quick Reference Table

The Three Criteria

1️⃣ SERIOUS

2️⃣ UNEXPECTED

3️⃣ SUSPECTED

🏥 SAE Criteria Quick Reference

The Six Criteria

Reference Table

Memory Aid

Hospitalization Clarification

✅ QUALIFIES as SAE

❌ Does NOT Qualify

⚠️ Serious vs. Severe

Side-by-Side Comparison

Key Distinction

Severity Grading Scale

Classic Exam Scenarios

🔵 SEVERE but NOT Serious

🔴 SERIOUS but NOT Severe

Quick Classification Guide

Common Exam Traps

cssClasses: [table-lines, table-max]

⏱️ IND Safety Reporting Timelines

Timeline Visual

Report Types Summary

Critical Reminder

Detailed Report Requirements

🔴 7-Day Report (IND Safety Report - Fatal/Life-Threatening)

🟡 15-Day Report (IND Safety Report - Other Serious)

🔵 Annual Report

🟢 No Expedited Report

Sponsor Awareness: When Does the Clock Start?

✅ Clock STARTS When:

❌ Clock Does NOT Start When:

Timeline Calculation Example

Follow-Up Reports

Key Reminders

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🧠 Week 7 Memory Aids

Core Mnemonics

Quick Decision Tables

Expedited Reporting Decision

Report Type Decision

Causality Quick Reference

Common Exam Traps

The 5 P's of Causality

Key Definitions to Know

Reporting Responsibilities

Timeline Calculation Checklist