SOCRA CCRP Exam Preparation — Comprehensive Study Guide

Course Position: Week 7 of 12 (Follows Data Integrity; Precedes Protocol Development)
Regulatory Framework: ICH E2A, 21 CFR 312.32, ICH E6(R2/R3)
Exam Weight: HIGH — Timeline calculations are among the most frequently tested topics

Learning Objectives

By the end of this week, you will be able to:

1. Define all AE terminology using ICH E2A standard definitions
2. Apply the six SAE criteria to clinical scenarios accurately
3. CRITICAL: Distinguish between "serious" and "severe"
4. HIGH-YIELD: Calculate IND safety reporting timelines from sponsor awareness
5. Determine report type (7-day vs. 15-day) based on event characteristics
6. Assess causality using standard relationship categories
7. Evaluate expectedness using the Investigator's Brochure as reference
8. Describe investigator vs. sponsor safety reporting obligations
9. Explain DSMB roles, composition, and communication requirements

Section 1: Adverse Event Terminology

1.1 Adverse Event (AE)

Definition: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

Key Points:

• Broadest category — includes ANY unfavorable sign, symptom, or disease
• NO causality required — temporal association is sufficient
• Includes abnormal laboratory findings
• Includes pre-existing conditions that worsen
• A car accident during a trial IS an adverse event

EXAM TRAP: Questions may present clearly unrelated events — they're STILL adverse events and must be documented.

1.2 Adverse Drug Reaction (ADR)

Pre-Approval Definition: All noxious and unintended responses to a medicinal product related to any dose.

Post-Marketing Definition: A response to a drug which is noxious and unintended and which occurs at doses normally used in man.

Key Distinction:

• AE = temporal association only (may or may not be drug-related)
• ADR = reasonable possibility of causal relationship exists

1.3 Suspected Adverse Reaction

Definition: An adverse event for which there is a reasonable possibility that the drug caused the adverse event.

Key Points:

• "Reasonable possibility" means relationship cannot be ruled out
• This is the standard for expedited reporting to FDA
• Investigators make initial assessment; sponsors make final determination

1.4 Unexpected Adverse Reaction

Definition: An adverse reaction, the nature or severity of which is not consistent with the Investigator's Brochure (IB).

Two Ways to be "Unexpected":

1. Not listed in the IB at all
2. Listed but more severe or different in nature than described

EXAM TRAP: An event can be "expected" based on the disease being studied but still be "unexpected" if not listed in the IB for the specific drug.

1.5 SUSAR (Suspected Unexpected Serious Adverse Reaction)

Combines all three criteria for expedited reporting:

• Serious — meets SAE criteria
• Unexpected — not in IB or more severe
• Suspected — reasonable possibility of causal relationship

Section 2: Serious Adverse Event (SAE) Criteria

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

The Six SAE Criteria

Memory Device: DLIHC-B

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

Common SAE Exam Traps

ER Visit Trap:

• Subject treated in ER for 6 hours and discharged → NOT SAE by hospitalization criterion
• Must be inpatient admission to qualify

Elective Surgery Trap:

• Pre-planned knee surgery → NOT SAE
• Post-op complication requiring extended stay → YES SAE

Life-Threatening Trap:

• Cancer diagnosis → Serious (important medical event) but NOT "life-threatening" by criterion
• Anaphylactic shock → YES life-threatening (immediate risk at time of event)

Section 3: SERIOUS vs. SEVERE — The Critical Distinction

This appears on many of the safety-related SOCRA exam questions.

Side-by-Side Comparison

Classic Examples

Severe but NOT Serious:

• Grade 3 headache (10/10 pain), treated at home with OTC medication
• Severity: SEVERE (Grade 3)
• Serious: NO — meets no SAE criteria

Serious but NOT Severe:

• Mild chest discomfort, diagnosed as MI, hospitalized for observation
• Severity: Mild to Moderate
• Serious: YES — requires hospitalization

Severity Grading Scale

Note: Grade 4 and 5 are always serious by definition. Grades 1-3 may or may not be serious.

Section 4: IND Safety Reporting Requirements (21 CFR 312.32)

The Three-Part Test for Expedited Reporting

ALL THREE conditions must be met:

1. SERIOUS — meets at least one SAE criterion
2. UNEXPECTED — not in IB or more severe than listed
3. SUSPECTED — reasonable possibility of causal relationship

Memory Aid: "SUS Report"

• Serious + Unexpected + Suspected = Expedited Report Required

Report Types and Timelines

Calculating "Sponsor Awareness"

The clock starts when the SPONSOR first becomes aware — NOT when the event occurs.

Sponsor Awareness STARTS When:

• Sponsor receives notification from investigator
• Sponsor receives info from CRO
• Sponsor's medical monitor reviews case
• ANY employee or agent becomes aware

Clock Does NOT Start When:

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

Timeline Calculation Example

Section 5: Causality Assessment

Relationship Categories

The 5 P's of Causality

1. Proximate (temporal relationship)
2. Pharmacologically plausible
3. Positive dechallenge (improved when stopped)
4. Positive rechallenge (recurred when restarted)
5. Pattern (no alternative explanation)

Who Makes the Assessment?

Section 6: Expectedness Determination

The Reference Document

The Investigator's Brochure (IB) is the definitive source for expectedness determination.

When is an Event UNEXPECTED?

1. Not listed in the IB at all
2. Listed but more severe than described
3. Listed but different in nature than described

Examples

Section 7: Reporting Obligations

Investigator Responsibilities

To Sponsor (21 CFR 312.64):

• Report serious, unexpected, or protocol-required AEs immediately (typically 24 hours)
• Provide follow-up information as available

To IRB (21 CFR 56.108):

• Unanticipated problems involving risks
• Serious AEs per IRB requirements
• Timeline varies by institution

Sponsor Responsibilities

• Report to FDA (not investigator's job!)
• Aggregate safety analysis
• Update Investigator's Brochure
• Notify all participating investigators

EXAM TIP: Investigators report to sponsors; sponsors report to FDA.

Section 8: Data Safety Monitoring Boards (DSMB)

Purpose

Independent group monitoring patient safety and treatment efficacy during ongoing trials.

Composition

• Clinical experts (2-3 minimum)
• Biostatistician
• Ethicist (often)
• Patient advocate (sometimes)

Key Authority

DSMBs RECOMMEND — they don't decide.

The sponsor makes final decisions. DSMB can recommend:

• Continue trial as planned
• Modify trial
• Temporarily suspend enrollment
• Terminate early (safety, futility, or overwhelming efficacy)

Quick Reference Tables

Table A: Timeline Quick Reference

Table B: SAE Criteria Quick Reference

Memory Aids Summary

DLIHC-B (SAE Criteria): Death, Life-threatening, Inpatient hospitalization, Handicap, Congenital anomaly, Big medical event

SUS Report (Expedited Reporting): Serious + Unexpected + Suspected = Expedited

7-15 Phone Home (Timelines): 7 days phone (fatal/life-threatening), 15 days written, 60 days annual

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

Practice Questions Preview

1. What distinguishes an AE from an ADR?
2. A subject has severe (Grade 3) nausea, treated in ER for 4 hours, discharged. Is this an SAE?
3. Calculate deadlines: Sponsor learns of fatal unexpected suspected reaction on March 10.
4. Subject is hospitalized for elective surgery. Post-op infection extends stay. What's reportable?
5. Causality assessed as "unlikely" for a serious, unexpected event. Expedited report required?

Connection to Course

From Week 6 (Data Integrity):

• ALCOA+ principles apply to safety data
• SDV includes AE/SAE documentation
• Risk-based monitoring focuses on safety-critical data

To Week 8 (Protocol Development):

• Protocol must define AE collection procedures
• Safety monitoring plans built into protocol
• Informed consent addresses known risks (from IB)
• Stopping rules based on safety outcomes

Document prepared for SOCRA CCRP Exam Preparation — Week 7
Regulatory Framework: ICH E2A, 21 CFR 312.32, ICH E6(R2/R3)