Table of Contents
- 1. THE 13 GCP PRINCIPLES - VISUAL HIERARCHY
- 2. SPONSOR vs. INVESTIGATOR RESPONSIBILITY MATRIX
- 3. QUALITY MANAGEMENT SYSTEM FRAMEWORK (E6(R2) & E6(R3))
- 4. RISK-BASED MONITORING DECISION FLOWCHART
- 5. INVESTIGATOR RESPONSIBILITIES - COMPLETE FLOWCHART
- 6. SPONSOR RESPONSIBILITIES - QUALITY MANAGEMENT FOCUS
- 7. ESSENTIAL DOCUMENTS BY TRIAL PHASE
- 8. ICH E6(R2) vs. E6(R3) MAJOR CHANGES TIMELINE
- 9. SAFETY REPORTING CHAIN
- 10. INFORMED CONSENT PROCESS - STEP BY STEP
- 11. PROTOCOL AMENDMENT WORKFLOW
- 12. CENTRALIZED vs. ON-SITE MONITORING COMPARISON
- 13. DATA INTEGRITY & AUDIT TRAILS (E6(R3) Enhanced)
- 14. STUDY STARTUP TO CLOSEOUT TIMELINE
- 15. SOCRA EXAM SUCCESS FORMULA
- The 13 GCP Principles - Memory Framework
- Diagram 2: Safety Reporting Timeline Decision Tree
- Diagram 3: Sponsor vs. Investigator Responsibilities Matrix
- Diagram 4: Essential Documents Organized by Trial Phase
- Diagram 5: ICH E6(R2) vs. E6(R3) Comparison
- Diagram 6: Quality Management Framework - Risk to Control
- Diagram 7: Risk-Based Monitoring Decision Flowchart
- Protocol Amendment vs. Deviation Process
- Informed Consent Process Flow
- Conflict of Interest Identification & Management
- Serious Adverse Event Classification
- Data Integrity - Source Documents to Database
- SOCRA Top 5 Memory Tips
1. THE 13 GCP PRINCIPLES - VISUAL HIERARCHY
graph TD
A["THE 13 GCP PRINCIPLES
Foundation of Clinical Trial Conduct"] --> B["GROUP 1: ETHICAL FOUNDATION"]
A --> C["GROUP 2: OPERATIONAL EXCELLENCE"]
A --> D["GROUP 3: DATA INTEGRITY & QUALITY"]
B --> B1["Principle 1:
ETHICAL CONDUCT
Declaration of Helsinki
Rights/Safety Paramount"]
B --> B2["Principle 2:
INFORMED CONSENT
Voluntary, Documented
Comprehension Required"]
B --> B3["Principle 3:
INDEPENDENT REVIEW
IRB/IEC Approval
Continuing Oversight"]
C --> C1["Principle 4:
SCIENTIFIC SOUNDNESS
Adequate Evidence
Appropriate Design"]
C --> C2["Principle 5:
QUALIFIED INDIVIDUALS
Education/Training
Experience Required"]
C --> C3["Principle 6:
FAVORABLE RISK-BENEFIT
Risk Assessment
Benefit Justification"]
C --> C4["Principle 7:
REGULATORY COMPLIANCE
Laws & Regulations
Protocol Adherence"]
C --> C5["Principle 8:
COMPETENT CARE
Qualified Physician
Medical Decisions"]
C --> C6["Principle 9:
SUBJECT WELFARE
Safety Primary
Medical Priority"]
D --> D1["Principle 10:
CLEAR ROLES
Responsibility Assignment
Oversight Required"]
D --> D2["Principle 11:
QUALITY ASSURANCE
Systems & Audits
Compliance Verification"]
D --> D3["Principle 12:
DATA CREDIBILITY
Accurate Recording
Audit Trails"]
D --> D4["Principle 13:
RECORDS MANAGEMENT
Documentation
Retention/Access"]2. SPONSOR vs. INVESTIGATOR RESPONSIBILITY MATRIX
graph LR
subgraph "TRIAL INITIATION"
S1["SPONSOR:
Protocol Design
IRB Submission
Investigator Selection"]
I1["INVESTIGATOR:
Form FDA 1572
Facility Assessment
IRB Communication"]
end
subgraph "TRIAL CONDUCT"
S2["SPONSOR:
Safety Monitoring
Data Oversight
Adverse Event Report"]
I2["INVESTIGATOR:
Subject Safety
Protocol Compliance
Record Keeping"]
end
subgraph "TRIAL CLOSURE"
S3["SPONSOR:
Final Report
Data Analysis
Regulatory Submission"]
I3["INVESTIGATOR:
Final Subject Assessment
Record Retention
Data Verification"]
end
S1 --> S2 --> S3
I1 --> I2 --> I3
style S1 fill:#ff9999
style S2 fill:#ff9999
style S3 fill:#ff9999
style I1 fill:#9999ff
style I2 fill:#9999ff
style I3 fill:#9999ff3. QUALITY MANAGEMENT SYSTEM FRAMEWORK (E6(R2) & E6(R3))
graph TD
QM["QUALITY MANAGEMENT SYSTEM
Proportionate Risk-Based Approach"]
QM --> RISK["RISK MANAGEMENT CYCLE"]
RISK --> ID["1. RISK IDENTIFICATION
What could go wrong?
- Safety risks
- Data integrity risks
- Operational risks"]
ID --> EV["2. RISK EVALUATION
How likely? How bad?
- Probability assessment
- Impact assessment
- Risk scoring"]
EV --> CS["3. CONTROL STRATEGY
How to prevent/mitigate?
- Prevent
- Detect
- Mitigate
- Accept"]
CS --> MON["4. RISK MONITORING
Is control working?
- Centralized review
- On-site monitoring
- Audit findings
- KPI tracking"]
MON --> ADJ["5. RISK ADJUSTMENT
Modify if new info
- Safety signals
- Data quality issues
- Enrollment challenges
- Regulatory feedback"]
ADJ --> MON
QM --> CTQ["CRITICAL TO QUALITY FACTORS
Identify CtQ Factors:
- Subject safety events
- Primary endpoint accuracy
- Inclusion/exclusion compliance
- Informed consent validity"]
CTQ --> PROP["PROPORTIONATE APPROACH
Allocate Resources by Risk:
- HIGH-RISK: Intensive monitoring
- MEDIUM-RISK: Balanced approach
- LOW-RISK: Sampling/reduced oversight"]
style QM fill:#ccffcc
style RISK fill:#ffffcc
style ID fill:#ffcccc
style EV fill:#ffcccc
style CS fill:#ffcccc
style MON fill:#ffffcc
style ADJ fill:#ffffcc
style CTQ fill:#ccccff
style PROP fill:#ccffff4. RISK-BASED MONITORING DECISION FLOWCHART
graph TD
A["TRIAL COMPLEXITY &
RISK ASSESSMENT"]
A --> B{"Phase &
Population?"}
B -->|Phase 1, Narrow Safety Margin| C["HIGH-RISK TRIAL"]
B -->|Phase 2/3, Novel Mechanism| C
B -->|Phase 4, Known Drug| D["LOW-RISK TRIAL"]
B -->|Phase 4, Common Disease| D
C --> C1["MONITORING STRATEGY:
ON-SITE FOCUSED"]
C1 --> C2["- Frequent on-site visits
- 100% SDV critical data
- Real-time safety review
- Weekly sponsor-site calls
- Possible IDMC"]
D --> D1["MONITORING STRATEGY:
CENTRAL FOCUSED"]
D1 --> D2["- Centralized review primary
- Risk-based SDV sampling
- Monthly communications
- On-site visits as-needed
- No IDMC typically"]
C --> E["CRITICAL TO QUALITY FACTORS:
Multiple high-risk areas"]
D --> F["CRITICAL TO QUALITY FACTORS:
Limited high-risk areas"]
E --> E1["- Safety event identification
- Dose escalation criteria
- Subject eligibility
- Investigator competence
- Emergency equipment"]
F --> F1["- Primary endpoint accuracy
- Subject safety events
- Inclusion/exclusion verification
- Data completeness"]
style A fill:#ffeeee
style C fill:#ff9999
style D fill:#99ff99
style C1 fill:#ffcccc
style D1 fill:#ccffcc
style E fill:#ff6666
style F fill:#66ff665. INVESTIGATOR RESPONSIBILITIES - COMPLETE FLOWCHART
graph TD
A["INVESTIGATOR RESPONSIBILITIES
Per ICH E6 Section 4"]
A --> B["PRE-TRIAL"]
A --> C["DURING TRIAL"]
A --> D["POST-TRIAL"]
B --> B1["4.1 Qualifications"]
B1 --> B1A["- Form FDA 1572
- Curriculum Vitae
- Facility Assessment"]
B --> B2["4.2 Adequate Resources"]
B2 --> B2A["- Personnel
- Facilities
- Equipment"]
B --> B3["4.4 IRB Communication"]
B3 --> B3A["- Submit Protocol
- ICF for Approval
- IB Distribution"]
C --> C1["4.3 Medical Care"]
C1 --> C1A["- Subject Safety Primary
- Emergency Procedures
- Alternative Treatment"]
C --> C2["4.5 Protocol Compliance"]
C2 --> C2A["- Inclusion/Exclusion
- Study Procedures
- Dosing Schedule"]
C --> C3["4.8 Informed Consent"]
C3 --> C3A["- Valid Process
- Comprehension Assessment
- Documented Signature"]
C --> C4["4.9 Records & Reports"]
C4 --> C4A["- CRF Completion
- Source Documentation
- Data Accuracy"]
C --> C5["4.11 Safety Reporting"]
C5 --> C5A["- SAE Assessment
- 24-Hour Report to Sponsor
- IRB Notification"]
C --> C6["4.6 Product Control"]
C6 --> C6A["- Inventory Tracking
- Secure Storage
- Subject Accountability"]
D --> D1["4.9 Final Report"]
D1 --> D1A["- Subject Summary
- AE Summary
- Final CRFs"]
D --> D2["4.9 Record Retention"]
D2 --> D2A["- Archive Securely
- Retain per Regulations
- Maintain Access"]
style A fill:#e6f2ff
style B fill:#ffe6e6
style C fill:#e6ffe6
style D fill:#fff9e66. SPONSOR RESPONSIBILITIES - QUALITY MANAGEMENT FOCUS
graph TD
S["SPONSOR RESPONSIBILITIES
Per ICH E6 Section 5
Quality Management System"]
S --> S1["5.0 QUALITY MANAGEMENT"]
S1 --> S1A["Establish QM System:
- Risk-based approach
- CtQ identification
- Proportionate controls
- Continuous monitoring"]
S --> S2["5.1 QA/QC"]
S2 --> S2A["Quality Assurance:
- Training programs
- SOPs development
- Audit program
Quality Control:
- SDV implementation
- CRF review
- Database validation"]
S --> S3["5.3 Medical Expertise"]
S3 --> S3A["Medical monitoring:
- Real-time safety review
- Adverse event assessment
- Regulatory correspondence"]
S --> S4["5.18 MONITORING"]
S4 --> S4A["Monitor Strategy:
- Central monitoring
- On-site visits
- Risk-based SDV
- Extent & nature"]
S --> S5["5.19 AUDIT"]
S5 --> S5A["Audit Program:
- Independent audit
- Systematic review
- GCP compliance
- Corrective actions"]
S --> S6["5.5-5.17 Operational"]
S6 --> S6A["- Investigator selection
- CRO oversight
- Safety reporting
- Data handling
- Record retention"]
style S fill:#fff0e6
style S1 fill:#ffcccc
style S2 fill:#ffddcc
style S3 fill:#ffeecc
style S4 fill:#ffffcc
style S5 fill:#eeffcc
style S6 fill:#ddffcc7. ESSENTIAL DOCUMENTS BY TRIAL PHASE
graph LR
subgraph "BEFORE TRIAL"
BEFORE["ESSENTIAL DOCUMENTS
BEFORE INITIATION"]
BEFORE --> B1["Chemistry:
- Formulation
- Stability
- GMP"]
BEFORE --> B2["Nonclinical:
- Toxicology
- Pharmacology
- Animal studies"]
BEFORE --> B3["Clinical:
- Prior experience
- Clinical overview
- PK/PD data"]
BEFORE --> B4["Trial:
- Protocol
- ICF (blank)
- IB"]
BEFORE --> B5["Regulatory:
- Form 1572
- Form 3454/3455
- IRB approval"]
end
subgraph "DURING TRIAL"
DURING["ESSENTIAL DOCUMENTS
DURING CONDUCT"]
DURING --> D1["Trial Records:
- CRFs
- Source data
- Visit notes"]
DURING --> D2["Safety:
- AE documentation
- SAE reports
- Safety updates"]
DURING --> D3["Regulatory:
- Protocol amendments
- IRB amendments
- Safety reports"]
DURING --> D4["Pharmacy:
- Inventory records
- Dispensing records
- Temperature logs"]
end
subgraph "AFTER TRIAL"
AFTER["ESSENTIAL DOCUMENTS
AFTER COMPLETION"]
AFTER --> A1["Study Report:
- Clinical Study Report
- Final investigator report
- Statistical analysis"]
AFTER --> A2["Safety:
- Final SAE summary
- Safety conclusions
- Adverse event listing"]
AFTER --> A3["Archive:
- All documents
- Organized index
- Retention timeline"]
end
style BEFORE fill:#ffe6e6
style DURING fill:#e6ffe6
style AFTER fill:#e6e6ff8. ICH E6(R2) vs. E6(R3) MAJOR CHANGES TIMELINE
graph LR
subgraph "E6/R1 (1996)"
R1["Original GCP
13 Principles
Paper-based"]
end
subgraph "E6(R2) (2016-2025)"
R2["E6(R2) ADDENDUM
Quality Management Intro
Electronic Records
Centralized Monitoring
Risk-based Monitoring"]
R2 --> R2A["Section 5.0: QM System
Risk-based approaches
CtQ identification
Proportionality concept"]
end
subgraph "E6(R3) (2025-2026)"
R3["E6(R3) RESTRUCTURING
Annex 1: Traditional Trials
Annex 2: Non-traditional TBD
Enhanced QM Framework"]
R3 --> R3A["NEW FOCUS AREAS:
DCT guidance
eConsent procedures
Wearables/digital health
Real-world evidence"]
R3 --> R3B["EXPANDED SECTIONS:
Data governance lifecycle
Service provider oversight
Quality by Design principle
Proportionate requirement"]
end
R1 --> R2 --> R3
SOCRA["SOCRA EXAM TIMELINE:
Until Dec 31, 2025: E6(R2)
Jan 1, 2026 onward: E6(R3)"]
style R1 fill:#cccccc
style R2 fill:#ffffcc
style R3 fill:#ccffcc
style R2A fill:#ffff99
style R3A fill:#99ff99
style R3B fill:#99ff99
style SOCRA fill:#ff99ff9. SAFETY REPORTING CHAIN
graph LR
A["SUBJECT EXPERIENCES
SERIOUS ADVERSE EVENT"] --> B["INVESTIGATOR:
Assess Event
Medical Care"]
B --> C["INVESTIGATOR
24-Hour Report
to SPONSOR"]
C --> D["SPONSOR
Medical Expert
Assessment"]
D --> E{"Serious &
Unexpected?"}
E -->|YES| F["EXPEDITED REPORT
to FDA
within 7 days
Form 3500A"]
E -->|NO| G["Annual Report
to FDA
Comprehensive"]
C --> H["INVESTIGATOR
Report to IRB/IEC
per timeline"]
H --> I["IRB/IEC
Reviews Safety
Determines if continue"]
D --> J["SPONSOR
Report to All
Investigators"]
style A fill:#ff6666
style B fill:#ffcc99
style C fill:#ffff99
style D fill:#ffff99
style F fill:#ff6666
style G fill:#ffff99
style H fill:#99ccff
style J fill:#99ff9910. INFORMED CONSENT PROCESS - STEP BY STEP
graph TD
IC["INFORMED CONSENT PROCESS
Must be voluntary, informed, documented"]
IC --> S1["STEP 1:
DISCUSSION & REVIEW"]
S1 --> S1A["- Investigator explains trial
- Subject reviews ICF
- Subject asks questions
- Subject has time to consider"]
S1A --> S2["STEP 2:
COMPREHENSION ASSESSMENT"]
S2 --> S2A["- Investigator assesses understanding
- Subject can explain key elements
- Subject understood risks/benefits
- Subject understood voluntary nature"]
S2A --> S3{"Comprehension
Adequate?"}
S3 -->|NO| S2B["Re-educate on
misunderstood areas"]
S2B --> S2A
S3 -->|YES| S4["STEP 3:
SIGNATURE"]
S4 --> S4A["- Subject signs & dates ICF
- Investigator signs & dates
- Witness signs if applicable
- Duplicate provided to subject"]
S4A --> S5["STEP 4:
DOCUMENTATION"]
S5 --> S5A["- Original filed in medical record
- Copy to subject
- Copy to sponsor
- Date/time documented"]
S5A --> S6["STEP 5:
SUBJECT ENROLLED
Trial participation begins"]
style IC fill:#e6f3ff
style S1 fill:#cce5ff
style S2 fill:#99ccff
style S3 fill:#66b3ff
style S4 fill:#3399ff
style S5 fill:#0080ff
style S6 fill:#0059b311. PROTOCOL AMENDMENT WORKFLOW
graph TD
INIT["PROTOCOL AMENDMENT NEEDED
Change in protocol required"]
INIT --> ASSESS{"Type of
Amendment?"}
ASSESS -->|SAFETY EMERGENCY| EMERGENCY["IMMEDIATE IMPLEMENTATION
- Change made immediately
- IRB/Sponsor notified ASAP
- Risk to subjects eliminated"]
ASSESS -->|ROUTINE AMENDMENT| ROUTINE["STANDARD PROCESS"]
ROUTINE --> R1["Sponsor Prepares Amendment
- Clear rationale
- Justification documented
- Changes specified"]
R1 --> R2["Sponsor → IRB/IEC
for review & approval"]
R2 --> R3["IRB/IEC Reviews
- Timing: 30-60 days typical
- IRB Approval obtained"]
R3 --> R4["Sponsor → FDA/Regulatory
if required by regulation"]
R4 --> R5["Sponsor → Investigators
IRB Approval + Amendment"]
R5 --> R6["Implementation
- All investigators update
- Staff trained
- All subjects notified"]
EMERGENCY --> E1["IRB/Sponsor Notified"]
E1 --> E2["Formal amendment prepared
& submitted to IRB"]
E2 --> E3["IRB reviews for approval
at next convened meeting"]
style INIT fill:#ffcccc
style ASSESS fill:#ffeecc
style EMERGENCY fill:#ff0000
style ROUTINE fill:#0000ff
style E1 fill:#ff6666
style E2 fill:#ff9999
style E3 fill:#ffcccc12. CENTRALIZED vs. ON-SITE MONITORING COMPARISON
graph LR
subgraph "CENTRALIZED MONITORING"
CM["CENTRALIZED
Electronic Review"]
CM --> CM1["Database Review
- Outliers
- Inconsistencies
- Missing data"]
CM --> CM2["Automated Checks
- Range validation
- Consistency rules
- Queries generated"]
CM --> CM3["Query Resolution
- Site responds
- Corrections made
- Trends identified"]
CM --> CM4["APPROPRIATE FOR:
- Lower-risk trials
- Standard assessments
- High EDC reliability"]
end
subgraph "ON-SITE MONITORING"
OM["ON-SITE
Direct Observation"]
OM --> OM1["Source Data Verification
- 100% or sampling
- Records reviewed
- CRF accuracy"]
OM --> OM2["Direct Observation
- Subject interaction
- Procedure compliance
- Facility assessment"]
OM --> OM3["Problem Resolution
- Training provided
- Issue identification
- Immediate feedback"]
OM --> OM4["APPROPRIATE FOR:
- Higher-risk trials
- Investigator inexperience
- Complex procedures"]
end
CM -.->|Can be
COMBINED| HYBRID["HYBRID APPROACH
Risk-based allocation:
Central + On-site"]
OM -.->|Can be
COMBINED| HYBRID
style CM fill:#e6f2ff
style OM fill:#ffe6e6
style HYBRID fill:#e6ffe613. DATA INTEGRITY & AUDIT TRAILS (E6(R3) Enhanced)
graph TD
DL["DATA LIFE CYCLE
E6(R3) Section 4"]
DL --> DC["DATA CAPTURE"]
DC --> DC1["Source documentation
EDC entry
Direct data entry by subject"]
DC --> DM["METADATA & AUDIT TRAILS"]
DM --> DM1["User ID captured
Timestamp recorded
Change recorded
Reason documented
Immutable records"]
DM --> DR["DATA REVIEW"]
DR --> DR1["Quality checks
Completeness review
Consistency verification
Outlier assessment"]
DR --> DCC["DATA CORRECTIONS"]
DCC --> DCC1["Amendment with audit trail
Original data visible
Change reason documented
Authorized person approval"]
DCC --> DTE["DATA TRANSFER/EXCHANGE"]
DTE --> DTE1["Secure transfer methods
Encryption
Integrity verification
Chain of custody"]
DTE --> DF["DATA FINALIZATION"]
DF --> DF1["Database locked
Final validation
Sign-off for analysis
Documentation retained"]
DF --> DA["DATA ANALYSIS"]
DA --> DA1["Statistical analysis
Results generation
Result reporting
Retention forever"]
style DL fill:#f0f0ff
style DC fill:#e0e0ff
style DM fill:#d0d0ff
style DR fill:#c0c0ff
style DCC fill:#b0b0ff
style DTE fill:#a0a0ff
style DF fill:#9090ff
style DA fill:#8080ff14. STUDY STARTUP TO CLOSEOUT TIMELINE
graph LR
A["STARTUP
Sponsor prepares:
- Protocol
- IB
- CRF
- Training materials"]
B["SITE INIT
Investigator:
- Submits 1572
- Receives training
- Reviews documents
- Tests systems"]
C["ENROLLMENT
- Subjects screened
- Subjects consented
- Baseline assessments
- Randomization"]
D["CONDUCT
- Study visits
- Data collection
- Safety monitoring
- CRF completion"]
E["MONITORING
- Ongoing reviews
- Site visits
- Data verification
- Problem resolution"]
F["FINAL SUBJECT
- Last visit
- Final assessments
- Final CRFs
- Product return"]
G["CLOSEOUT
- Reconciliation
- Final audit
- Records archived
- Site finalized"]
H["ANALYSIS
- Data lock
- Statistical analysis
- Report generation
- Regulatory submission"]
I["POST-TRIAL
- Publications
- Record retention
- Pharmacovigilance
- Subject follow-up"]
A --> B --> C --> D --> E --> F --> G --> H --> I
style A fill:#ffe6e6
style B fill:#ffcccc
style C fill:#ffb3b3
style D fill:#ff9999
style E fill:#ff8080
style F fill:#ff6666
style G fill:#ff4d4d
style H fill:#ff3333
style I fill:#ff1a1a15. SOCRA EXAM SUCCESS FORMULA
graph TD
EXAM["SOCRA CCRP EXAM
130 Questions | 100 Scored
Pass: 72 correct"]
EXAM --> DOMAIN1["40% - RESEARCH STUDY STARTUP"]
DOMAIN1 --> D1A["IRB/IEC requirements
Sponsor duties
Investigator qualifications
Informed consent"]
EXAM --> DOMAIN2["45% - RESEARCH STUDY IMPLEMENTATION"]
DOMAIN2 --> D2A["Protocol compliance
Safety reporting
Subject management
Data collection
Monitoring & audits"]
EXAM --> DOMAIN3["15% - RESEARCH STUDY CLOSURE"]
DOMAIN3 --> D3A["Study termination
Final reports
Record retention
Archive management"]
EXAM --> FOCUS["CRITICAL FOCUS AREAS"]
FOCUS --> F1["13 GCP Principles (15-20%)
Sponsor vs. Investigator (25%)
Essential Documents (20%)
FDA 21 CFR Alignment (10%)
Quality Management (10%)"]
EXAM --> STRATEGY["EXAM STRATEGY"]
STRATEGY --> S1["Read Q fully; eliminate wrong answers
Scenario-based: apply GCP principles
Watch for sponsor vs. investigator distinction
Remember: Subject safety is PARAMOUNT
E6(R2) through Dec 31, 2025
E6(R3) from Jan 1, 2026"]
style EXAM fill:#fff0f0
style DOMAIN1 fill:#ffe0e0
style DOMAIN2 fill:#ffcccc
style DOMAIN3 fill:#ffb3b3
style FOCUS fill:#ff9999
style STRATEGY fill:#ff8080The 13 GCP Principles - Memory Framework
mindmap root((ICH GCP
13 PRINCIPLES)) ETHICAL FOUNDATION Principle 1 Scientific Rigor Ethical Standards Principle 2 Informed Consent Voluntary Principle 3 IRB/IEC Authority Independent Review QUALITY & DATA Principle 6 Scientific Validity Justified Design Principle 9 Data Integrity Accurate Records Principle 10 Blinding & Random Reduce Bias PEOPLE & OVERSIGHT Principle 4 Investigator Qualified Education & Training Principle 5 Staff Training Competency Principle 8 Safety Monitoring Event Reporting CONDUCT & COMPLIANCE Principle 7 Protocol Adherence Amendment Process Principle 11 Confidentiality Privacy Protection Principle 12 Post-Trial Obligations Results Publishing Principle 13 Conflicts of Interest Transparency
Safety Reporting Timeline Decision Tree
graph TD
A["SAFETY EVENT OCCURS"] --> B{What type of event?}
B -->|Serious Adverse Event
unexpected| C{Fatal or
life-threatening?}
B -->|Expected adverse event| D["Annual Report
or if pattern emerges"]
B -->|Not serious| E["Document in source
No expedited reporting"]
C -->|YES| F["7 CALENDAR DAY
DEADLINE TO FDA
SPONSOR REPORTS"]
C -->|NO| G["15 CALENDAR DAY
DEADLINE TO FDA
SPONSOR REPORTS"]
F --> H["Investigator notifies
SPONSOR: ASAP
same day or 24 hrs"]
G --> H
H --> I["Sponsor prepares
Expedited Report"]
I --> J["SUBMIT TO FDA
within 7 or 15 days"]
J --> K["Sponsor notifies
IRB of FDA submission"]
style F fill:#ff6b6b
style G fill:#ff8c8c
style H fill:#ffd93d
style K fill:#6bcf7fSponsor vs. Investigator Responsibilities
graph LR
A["CLINICAL TRIAL
RESPONSIBILITIES"] --> B["INVESTIGATOR
Site-Level"]
A --> C["SPONSOR
Trial-Level"]
A --> D["IRB/IEC
Ethical Oversight"]
B --> B1["✓ Subject eligibility
verification"]
B --> B2["✓ Obtain informed
consent"]
B --> B3["✓ Dispense study drug"]
B --> B4["✓ Conduct trial visits"]
B --> B5["✓ Assess adverse events
& report to sponsor"]
B --> B6["✓ Maintain accurate
records"]
B --> B7["✓ Report protocol
deviations"]
B --> B8["✓ Cooperate with
monitors/audits"]
B --> B9["✓ Notify IRB of
significant issues"]
C --> C1["✓ Prepare & approve
protocol"]
C --> C2["✓ Prepare informed
consent form"]
C --> C3["✓ Manufacture/supply
drug"]
C --> C4["✓ Submit IND to FDA"]
C --> C5["✓ Monitor all sites"]
C --> C6["✓ Review adverse events"]
C --> C7["✓ Report to FDA per
timeline"]
C --> C8["✓ Approve protocol
amendments"]
C --> C9["✓ Audit trial conduct"]
C --> C10["✓ Manage CRO/vendors"]
D --> D1["✓ Approve protocol
before enrollment"]
D --> D2["✓ Review & approve
informed consent"]
D --> D3["✓ Conduct continuing
review"]
D --> D4["✓ Receive safety
updates"]
D --> D5["✓ Review protocol
amendments"]
D --> D6["✓ Assess conflicts
of interest"]
D --> D7["✓ Suspend/terminate
trial if needed"]
style B fill:#c3e7fc
style C fill:#fff4c3
style D fill:#d9f5e9Essential Documents Organized by Trial Phase
graph TD
A["ESSENTIAL DOCUMENTS
CHECKLIST"] --> B["BEFORE TRIAL"]
A --> C["DURING TRIAL"]
A --> D["AFTER TRIAL"]
B --> B1["Regulatory/Ethical
📋 Protocol & amendments
📋 ICF approval
📋 IRB approval letter
📋 FDA Form 1572
📋 Financial forms 3454/3455"]
B --> B2["Clinical Background
📋 Investigator CV
📋 Investigator's Brochure
📋 Chemistry/manufacturing info
📋 Pharmacology/toxicology
📋 Previous human experience"]
B --> B3["Trial Planning
📋 Quality assurance plan
📋 Monitoring plan
📋 Statistical analysis plan
📋 CRF specifications
📋 DSMB charter if applicable"]
C --> C1["Regulatory Docs
📋 Safety reports to FDA
📋 IRB continuing reviews
📋 Protocol amendments
📋 FDA correspondence"]
C --> C2["Trial Conduct
📋 Subject screening logs
📋 Signed ICF per subject
📋 Case Report Forms
📋 Source documents
📋 Medical records"]
C --> C3["Safety & Quality
📋 Adverse event reports
📋 DSMB meeting minutes
📋 Monitoring visit reports
📋 Audit reports
📋 Protocol deviation logs
📋 Training records"]
C --> C4["Drug Accountability
📋 Dispensing logs
📋 Storage/temp logs
📋 Return/destruction docs"]
D --> D1["Closeout Docs
📋 Final ICF versions
📋 Subject follow-up info
📋 Final monitoring report
📋 Drug return records"]
D --> D2["Reporting
📋 Final study report
📋 Statistical analysis report
📋 Clinical trial report
📋 Publications"]
D --> D3["Archive
📋 Trial Master File
📋 Investigator files
📋 Retain minimum 5 years"]
style B fill:#e8f4f8
style C fill:#fff9e6
style D fill:#f0f8e8
style B1 fill:#d0e8f2
style C1 fill:#ffe8b6
style D1 fill:#d9f5d9ICH E6(R2) vs. E6(R3) Comparison
graph TD
A["ICH GCP EVOLUTION"] --> B["E6(R2)
Released 2016"]
A --> C["E6(R3)
Released Jan 2025"]
B --> B1["13 Principles
Linear organization"]
B --> B2["Traditional RCT
focused"]
B --> B3["Quality Assurance
basic mention"]
B --> B4["Electronic systems
basic 21 CFR Part 11"]
B --> B5["On-site monitoring
emphasized"]
B --> B6["Limited guidance
special populations"]
C --> C1["11 Principles
Reorganized + integrated"]
C --> C2["Diverse designs
pragmatic, DCT, RWD"]
C --> C3["Quality Management
Section 4 - comprehensive"]
C --> C4["Data Governance
eConsent, eCRF, wearables"]
C --> C5["Risk-based monitoring
proportionate approach"]
C --> C6["Expanded populations
pediatric, vulnerable, remote"]
C --> C7["NEW Annex 2
non-traditional designs"]
B -.->|Builds on| C
style B fill:#e3f2fd
style C fill:#fff3e0
style B1 fill:#bbdefb
style C1 fill:#ffe0b2Quality Management Framework - Risk to Control
graph LR
A["CLINICAL TRIAL
PLANNING"] --> B["1. IDENTIFY
CRITICAL-TO-QUALITY
FACTORS"]
B --> C["2. ASSESS RISK
Probability × Severity
÷ Detectability"]
C --> D{Risk
Level?}
D -->|HIGH RISK| E["3. CONTROL
Intensive Monitoring
✓ On-site verification
✓ Real-time review
✓ Multiple controls"]
D -->|MEDIUM RISK| F["3. CONTROL
Targeted Monitoring
✓ Remote + audit
✓ Periodic on-site
✓ Statistical checks"]
D -->|LOW RISK| G["3. CONTROL
Automated Controls
✓ System validations
✓ Post-DB lock audit
✓ Electronic controls"]
E --> H["4. ASSURE
Quality Achieved"]
F --> H
G --> H
H --> I["ONGOING REVIEW &
ADJUSTMENTS"]
I -.->|If issues found| C
style B fill:#fff9c4
style C fill:#ffd54f
style D fill:#ffb74d
style E fill:#ff7043
style F fill:#ffa726
style G fill:#66bb6a
style H fill:#42a5f5
style I fill:#ab47bcRisk-Based Monitoring Decision Flowchart
graph TD
A["NEW TRIAL SITE
ASSIGNED"] --> B["ASSESS SITE RISK"]
B --> C{Investigator
Experience?}
C -->|New| D["HIGH RISK
PROFILE"]
C -->|Moderate| E["MEDIUM RISK
PROFILE"]
C -->|Experienced| F["CHECK OTHER
FACTORS"]
B --> G{Protocol
Complexity?}
G -->|Complex| D
G -->|Moderate| E
G -->|Simple| F
B --> H{Enrollment
Pace?}
H -->|Slow| D
H -->|Normal| E
H -->|Rapid| F
B --> I{Past Audit
Findings?}
I -->|Yes| D
I -->|No| E
D --> D1["HIGH-RISK SITE
MONITORING PLAN"]
D1 --> D1A["Monthly on-site visits"]
D1 --> D1B["25% SDV"]
D1 --> D1C["Weekly remote review"]
D1 --> D1D["Real-time SAE tracking"]
E --> E1["MEDIUM-RISK SITE
MONITORING PLAN"]
E1 --> E1A["Quarterly on-site visits"]
E1 --> E1B["10% targeted SDV"]
E1 --> E1C["Biweekly remote review"]
E1 --> E1D["Statistical validation"]
F --> F1["LOW-RISK SITE
MONITORING PLAN"]
F1 --> F1A["Semi-annual on-site visits"]
F1 --> F1B["5% post-study audit"]
F1 --> F1C["Monthly statistical review"]
F1 --> F1D["System-based controls"]
style D fill:#ffcdd2
style E fill:#fff3cd
style F fill:#c8e6c9
style D1 fill:#ef9a9a
style E1 fill:#ffe082
style F1 fill:#a5d6a7Protocol Amendment vs. Deviation Process
graph TD
A["CHANGE NEEDED
IN TRIAL CONDUCT"] --> B{Intentional or
Unintentional?}
B -->|INTENTIONAL| C["PROTOCOL
AMENDMENT"]
B -->|UNINTENTIONAL| D["PROTOCOL
DEVIATION"]
C --> C1["Sponsor prepares
written amendment"]
C1 --> C2["Submit to IRB
for PRIOR approval"]
C2 --> C3{IRB Decision}
C3 -->|Approve| C4["Amendment
EFFECTIVE"]
C3 -->|Requires changes| C5["Revise & resubmit"]
C3 -->|Disapprove| C6["Cannot proceed
or use alternative"]
C4 --> C7["Implement per
approved amendment"]
C5 --> C2
D --> D1["Investigator discovers
deviation occurred"]
D1 --> D2["Document in trial
records"]
D2 --> D3{Serious or
Pattern?}
D3 -->|Serious| D4["Report to sponsor
& IRB within 24 hrs"]
D3 -->|Minor/Isolated| D5["Report at next
IRB continuing review"]
D4 --> D6["Sponsor & investigator
determine corrective action"]
D5 --> D6
D6 --> D7["Continue or modify
trial conduct"]
C -.-> |MUST happen| C2
D -.-> |After the fact| D1
style C fill:#c8e6c9
style D fill:#ffccbc
style C2 fill:#81c784
style D2 fill:#ff8a65
style C4 fill:#66bb6a
style D4 fill:#ff7043Informed Consent Process Flow
graph TD
A["INFORMED CONSENT
PROCESS BEGINS"] --> B["Investigator prepares
IRB-approved ICF"]
B --> C["Subject reviews ICF
before enrollment"]
C --> D["Investigator discusses
protocol, risks, benefits"]
D --> E["Subject asks questions
& receives answers"]
E --> F{Subject
agrees?}
F -->|NO| G["Subject declines
trial participation"]
F -->|YES| H["Subject signs ICF
dates signature"]
H --> I["Investigator signs &
dates ICF"]
I --> J["Witness signs
if required"]
J --> K["Subject receives
copy of ICF"]
K --> L["Original ICF filed
in trial records"]
L --> M["Trial procedures begin"]
M --> N["Throughout trial
subject can withdraw
at any time without
penalty"]
N --> O{Subject
remains
enrolled?}
O -->|YES| P["Complete trial
procedures"]
O -->|NO| Q["Subject withdraws"]
P --> R["End of trial
subject informed
of results"]
Q --> S["End of participation
follow-up care arranged"]
style A fill:#e8f5e9
style H fill:#81c784
style K fill:#66bb6a
style M fill:#4caf50
style R fill:#2e7d32
style G fill:#ffccbc
style Q fill:#ff7043Conflict of Interest Identification & Management
graph TD
A["CONFLICT OF INTEREST
ASSESSMENT"] --> B{Financial Interest
in Sponsor?}
B -->|Equity ≥$5K
or Options| C["FINANCIAL
CONFLICT"]
B -->|Compensation ≥$25K| C
B -->|Proprietary
Interest| C
B -->|No/Below
threshold| D["NO FINANCIAL
CONFLICT"]
A --> E{Professional
Conflict?}
E -->|Desire for
positive results| F["PROFESSIONAL
CONFLICT"]
E -->|Researcher in
competing trial| F
E -->|Author of IB
or protocol| F
E -->|No obvious| G["NO PROFESSIONAL
CONFLICT"]
C --> H["DISCLOSURE
REQUIRED"]
F --> H
D --> I["DISCLOSE
No conflict"]
G --> I
H --> J["Complete FDA Forms
3454 & 3455"]
I --> J
J --> K["Submit to Sponsor
& IRB"]
K --> L{Conflict
Identified?}
L -->|YES| M["MANAGEMENT PLAN"]
L -->|NO| N["Continue trial"]
M --> M1["Option 1: Recusal
from certain decisions"]
M --> M2["Option 2: Enhanced
monitoring"]
M --> M3["Option 3: Monitoring
& disclosure"]
M1 --> N
M2 --> N
M3 --> N
style C fill:#ffcccc
style F fill:#ffe0cc
style H fill:#ff9999
style J fill:#ffc266
style M fill:#ffb3b3
style N fill:#c8e6c9Serious Adverse Event Classification
graph TD
A["ADVERSE EVENT
OCCURS"] --> B{Is it
SERIOUS?}
B -->|Death| C["SERIOUS
ADVERSE EVENT"]
B -->|Life-threatening| C
B -->|Requires hospitalization| C
B -->|Results in persistent
disability| C
B -->|Medical event requiring
intervention| C
B -->|No| D["ADVERSE EVENT
Not serious"]
C --> E{Is it
EXPECTED?}
E -->|Predicted in IB
or ICF| F["Expected SAE"]
E -->|Not mentioned
or surprising| G["UNEXPECTED SAE"]
D --> H["Document
No expedited
reporting"]
F --> I["Annual report
or if pattern
emerges"]
G --> J{Fatal or
Life-threatening?}
J -->|YES| K["7-DAY
REPORTING
to FDA"]
J -->|NO| L["15-DAY
REPORTING
to FDA"]
K --> M["Sponsor reports
within 7 calendar days
of learning of SAE"]
L --> N["Sponsor reports
within 15 calendar days
of learning of SAE"]
M --> O["Investigator informed
IRB informed
by Sponsor"]
N --> O
style C fill:#ffcccc
style G fill:#ff9999
style K fill:#cc0000
style L fill:#ff6666
style M fill:#990000
style N fill:#cc3333Data Integrity - Source Documents to Database
graph LR
A["SOURCE
DOCUMENTS
(Original)"]
A -->|Medical records
Lab reports
EKGs
Vital signs
Subject visit notes| B["CASE REPORT
FORMS
(CRF)"]
B -->|Data entry by
investigator or
coordinator| C["DATA ENTRY
into eCRF"]
C -->|Query process
if discrepancies| D["DATA REVIEW
&
VERIFICATION"]
D -->|SDV 5-100%
match CRF to source| E["SOURCE DATA
VERIFICATION"]
E -->|Corrections
tracked with
audit trail| F["CORRECTED
DATA"]
F -->|Statistical
validation checks| G["DATA
VALIDATION"]
G -->|Final review
all data locked| H["DATABASE
LOCK"]
H -->|Statistical
analysis| I["FINAL
RESULTS"]
style A fill:#c3e7fc
style B fill:#b3e5fc
style C fill:#81d4fa
style D fill:#4fc3f7
style E fill:#29b6f6
style F fill:#1e88e5
style G fill:#1565c0
style H fill:#0d47a1
style I fill:#041e78SOCRA Top 5 Memory Tips
graph TB
A["SOCRA EXAM
TOP 5 MEMORY TIPS"]
A --> B["1️⃣ SAFETY TIMELINES
7 days = FATAL
15 days = OTHER SERIOUS
5 working days = EMERGENCY DEV"]
A --> C["2️⃣ AMENDMENT vs DEVIATION
AMENDMENT = Intentional
requires IRB PRIOR approval
DEVIATION = Unintentional
document & report"]
A --> D["3️⃣ INVESTIGATOR CANNOT DELEGATE
✗ Informed Consent
✗ Medical Oversight
✓ CRF completion
✓ Trial activities"]
A --> E["4️⃣ 13 GCP PRINCIPLES
Remember: RESPECT FOR SCIENCE
Rights (2,3,11,12)
Ethics (1,3,13)
Science (6,7,9)"]
A --> F["5️⃣ ESSENTIAL DOCUMENTS
BEFORE: Protocol, ICF, CV
DURING: CRF, Source docs
AFTER: Final report, Archive"]
style B fill:#fff9c4
style C fill:#ffeb99
style D fill:#ffe0b2
style E fill:#ffccbc
style F fill:#ffb3ba