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Study Conduct and Subject Management

1. Subject Lifecycle Overview

flowchart LR
    subgraph Phase1[" "]
        A[🎯 RECRUITMENT]
    end
    subgraph Phase2[" "]
        B[🔍 SCREENING]
    end
    subgraph Phase3[" "]
        C[✅ ENROLLMENT]
    end
    subgraph Phase4[" "]
        D[📋 CONDUCT]
    end
    subgraph Phase5[" "]
        E[🏁 CLOSEOUT]
    end
    
    A -->|IRB-approved
materials| B
    B -->|Consent
obtained| C
    C -->|Eligibility
confirmed| D
    D -->|Study
completion| E
    
    style A fill:#BB0000,color:#fff,stroke:#990000
    style B fill:#CC3333,color:#fff,stroke:#AA2222
    style C fill:#666666,color:#fff,stroke:#444444
    style D fill:#888888,color:#fff,stroke:#666666
    style E fill:#333333,color:#fff,stroke:#111111

Key Principle: Subject safety and rights must always prevail over scientific interests (ICH GCP Principle 1)

R-R-B-A-C-C-C-V Mnemonic

flowchart TB
    subgraph PART1["PART 1: R-R-B-A"]
        R1["🔬 R - RESEARCH
Purpose, duration, procedures,
experimental aspects"]
        R2["⚠️ R - RISKS
Reasonably expected risks
and discomforts"]
        B["✨ B - BENEFITS
Reasonably expected benefits
to subject or others"]
        A["💊 A - ALTERNATIVES
Alternative treatments
or procedures available"]
    end
    
    subgraph PART2["PART 2: C-C-C-V"]
        C1["🔒 C - CONFIDENTIALITY
How records will
be protected"]
        C2["💰 C - COMPENSATION
For research-related
injury (if >minimal risk)"]
        C3["📞 C - CONTACT
Whom to call for questions,
injury, or rights"]
        V["🆓 V - VOLUNTARY
Participation is voluntary,
may withdraw anytime"]
    end
    
    R1 --> R2 --> B --> A
    C1 --> C2 --> C3 --> V
    
    style R1 fill:#BB0000,color:#fff
    style R2 fill:#BB0000,color:#fff
    style B fill:#BB0000,color:#fff
    style A fill:#BB0000,color:#fff
    style C1 fill:#666666,color:#fff
    style C2 fill:#666666,color:#fff
    style C3 fill:#666666,color:#fff
    style V fill:#666666,color:#fff

Citation: 21 CFR 50.25(a)(1-8)

3. Visit Window Calculation: The TED Formula

flowchart LR
    subgraph FORMULA["TED FORMULA"]
        T["📅 TARGET
Scheduled Date"]
        E["⬅️ EARLIEST
Target − Window"]
        D["➡️ LATEST
Target + Window"]
    end
    
    T --- E
    T --- D
    
    style T fill:#BB0000,color:#fff,stroke:#990000
    style E fill:#157524,color:#fff,stroke:#0D4D17
    style D fill:#157524,color:#fff,stroke:#0D4D17

Example Calculation

flowchart TB
    subgraph SCENARIO["Week 8 Visit | Target: March 15 | Window: ±5 days"]
        EARLIEST["EARLIEST
March 10
(15 - 5 = 10)"]
        TARGET["TARGET
March 15
(Ideal date)"]
        LATEST["LATEST
March 20
(15 + 5 = 20)"]
    end
    
    EARLIEST ---|"Valid Window"| TARGET
    TARGET ---|"Valid Window"| LATEST
    
    style EARLIEST fill:#D4EDDA,color:#155724,stroke:#28A745
    style TARGET fill:#BB0000,color:#fff,stroke:#990000
    style LATEST fill:#D4EDDA,color:#155724,stroke:#28A745

Window Decision Tree

flowchart TD
    START["Actual Visit Date"] --> CHECK{"Is Actual Date
within Window?"}
    
    CHECK -->|"Earliest ≤ Actual ≤ Latest"| VALID["✅ VALID
Within Window"]
    CHECK -->|"Actual < Earliest OR
Actual > Latest"| DEVIATION["❌ DEVIATION
Out of Window"]
    
    DEVIATION --> DOC["Document:
1. Date discovered
2. Date occurred
3. Description
4. Root cause
5. Impact"]
    DOC --> CAPA["Complete CAPA:
• Corrective Action
• Preventive Action"]
    
    style VALID fill:#D4EDDA,color:#155724
    style DEVIATION fill:#F8D7DA,color:#721C24
    style DOC fill:#FFF3CD,color:#856404
    style CAPA fill:#CCE5FF,color:#004085

4. Three Types of Withdrawal

flowchart TB
    subgraph TYPES["WITHDRAWAL TYPES"]
        direction TB
        
        subgraph T1["TREATMENT WITHDRAWAL"]
            T1A["🛑 Stops study drug ONLY"]
            T1B["📋 Continues assessments"]
            T1C["👁️ Safety monitoring continues"]
            T1D["📊 Data collection continues"]
        end
        
        subgraph T2["PARTIAL WITHDRAWAL"]
            T2A["🛑 Stops drug AND most assessments"]
            T2B["📋 Minimal safety follow-up only"]
            T2C["👁️ Limited monitoring"]
            T2D["📊 Reduced data collection"]
        end
        
        subgraph T3["COMPLETE WITHDRAWAL"]
            T3A["🛑 Stops ALL participation"]
            T3B["📋 No further assessments"]
            T3C["❌ No contact allowed"]
            T3D["📊 Prior data retained"]
        end
    end
    
    style T1 fill:#D4EDDA,color:#155724
    style T2 fill:#FFF3CD,color:#856404
    style T3 fill:#F8D7DA,color:#721C24

Withdrawal Decision Flowchart

flowchart TD
    START["Subject expresses
desire to stop"] --> LISTEN["Listen without
pressure"]
    
    LISTEN --> PRESENT["Present ALL options:
Continue, Treatment WD,
Partial WD, Complete WD"]
    
    PRESENT --> DECISION{"Subject's
Decision?"}
    
    DECISION -->|"Continue with
support"| CONTINUE["Document discussion
Address concerns
Schedule follow-up"]
    
    DECISION -->|"Treatment
Withdrawal"| TWD["Stop drug only
Continue visits
Safety monitoring
Stays in ITT"]
    
    DECISION -->|"Partial
Withdrawal"| PWD["Stop drug
Minimal visits
Survival follow-up
Stays in ITT"]
    
    DECISION -->|"Complete
Withdrawal"| CWD["Stop everything
No further contact
Prior data retained
Stays in ITT"]
    
    style START fill:#CCE5FF,color:#004085
    style CONTINUE fill:#D4EDDA,color:#155724
    style TWD fill:#D4EDDA,color:#155724
    style PWD fill:#FFF3CD,color:#856404
    style CWD fill:#F8D7DA,color:#721C24

5. Withdrawal vs. Lost to Follow-Up (LTFU)

flowchart TB
    subgraph COMPARISON["CRITICAL DISTINCTION"]
        direction LR
        
        subgraph WD["WITHDRAWAL"]
            WD1["✋ ACTIVE decision"]
            WD2["💬 Subject communicates"]
            WD3["📝 Document immediately"]
            WD4["✅ Respect decision"]
        end
        
        subgraph LTFU["LOST TO FOLLOW-UP"]
            LTFU1["❓ NO active decision"]
            LTFU2["📵 Unable to contact"]
            LTFU3["📋 Document ALL attempts"]
            LTFU4["⏳ Exhaust due diligence"]
        end
    end
    
    style WD fill:#BB0000,color:#fff
    style LTFU fill:#666666,color:#fff

6. SWOG 3-2-1 Rule for LTFU

flowchart TD
    subgraph RULE["SWOG 3-2-1 RULE"]
        THREE["3️⃣ THREE
Minimum 3 contact attempts
at different times/days"]
        TWO["2️⃣ TWO
Over minimum
2-year period"]
        ONE["1️⃣ ONE
At least 1 attempt
must be certified letter"]
    end
    
    THREE --> TWO --> ONE
    
    style THREE fill:#BB0000,color:#fff
    style TWO fill:#CC3333,color:#fff
    style ONE fill:#DD4444,color:#fff

LTFU Contact Process

flowchart TD
    START["Subject misses
scheduled visit"] --> ATTEMPT1["Attempt 1:
Phone call
(different time of day)"]
    
    ATTEMPT1 -->|"No response"| ATTEMPT2["Attempt 2:
Text/Email
(if consented)"]
    
    ATTEMPT2 -->|"No response"| ATTEMPT3["Attempt 3:
Regular mail"]
    
    ATTEMPT3 -->|"No response"| CERT["REQUIRED:
Certified letter
with tracking"]
    
    CERT -->|"No response"| EMERGENCY["Contact emergency
contacts (per consent)"]
    
    EMERGENCY -->|"No response"| PUBLIC["Check public records
(obituaries, SSDI)
per HIPAA 45 CFR 164.512(i)"]
    
    PUBLIC -->|"No information"| LTFU_STATUS["Document as LTFU
after due diligence
completed"]
    
    subgraph DOCUMENTATION["DOCUMENT EACH ATTEMPT"]
        DOC1["📅 Date & Time"]
        DOC2["📞 Method used"]
        DOC3["📱 Contact info used"]
        DOC4["📝 Result/Outcome"]
        DOC5["✍️ Staff initials"]
    end
    
    style CERT fill:#BB0000,color:#fff
    style LTFU_STATUS fill:#666666,color:#fff

7. Compliance Assessment Hierarchy

flowchart TB
    subgraph HIERARCHY["MOST OBJECTIVE → LEAST OBJECTIVE"]
        BIO["🔬 BIOMARKERS
Drug levels in blood/urine
MOST OBJECTIVE"]
        ELEC["📱 ELECTRONIC MONITORING
MEMS caps, smart bottles"]
        PILL["💊 PILL COUNTS
Dispensed vs. returned"]
        DIARY["📓 PATIENT DIARIES
Self-reported logs"]
        SELF["🗣️ SELF-REPORT
Verbal confirmation
LEAST OBJECTIVE"]
    end
    
    BIO --> ELEC --> PILL --> DIARY --> SELF
    
    style BIO fill:#006600,color:#fff
    style ELEC fill:#228B22,color:#fff
    style PILL fill:#666666,color:#fff
    style DIARY fill:#999999,color:#fff
    style SELF fill:#BB0000,color:#fff

8. Recruitment Materials Decision Tree

flowchart TD
    CONTENT["Review Recruitment
Material Content"] --> Q1{"Claims treatment
is 'safe' or 'effective'?"}
    
    Q1 -->|"YES"| REJECT1["❌ PROHIBITED
No efficacy claims allowed"]
    Q1 -->|"NO"| Q2{"Uses 'FREE' for
study drug?"}
    
    Q2 -->|"YES"| REJECT2["❌ PROHIBITED
Cannot use 'free' for
investigational products"]
    Q2 -->|"NO"| Q3{"Contains exculpatory
language?"}
    
    Q3 -->|"YES"| REJECT3["❌ PROHIBITED
21 CFR 50.20 violation"]
    Q3 -->|"NO"| Q4{"Emphasizes payment
as primary benefit?"}
    
    Q4 -->|"YES"| REJECT4["❌ PROHIBITED
Undue inducement"]
    Q4 -->|"NO"| Q5{"IRB approved?"}
    
    Q5 -->|"NO"| SUBMIT["Submit to IRB
for review"]
    Q5 -->|"YES"| APPROVE["✅ ACCEPTABLE
May be used"]
    
    style REJECT1 fill:#F8D7DA,color:#721C24
    style REJECT2 fill:#F8D7DA,color:#721C24
    style REJECT3 fill:#F8D7DA,color:#721C24
    style REJECT4 fill:#F8D7DA,color:#721C24
    style APPROVE fill:#D4EDDA,color:#155724
    style SUBMIT fill:#FFF3CD,color:#856404
flowchart TD
    TRIGGERS["When is RE-CONSENT required?"]
    
    TRIGGERS --> T1["📝 Protocol amendment
affecting risk/benefit"]
    TRIGGERS --> T2["⚠️ New safety
information emerges"]
    TRIGGERS --> T3["🧠 Subject's capacity
changes"]
    TRIGGERS --> T4["🎂 Minor becomes
adult (18 years)"]
    TRIGGERS --> T5["🔬 Significant new
findings discovered"]
    
    T1 --> ACTION
    T2 --> ACTION
    T3 --> ACTION
    T4 --> ACTION
    T5 --> ACTION
    
    ACTION["RE-CONSENT PROCESS:
1. New signature on updated form
2. Date of re-consent
3. Who conducted discussion
4. Copy provided to subject
5. Version number documented"]
    
    style TRIGGERS fill:#BB0000,color:#fff
    style ACTION fill:#D4EDDA,color:#155724

10. Intent-to-Treat (ITT) Analysis

flowchart LR
    subgraph ITT["INTENT-TO-TREAT PRINCIPLE"]
        RAND["Subject
Randomized"] --> ANALYZED["Analyzed in
Original Group"]
    end
    
    subgraph APPLIES["APPLIES REGARDLESS OF:"]
        A1["Withdrawal"]
        A2["Non-compliance"]
        A3["Protocol deviation"]
        A4["Loss to follow-up"]
    end
    
    RAND -.->|"Once randomized
ALWAYS analyzed"| A1
    RAND -.->|"Once randomized
ALWAYS analyzed"| A2
    RAND -.->|"Once randomized
ALWAYS analyzed"| A3
    RAND -.->|"Once randomized
ALWAYS analyzed"| A4
    
    style RAND fill:#BB0000,color:#fff
    style ANALYZED fill:#157524,color:#fff

Why ITT Matters:

Citation: ICH E9(R1)

11. Special Populations: Additional Protections

flowchart TB
    subgraph POPULATIONS["45 CFR 46 SUBPARTS"]
        direction TB
        
        subgraph B["SUBPART B: Pregnant Women"]
            B1["Minimal risk to fetus"]
            B2["Father's consent may be required"]
            B3["Research must address maternal/fetal health"]
        end
        
        subgraph C["SUBPART C: Prisoners"]
            C1["Special IRB composition"]
            C2["Limited to prison-related research"]
            C3["Cannot use for parole consideration"]
        end
        
        subgraph D["SUBPART D: Children"]
            D1["Parent PERMISSION"]
            D2["Child ASSENT (typically 7+)"]
            D3["Prospect of direct benefit required"]
        end
    end
    
    style B fill:#BB0000,color:#fff
    style C fill:#856404,color:#fff
    style D fill:#1976D2,color:#fff
flowchart TD
    START["Pediatric Research
Subject Identified"] --> PARENT["PARENT/GUARDIAN
PERMISSION
(Adult consent elements)"]
    
    PARENT -->|"Permission granted"| AGE{"Child's
Age?"}
    
    AGE -->|"Under 7"| ASSENT_WAIVED["Assent typically
not required"]
    AGE -->|"7-17"| ASSENT["CHILD ASSENT
Age-appropriate explanation
Child's affirmative agreement"]
    
    ASSENT -->|"Assent given"| ENROLLED["✅ ENROLLED"]
    ASSENT -->|"Child dissents"| DISSENT["Generally cannot
override dissent"]
    
    PARENT -->|"Permission denied"| NOT_ENROLLED["❌ NOT ENROLLED"]
    
    style PARENT fill:#BB0000,color:#fff
    style ASSENT fill:#666666,color:#fff
    style ENROLLED fill:#D4EDDA,color:#155724
    style DISSENT fill:#F8D7DA,color:#721C24

12. ICH E6(R3) Transition Timeline

timeline
    title ICH E6 Evolution
    
    1996 : E6(R1) Original GCP
         : Foundation of clinical trial conduct
    
    2016 : E6(R2) First Revision
         : Risk-based monitoring
         : Electronic records guidance
    
    2024 : E6(R3) Published
         : Decentralized trials
         : eConsent provisions
    
    2026 : E6(R3) Effective
         : January 1, 2026
         : Full implementation required

E6(R3) Key Changes

mindmap
  root((ICH E6 R3))
    Risk-Based Quality Management
      Proportionate monitoring
      Critical data focus
      Quality tolerance limits
    Decentralized Trials
      Remote visits
      Direct-to-patient shipping
      Telemedicine assessments
    Electronic Consent
      21 CFR Part 11 compliance
      Remote consent capability
      Comprehension verification
    Digital Health Technologies
      Wearables
      Mobile apps
      Electronic diaries
    Participant-Centric
      Reduced burden
      Flexible scheduling
      Local testing options

13. Case Study Decision Framework: Mrs. Johnson

flowchart TD
    SCENARIO["Mrs. Johnson, Week 32
• Grade 1 nausea
• Daughter's wedding next month
• Time commitment concerns"]
    
    SCENARIO --> LISTEN["LISTEN without pressure
Acknowledge concerns"]
    
    LISTEN --> ASSESS["ASSESS:
Is this withdrawal request
or problem-solving need?"]
    
    ASSESS --> OPTIONS["PRESENT ALL OPTIONS
(No pressure, no coercion)"]
    
    OPTIONS --> O1["OPTION 1: Continue
• Address nausea (antiemetics)
• Schedule around wedding
• Reduce burden if possible"]
    
    OPTIONS --> O2["OPTION 2: Treatment WD
• Stop study drug
• Continue safety visits
• Addresses time concerns"]
    
    OPTIONS --> O3["OPTION 3: Partial WD
• Stop drug
• Minimal follow-up only"]
    
    OPTIONS --> O4["OPTION 4: Complete WD
• Her absolute right
• No further contact
• Prior data retained"]
    
    O1 --> DOC
    O2 --> DOC
    O3 --> DOC
    O4 --> DOC
    
    DOC["DOCUMENT:
• Discussion date/time
• Options presented
• Subject's decision
• Rationale given"]
    
    style SCENARIO fill:#CCE5FF,color:#004085
    style O1 fill:#D4EDDA,color:#155724
    style O2 fill:#D4EDDA,color:#155724
    style O3 fill:#FFF3CD,color:#856404
    style O4 fill:#F8D7DA,color:#721C24

14. Exam Quick Reference: High-Yield Topics

mindmap
  root((WEEK 9
HIGH-YIELD))
    Consent Elements
      R-R-B-A-C-C-C-V
      8 basic required
      6 additional when applicable
      ClinicalTrials.gov statement
    Visit Windows
      TED Formula
      Target ± Days
      Deviation documentation
      CAPA requirements
    Withdrawal
      3 types T-P-C
      Active decision
      Data retention
      ITT analysis
    LTFU
      NOT withdrawal
      SWOG 3-2-1 Rule
      Documentation required
      HIPAA provisions
    Recruitment
      IRB approval required
      No efficacy claims
      No exculpatory language
      21 CFR 50.20

15. Common Exam Traps

flowchart TB
    subgraph TRAPS["⚠️ COMMON EXAM TRAPS"]
        direction TB
        
        TRAP1["❌ TRAP: Confusing withdrawal types
✅ FIX: Treatment = drug only,
Partial = limited follow-up,
Complete = all contact ends"]
        
        TRAP2["❌ TRAP: Miscounting window days
✅ FIX: Use TED formula:
Earliest = Target - Window
Latest = Target + Window"]
        
        TRAP3["❌ TRAP: Missing exculpatory language
✅ FIX: Look for 'waive,' 'release,'
'hold harmless' - ALL prohibited"]
        
        TRAP4["❌ TRAP: Treating LTFU as withdrawal
✅ FIX: Withdrawal = active decision,
LTFU = unable to contact"]
        
        TRAP5["❌ TRAP: Forgetting re-consent triggers
✅ FIX: Amendment affecting risk,
new safety info, capacity change,
minor turns 18"]
    end
    
    style TRAP1 fill:#FFF3CD,color:#856404
    style TRAP2 fill:#FFF3CD,color:#856404
    style TRAP3 fill:#FFF3CD,color:#856404
    style TRAP4 fill:#FFF3CD,color:#856404
    style TRAP5 fill:#FFF3CD,color:#856404

Quick Reference Tables

Common Visit Windows

Visit Type Typical Window Example
Screening ±7-14 days Flexibility for scheduling
Weekly ±2-3 days Tight control, frequent visits
Monthly ±5-7 days Standard follow-up
Quarterly ±14-21 days Less frequent monitoring

Regulatory Citations

Topic Citation
Exculpatory language prohibition 21 CFR 50.20
8 basic consent elements 21 CFR 50.25(a)(1-8)
6 additional consent elements 21 CFR 50.25(b)
ClinicalTrials.gov statement 21 CFR 50.25(c)
Right to withdraw 21 CFR 50.25(a)(8)
IRB review of recruitment 21 CFR 56.109(a)
LTFU due diligence 21 CFR 312.62(b)
HIPAA research exception 45 CFR 164.512(i)
Vulnerable populations 45 CFR 46 Subparts B, C, D
Visit windows/deviations ICH E6(R2) Section 4.5
ITT analysis ICH E9(R1)

SOCRA CCRP Exam Preparation Course | Week 9 Visual Learning Aids Study Conduct and Subject Management