21 CFR Part 56 IRB Requirements and Oversight

DIAGRAM 1: RISK-MDP "Big 7" IRB Approval Criteria

graph TD
    Start["IRB APPROVAL REQUIRES ALL 7 CRITERIA
Missing even 1 = NO APPROVAL"] --> R["🔴 R - RISK IS MINIMIZED
21 CFR 56.111(a)(1)
─────────────
✓ Scientifically justified
✓ No unnecessary exposure
✓ Risk proportionate
✓ Use standard procedures
✗ FAIL: Excessive procedures"]
    
    Start --> I["🟡 I - INFORMED CONSENT
21 CFR 56.111(a)(2)
─────────────
✓ Purpose explained
✓ Risks with frequencies
✓ Benefits described
✓ Alternatives listed
✓ Confidentiality explained
✓ Right to withdraw
✗ FAIL: Vague risk language"]
    
    Start --> S["🟢 S - EQUITABLE SELECTION
21 CFR 56.111(a)(3)
─────────────
✓ Justified inclusion/exclusion
✓ Fair process
✓ No unnecessary exclusions
✓ No vulnerable population exploitation
✗ FAIL: Exclusions without justification"]
    
    Start --> K["🔵 K - KNOWLEDGEABLE REVIEW
21 CFR 56.111(a)(4)
─────────────
✓ Scientific expertise present
✓ External consultants if needed
✓ Members understand research area
✗ FAIL: No relevant expertise"]
    
    Start --> M["🟣 M - MONITORING PLAN
21 CFR 56.111(a)(4)
─────────────
✓ Safety schedule defined
✓ Stopping rules established
✓ AE reporting procedure
✓ Protocol deviation tracking
✗ FAIL: No monitoring plan"]
    
    Start --> D["🟠 D - DATA SAFETY & INTEGRITY
21 CFR 56.111(a)(4)
─────────────
✓ De-identification where possible
✓ Secure storage
✓ Limited access
✓ Encryption & backups
✗ FAIL: Unencrypted data"]
    
    Start --> P["⚫ P - VULNERABLE POPULATIONS
21 CFR 56.111(b)-(d)
─────────────
✓ Children: assent required
✓ Prisoners: minimal-risk only
✓ Pregnant women: protections
✓ Cognitive impairment: representative
✗ FAIL: No extra safeguards"]
    
    R --> Approve["✅ ALL 7 MET = IRB APPROVAL"]
    I --> Approve
    S --> Approve
    K --> Approve
    M --> Approve
    D --> Approve
    P --> Approve

DIAGRAM 2: IRB Composition Requirements

graph TD
    Comp["IRB COMPOSITION REQUIREMENTS
21 CFR 56.107"] --> Min["REQUIREMENT 1: MINIMUM MEMBERSHIP
───────────────
Minimum 5 Members
(Can be more, never fewer)"]
    
    Comp --> Sci["REQUIREMENT 2: SCIENTIFIC MEMBER
───────────────
At least 1 member with:
• Clinical research design training
• Biostatistics knowledge
• Current research knowledge
• Regulatory knowledge"]
    
    Comp --> NonSci["REQUIREMENT 3: NON-SCIENTIST MEMBER
───────────────
At least 1 member who is NOT:
• Scientist
• Physician
• IRB staff member
Examples: Ethics expert, chaplain,
community member, lawyer"]
    
    Comp --> Unafil["REQUIREMENT 4: UNAFFILIATED MEMBER
───────────────
At least 1 member with NO affiliation
to the institution (not employed,
no financial interest)
Rationale: External perspective"]
    
    Comp --> Diversity["REQUIREMENT 5: DIVERSITY
───────────────
Encourage representation in:
• Gender
• Race/ethnicity
• Professional background
• Geographic perspective"]
    
    Comp --> Chair["REQUIREMENT 6: CHAIR DESIGNATION
───────────────
IRB must have designated chair
(can be scientist or non-scientist)
Responsible for:
• Meetings scheduling
• Agenda development
• Conflict resolution
• IRB governance"]
    
    Comp --> Recusal["REQUIREMENT 7: CONFLICT RECUSAL
───────────────
Members must recuse from reviews
where they have:
• Financial interest
• Employment relationship
• Personal/family connection
• Research involvement"]
    
    Min --> Final["✅ IRB COMPOSITION VALID"]
    Sci --> Final
    NonSci --> Final
    Unafil --> Final
    Diversity --> Final
    Chair --> Final
    Recusal --> Final

DIAGRAM 3: Conflict of Interest Decision Tree

graph TD
    Start["IRB MEMBER REVIEWING PROTOCOL
───────────────
Potential Conflict of Interest?"] --> Q1{Any relationship with:
Investigator, Sponsor,
or Institution?}
    
    Q1 -->|NO| Continue1["✅ CONTINUE REVIEW
No conflict identified"]
    Q1 -->|UNSURE| Disclose1["⚠️ DISCLOSE & RECUSE
When in doubt:
disclose to IRB"]
    Q1 -->|YES| Q2{Relationship Type?}
    
    Q2 -->|Employment| EmpQ{Works for investigator's
institution?}
    EmpQ -->|YES| Recuse1["🚫 RECUSE
Employment conflict"]
    EmpQ -->|NO| Continue2["✅ CONTINUE"]
    
    Q2 -->|Financial| FinQ{Any financial interest?}
    FinQ -->|Stock/Equity| Recuse2["🚫 RECUSE
Equity interest"]
    FinQ -->|Paid Consulting| Recuse3["🚫 RECUSE
Consulting income"]
    FinQ -->|Patent/Royalty| Recuse4["🚫 RECUSE
Patent interest"]
    FinQ -->|Family Benefits| Recuse5["🚫 LIKELY RECUSE
Family financial benefit"]
    FinQ -->|Unpaid Board| Continue3["✅ CONTINUE
No financial benefit"]
    FinQ -->|Nominal Gift| Continue4["✅ CONTINUE
De minimis amount"]
    
    Q2 -->|Research| ResQ{Involvement level?}
    ResQ -->|Investigator| Recuse6["🚫 RECUSE
Active investigator"]
    ResQ -->|Co-Investigator| Recuse7["🚫 RECUSE
Co-investigator"]
    ResQ -->|Lab Provides Materials| Recuse8["🚫 LIKELY RECUSE
Material provider"]
    ResQ -->|Prior Co-publications| Continue5["✅ CONTINUE
Historical connection"]
    ResQ -->|Different Research Area| Continue6["✅ CONTINUE
No research overlap"]
    
    Q2 -->|Personal| PersQ{Type of relationship?}
    PersQ -->|Family Member| Recuse9["🚫 RECUSE
Family conflict"]
    PersQ -->|Close Friend| Recuse10["🚫 LIKELY RECUSE
Friendship bias"]
    PersQ -->|Professional in Other Context| Disclose2["⚠️ DISCLOSE
Multiple roles"]
    PersQ -->|Professional Only| Continue7["✅ CONTINUE
No friendship"]
    
    Recuse1 --> Final["Document in Minutes
Member leaves room
during discussion & vote"]
    Recuse2 --> Final
    Recuse3 --> Final
    Recuse4 --> Final
    Recuse5 --> Final
    Recuse6 --> Final
    Recuse7 --> Final
    Recuse8 --> Final
    Recuse9 --> Final
    Recuse10 --> Final
    Disclose1 --> Final
    Disclose2 --> Final
    Continue1 --> Final
    Continue2 --> Final
    Continue3 --> Final
    Continue4 --> Final
    Continue5 --> Final
    Continue6 --> Final
    Continue7 --> Final
    
    Final --> Standard["STANDARD: 'Objectivity might be questioned'
When in doubt: DISCLOSE & RECUSE"]

DIAGRAM 4: Continuing Review & Approval Timeline

graph TD
    Initial["INITIAL IRB APPROVAL
June 1, 2024"] --> Valid["APPROVAL VALID FOR
12 MONTHS"]
    
    Valid --> Deadline["⏰ CONTINUING REVIEW DEADLINE
June 1, 2025
(EXACTLY 12 months from approval)"]
    
    Deadline --> Choice{Was continuing review
submitted BEFORE deadline?}
    
    Choice -->|YES| Submitted["✅ CONTINUING REVIEW SUBMITTED
on time or early"]
    Choice -->|NO| Expired["❌ APPROVAL EXPIRES
Research halts
Regulatory violation"]
    
    Submitted --> IRBReview["IRB Reviews & Approves
Continuing Review"]
    IRBReview --> NewApproval["New Approval Issued
June 10, 2025"]
    NewApproval --> NewValid["Approval Valid Through
June 1, 2026"]
    NewValid --> Continue["✅ RESEARCH CONTINUES
with valid approval"]
    
    Continue --> Reminder["⚠️ SET NEW REMINDER
by March 15, 2026
90 days before deadline"]
    
    Expired --> NoEnroll["❌ NO NEW ENROLLMENT
❌ RESEARCH MUST STOP
❌ EXISTING SUBJECTS AT RISK"]
    NoEnroll --> Consequences["CONSEQUENCES:
• FDA inspection likely
• FDA Warning Letter
• Data may be invalidated
• Investigator discipline"]
    
    style Initial fill:#90EE90
    style Valid fill:#87CEEB
    style Deadline fill:#FFD700
    style Submitted fill:#90EE90
    style Expired fill:#FF6B6B
    style Continue fill:#90EE90
    style NoEnroll fill:#FF6B6B
    style Consequences fill:#FF6B6B

DIAGRAM 5: Adverse Event Reporting Process

graph TD
    AE["ADVERSE EVENT OCCURS
During Research"] --> Serious{Is it Serious or
Unexpected?}
    
    Serious -->|NO| Monitor["Minor/Expected AE
───────────
Document in file
Monitor ongoing
Report at continuing review"]
    
    Serious -->|YES| Report["SERIOUS/UNEXPECTED AE
───────────
Report to IRB
Within 7 DAYS
Do NOT wait for
continuing review"]
    
    Report --> Assessment["IRB SAFETY ASSESSMENT
───────────
Is research protocol
related to the AE?
Will AE impact risk/benefit?"]
    
    Assessment --> Action1{Conclusion?}
    Action1 -->|No change needed| Continue1["✅ CONTINUE RESEARCH
Monitor closely
Document in file"]
    Action1 -->|Modify protocol| Modify["⚠️ PROTOCOL MODIFICATION
Required
Submit for IRB review
Research pauses pending approval"]
    Action1 -->|Stop research| Stop["❌ HALT RESEARCH
Immediate safety concern
Notify subjects
FDA notification if IND study"]
    
    Continue1 --> FollowUp["Ongoing monitoring
Report at next
continuing review"]
    Modify --> IRBApproval["IRB reviews & approves
modifications"]
    IRBApproval --> Resume["Resume research
with new protocol"]
    Stop --> Investigation["Investigate root cause
Assess subject safety
Notify all relevant parties"]

DIAGRAM 6: Vulnerable Populations - Additional Safeguards

graph TD
    VP["VULNERABLE POPULATIONS
21 CFR 56.111(b)-(d)
IF APPLICABLE: ADD SAFEGUARDS"] --> Children["👶 CHILDREN"]
    VP --> Prisoners["🔒 PRISONERS"]
    VP --> Pregnant["👪 PREGNANT WOMEN/FETUSES"]
    VP --> Cogn["🧠 COGNITIVELY IMPAIRED"]
    VP --> Econ["💰 ECONOMICALLY DISADVANTAGED"]
    
    Children --> ChildSafe["Additional Requirements:
───────────
• Parental permission required
• Age-appropriate assent
• Assent process documented
• Extra risk minimization
• Benefit justification
• Community input considered"]
    
    Prisoners --> PrisonSafe["Additional Requirements:
───────────
• Minimal-risk only
• Independent advocate present
• NO coercion allowed
• NO sentence reduction offers
• Fair selection process
• Monitoring enhanced"]
    
    Pregnant --> PregSafe["Additional Requirements:
───────────
• Minimal-risk OR direct benefit
• Fetus protection plan
• Pregnant women informed consent
• Risk clearly documented
• Monitoring for fetal effects
• Breastfeeding impact noted"]
    
    Cogn --> CognSafe["Additional Requirements:
───────────
• Legally authorized representative
• Surrogate consent required
• Subject assent when possible
• Enhanced monitoring
• Easy withdrawal process
• Special communication methods"]
    
    Econ --> EconSafe["Additional Requirements:
───────────
• NOT exploited for easy enrollment
• Fair compensation (not coercive)
• No undue inducement
• Language services provided
• Community advisory board
• Equitable benefit sharing"]
    
    ChildSafe --> GenSafe["GENERAL SAFEGUARDS
FOR ALL VULNERABLE GROUPS:
───────────
✓ Community advisory board
✓ Enhanced monitoring
✓ Language/accessibility services
✓ Extra informed consent detail
✓ Ongoing training for staff"]

KEY REGULATORY REFERENCES

STUDY TIPS

• Remember RISK-MDP: All 7 approval criteria must be met for IRB approval
• Set reminders: 90 days before approval expiration to prepare continuing review
• When in doubt: Disclose conflicts of interest and allow IRB to make determination
• Serious/Unexpected AEs: Report within 7 days—don't wait for continuing review
• Vulnerable populations: Plan extra safeguards during initial protocol design