WEEK 8: VISUAL LEARNING AIDS
Diagrams, Flowcharts, Decision Matrices & Checklists
SOCRA CCRP Exam Preparation - Printable Study Materials
1. PROTOCOL REQUIRED ELEMENTS CHECKLIST
ICH E6(R2) Section 6 - Complete Protocol Contents
PROTOCOL REQUIRED ELEMENTS - PRINT & CHECK OFF
═════════════════════════════════════════════════════════════════
6.1 GENERAL INFORMATION
─────────────────────────────────────────────────────────────────
□ Protocol title
□ Protocol identifying number
□ Protocol version and date
□ Amendment number(s) and date(s) if applicable
□ Name and address of sponsor
□ Name, title, address, phone of sponsor's medical expert
□ Name and title of investigator(s) responsible for trial
□ Name(s) and address(es) of clinical laboratory(ies)
6.2 BACKGROUND INFORMATION
─────────────────────────────────────────────────────────────────
□ Name and description of investigational product
□ Summary of nonclinical study findings with clinical significance
□ Summary of known and POTENTIAL risks and benefits
□ Description and justification for:
□ Route of administration
□ Dosage
□ Dosage regimen
□ Treatment period
□ COMPLIANCE STATEMENT (protocol, GCP, regulatory)
□ Description of population to be studied
□ References to relevant literature and data
6.3 TRIAL OBJECTIVES AND PURPOSE
─────────────────────────────────────────────────────────────────
□ Detailed description of objectives
□ Statement of purpose
□ Primary hypothesis (if applicable)
□ Research questions the trial will answer
6.4 TRIAL DESIGN
─────────────────────────────────────────────────────────────────
□ Primary endpoint(s)
□ Secondary endpoint(s)
□ Type/design of trial (parallel, crossover, factorial, etc.)
□ Schematic diagram of trial design and procedures
□ Measures to minimize/avoid bias:
□ Randomization method and procedures
□ Blinding procedures and maintenance
□ Trial treatment(s):
□ Names
□ Doses
□ Dosage regimen
□ Route of administration
□ Duration
□ Dosage form
□ Packaging and labeling
□ Expected duration of subject participation
□ Sequence and duration of all trial periods
□ Stopping rules or discontinuation criteria:
□ For individual subjects
□ For parts of trial
□ For entire trial
□ Accountability procedures for investigational product
□ Maintenance of randomization codes
□ Procedures for breaking codes
□ Identification of data recorded directly on CRFs
6.5 SELECTION AND WITHDRAWAL OF SUBJECTS
─────────────────────────────────────────────────────────────────
□ Inclusion criteria (specific and justified)
□ Exclusion criteria (specific and justified)
□ Withdrawal criteria:
□ When to withdraw subjects
□ How to withdraw subjects
□ Type of data to be collected for withdrawn subjects
□ Timing of data collection for withdrawn subjects
□ Whether and how subjects are to be replaced
□ Follow-up procedures for withdrawn subjects
6.6 TREATMENT OF SUBJECTS
─────────────────────────────────────────────────────────────────
□ Treatment(s) to be administered:
□ Names
□ Doses
□ Schedules
□ Routes
□ Duration
□ Medication(s)/treatment(s) PERMITTED before/during trial
□ Medication(s)/treatment(s) PROHIBITED before/during trial
□ Procedures for monitoring subject compliance
6.7 ASSESSMENT OF EFFICACY
─────────────────────────────────────────────────────────────────
□ Specification of efficacy parameters
□ Methods for assessing efficacy parameters
□ Timing of efficacy assessments
□ Methods for recording efficacy parameters
□ Methods for analyzing efficacy parameters
6.8 ASSESSMENT OF SAFETY
─────────────────────────────────────────────────────────────────
□ Specification of safety parameters
□ Methods for assessing safety parameters
□ Timing of safety assessments
□ Methods for recording safety parameters
□ Methods for analyzing safety parameters
□ Procedures for eliciting reports of adverse events
□ Recording procedures for adverse events
□ Type and duration of follow-up after adverse events
6.9 STATISTICS
─────────────────────────────────────────────────────────────────
□ Description of statistical methods to be employed
□ Timing of interim analyses
□ Number of subjects planned:
□ Per site (for multicenter trials)
□ Reason for choice of sample size:
□ Power calculations
□ Clinical justification
□ Level of significance to be used (typically p<0.05)
□ Criteria for termination of trial
□ Procedures for accounting for:
□ Missing data
□ Unused data
□ Spurious data
□ Procedures for reporting deviations from original statistical plan
□ Selection of subjects to be included in analyses:
□ Intent-to-treat
□ Per-protocol
□ Evaluable
6.10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
─────────────────────────────────────────────────────────────────
□ Statement permitting direct access to source data
□ For whom (monitors, auditors, inspectors)
□ What data is accessible
6.11 QUALITY CONTROL AND QUALITY ASSURANCE
─────────────────────────────────────────────────────────────────
□ Procedures for quality control
□ Procedures for quality assurance
□ Data monitoring procedures
6.12 ETHICS
─────────────────────────────────────────────────────────────────
□ Description of informed consent procedure:
□ How/when informed consent obtained
□ Language of consent
□ Documentation procedure
□ IRB/IEC oversight requirements
□ Risks and benefits to subjects (summary)
□ Vulnerable populations protections (if applicable)
6.13 DATA HANDLING AND RECORD KEEPING
─────────────────────────────────────────────────────────────────
□ Procedure for maintaining trial records
□ Confidentiality protection procedures
□ Data entry procedures
□ Data validation procedures
□ Record retention requirements
6.14 FINANCING AND INSURANCE
─────────────────────────────────────────────────────────────────
□ Financing information
□ Insurance information (if applicable)
6.15 PUBLICATION POLICY
─────────────────────────────────────────────────────────────────
□ Publication approval procedures
□ Authorship criteria
□ Timing of publication
6.16 SUPPLEMENTS
─────────────────────────────────────────────────────────────────
□ Procedures for adding new information
□ Amendment vs. supplement criteria
═════════════════════════════════════════════════════════════════
TOTAL BOXES TO CHECK: 86
Use this checklist to audit protocol completeness.
2. ELIGIBILITY DECISION TREE FLOWCHART
SUBJECT SCREENING
│
▼
┌─────────────────────────────┐
│ DOES SUBJECT MEET ALL │
│ INCLUSION CRITERIA? │
└──────┬──────────────┬────────┘
YES NO
│ │
┌──────▼──┐ SCREEN FAIL
│ │ (Document
│ │ reason)
│
▼
┌──────────────────────────┐
│ DOES SUBJECT MEET ANY │
│ EXCLUSION CRITERIA? │
└──────┬──────────────┬────────┘
YES NO
│ │
SCREEN FAIL ┌──────▼──┐
(Document │ │
reason) │ │
│
▼
┌────────────────────────────┐
│ ELIGIBLE FOR ENROLLMENT │
│ │
│ Proceed to: │
│ • Informed consent │
│ • Baseline assessments │
│ • Randomization │
└────────────────────────────┘
CRITICAL RULE:
All inclusion AND all exclusion criteria assessed
AT TIME OF ENROLLMENT/RANDOMIZATION
(Not just at screening)
If not eligible at enrollment:
⊗ CANNOT enroll without BOTH:
1. Sponsor medical monitor approval (written)
2. IRB approval
⊗ Even with both approvals, risky & carefully monitored
3. AMENDMENT VS. ADMINISTRATIVE CHANGE DECISION MATRIX
DECISION MATRIX: Amendment vs. Administrative Change
═════════════════════════════════════════════════════════════════
CHANGE REQUIRES AMENDMENT?
CHANGE TYPE YES/NO REASONING
───────────────────────────────────────────────────────────────
SAFETY CHANGES
├─ Increase drug dose ✓ YES • Increased exposure
├─ Increase duration ✓ YES • Longer exposure
├─ Add safety test ✓ YES • Adds safety monitoring
├─ Drop safety test ✓ YES • Removes safety monitoring
├─ New inclusion limit ✓ YES • Restricts population (safety)
├─ New exclusion ✓ YES • Excludes risk group
└─ Change endpoint ✓ YES • Affects hypothesis
SCOPE CHANGES
├─ Increase subjects ✓ YES • Study scope expansion
├─ Add new site ✓ YES • Affects trial size
├─ Add treatment arm ✓ YES • Design change
└─ Drop control group ✓ YES • Design change
CONSENT/ETHICS CHANGES
├─ Update informed ✓ YES • Subject rights affected
│ consent form
├─ Add vulnerable pop. ✓ YES • Ethics/safety change
└─ Change compensation ✓ YES • Affects subject decision
ADMINISTRATIVE CHANGES
├─ Monitor name change ✗ NO • Contact only
├─ Phone number update ✗ NO • Contact only
├─ Email address update ✗ NO • Contact only
├─ Typo correction ✗ NO • Meaning unchanged
├─ CV updates ✗ NO • Qualifications update
├─ Clarifications ✗ NO • No meaning change
└─ Sponsor address ✗ NO • Administrative
INVESTIGATOR CHANGES
├─ Add new investigator ~ 30 DAY • Notify FDA within 30 days
├─ Remove investigator ✗ NO • Notification per protocol
└─ Change sub-investigator✗ NO • Usually institutional
═════════════════════════════════════════════════════════════════
DECISION RULE:
If change affects SAFETY, SCOPE, or QUALITY → AMENDMENT
Otherwise → ADMINISTRATIVE CHANGE (notification only)
WHEN IN DOUBT → Submit as amendment
IMPLEMENTATION:
✓ Amendments: FDA submission + IRB approval = Implementation OK
✗ Cannot implement before BOTH approvals
⚠ Exception: Immediate hazard elimination = implement, then notify
4. DEVIATION VS. VIOLATION CLASSIFICATION GUIDE
DEVIATION vs. VIOLATION DECISION TREE
═════════════════════════════════════════════════════════════════
PROTOCOL DEVIATION DETECTED
│
▼
┌──────────────────────────────┐
│ ASSESS IMPACT ON: │
│ • Subject Safety │
│ • Data Integrity │
│ • Regulatory Compliance │
└──────┬──────────────┬─────────┘
YES NO
│ │
SIGNIFICANT MINIMAL
IMPACT IMPACT
│ │
▼ ▼
┌──────────────┐ ┌──────────────┐
│ VIOLATION │ │MINOR DEVIATION│
│ │ │ │
│ Requirements:│ │Requirements: │
│ • Document │ │ • Document │
│ • Report │ │ • Track │
│ immediately│ │ • Evaluate │
│ • Sponsor │ │ • Continue │
│ SAME DAY │ │ • No escalate│
│ • IRB │ │ │
│ 24-48 hrs │ │ │
│ • FDA if │ │ │
│ safety │ │ │
└──────────────┘ └──────────────┘
EXAMPLES:
MINOR DEVIATIONS:
• Visit ±1 day within acceptable window
• Lab draw slight timing variation (within tolerance)
• Form page temporarily misfiled (source doc present)
• Minor data entry error (correctable)
MAJOR DEVIATIONS/VIOLATIONS:
• Visit 2+ weeks outside window
• Lab at completely wrong timepoint
• Enrollment of ineligible subject (creatinine high)
• Missing informed consent signature
• Prohibited medication given
• Administering wrong dose
DECISION FACTORS:
1. Is it within protocol tolerance?
YES → Minor Deviation
NO → Assess further
2. Does it affect subject safety?
YES → Major/Violation
NO → Minor
3. Does it compromise data integrity?
YES → Major/Violation
NO → Minor
4. Is it correctable?
YES → Major Deviation
NO → Violation (subject may exit)
5. Regulatory/GCP impact?
SIGNIFICANT → Violation
MINOR → Deviation
═════════════════════════════════════════════════════════════════
KEY: If in doubt → Escalate and let sponsor assess
5. PROTOCOL DEVIATIONS MANAGEMENT WORKFLOW
6-STEP DEVIATION MANAGEMENT PROCESS
═════════════════════════════════════════════════════════════════
STEP 1: DETECTION & DOCUMENTATION
┌─────────────────────────────────────────────────────────────┐
│ WHO detects? │
│ • Site staff (self-identification) │
│ • Monitor (during site visit) │
│ • Central review (data analysis) │
│ • Subject report │
│ • Audit findings │
│ │
│ WHAT to document: │
│ ✓ Date deviation discovered │
│ ✓ Description of what happened │
│ ✓ Subject ID and visit/timepoint │
│ ✓ Who discovered it │
└─────────────────────────────────────────────────────────────┘
│
▼
STEP 2: IMPACT ASSESSMENT
┌─────────────────────────────────────────────────────────────┐
│ Evaluate impact on: │
│ ✓ Subject SAFETY - was subject put at risk? │
│ ✓ DATA INTEGRITY - is data usable/valid? │
│ ✓ REGULATORY COMPLIANCE - did we violate GCP? │
│ │
│ Classification: │
│ • Minor Deviation: Impact minimal/none │
│ • Major Deviation: Significant impact on one area │
│ • Violation: Significant impact on safety/data/compliance │
└─────────────────────────────────────────────────────────────┘
│
▼
STEP 3: ROOT CAUSE ANALYSIS
┌─────────────────────────────────────────────────────────────┐
│ WHY did the deviation occur? │
│ • Investigator error? │
│ • Sponsor error? │
│ • Subject non-compliance? │
│ • System failure? │
│ • Training gap? │
│ • Procedure unclear? │
│ │
│ Document findings in writing │
└─────────────────────────────────────────────────────────────┘
│
▼
STEP 4: CAPA DEVELOPMENT (Corrective & Preventive Actions)
┌─────────────────────────────────────────────────────────────┐
│ CORRECTIVE ACTIONS (Fix Problem): │
│ • Re-obtain missing informed consent │
│ • Repeat procedure/assessment if needed │
│ • Provide staff training (if knowledge gap) │
│ • Correct data in database if error │
│ │
│ PREVENTIVE ACTIONS (Stop Recurrence): │
│ • Implement checklist before key step │
│ • Add electronic alert system │
│ • Update standard operating procedures │
│ • Conduct refresher training for all staff │
│ • Implement double-check system │
│ │
│ Document for EACH action: │
│ • What will be done │
│ • Who is responsible │
│ • Target completion date │
└─────────────────────────────────────────────────────────────┘
│
▼
STEP 5: REPORTING (Timeline Varies by Severity)
┌─────────────────────────────────────────────────────────────┐
│ MINOR DEVIATION: │
│ • Sponsor: Per protocol timeline │
│ • IRB: Per institutional policy │
│ • FDA: Not required │
│ │
│ MAJOR DEVIATION: │
│ • Sponsor: SAME DAY or next business day │
│ • IRB: Usually required │
│ • FDA: If safety impact │
│ │
│ VIOLATION: │
│ • Sponsor: IMMEDIATE (same day) │
│ • IRB: Within 24-48 hours │
│ • FDA: Within 15 days (if safety-related) │
└─────────────────────────────────────────────────────────────┘
│
▼
STEP 6: PREVENTION/FOLLOW-UP
┌─────────────────────────────────────────────────────────────┐
│ • Implement CAPA plan │
│ • Track action completion │
│ • Verify effectiveness (monitor for recurrence) │
│ • Document completion │
│ • Communicate completion to sponsor/IRB │
│ • Update protocols/procedures as needed │
│ • Provide staff feedback │
└─────────────────────────────────────────────────────────────┘
═════════════════════════════════════════════════════════════════
KEY TIMING:
✓ Minor deviation: Document and track
✓ Major deviation: Notify sponsor same day
✓ Violation: Contact sponsor immediately; assess continuation
6. IRT/IWRS SYSTEM WORKFLOW INFOGRAPHIC
IRT/IWRS SYSTEM: FROM SUBJECT ENROLLMENT TO DATA LOCK
═════════════════════════════════════════════════════════════════
┌─────────────────────────────────────────────────────────────┐
│ SUBJECT ENROLLMENT │
│ (Visit 1 - Baseline) │
│ │
│ 1. Subject meets all eligibility criteria │
│ 2. Informed consent obtained and signed │
│ 3. Baseline assessments completed │
└─────────────────────────┬──────────────────────────────────┘
│
▼
┌─────────────────────────────────────┐
│ RANDOMIZATION (IRT System) │
│ │
│ Investigator enters: │
│ • Subject ID │
│ • Visit information │
│ • Randomization factors (if any) │
│ │
│ IRT ASSIGNS TREATMENT │
│ • Subject → Treatment A or B │
│ • Assignment UNCONTROLLABLE │
│ • Prevents selection bias │
│ • Maintains allocation concealment │
└────────────────┬────────────────────┘
│
▼
┌─────────────────────────────────────┐
│ BLINDING MAINTENANCE (IRT) │
│ │
│ ✓ Treatment code secure │
│ ✓ Cannot be undetectably broken │
│ ✓ Only authorized personnel access │
│ ✓ Audit trail of all access │
│ ✓ Electronic controls prevent │
│ investigator seeing assignment │
│ ✓ Subject blinded (if applicable) │
└────────────────┬────────────────────┘
│
▼
┌────────────────────────────────────────────────┐
│ DRUG DISPENSING (IRT Tracks) │
│ │
│ Visit 1: │
│ • Assign drug kit to subject │
│ • IRT confirms: │
│ - Drug not expired │
│ - Correct amount │
│ - Not exceeding max dispensed │
│ • Record: subject, date, kit #, lot #, qty │
│ │
│ Ongoing (Visits 2-N): │
│ • Request drug from IRT │
│ • IRT confirms availability │
│ • Dispense as assigned │
│ • Record each dispensing │
│ • Monitor subject compliance │
└────────────────┬─────────────────────────────┘
│
▼
┌─────────────────────────────────────┐
│ VISIT WINDOW MONITORING │
│ │
│ IRT provides alerts: │
│ • Approaching visit deadline │
│ • Outside acceptable window │
│ • Missing scheduled visits │
│ • Non-compliance patterns │
└────────────────┬────────────────────┘
│
▼
┌─────────────────────────────────────┐
│ SUBJECT RETURNS (IRT Tracks) │
│ │
│ At end or withdrawal: │
│ • Subject returns unused drug │
│ • Count returned units │
│ • Reconcile: Dispensed - Returned │
│ • Store separately │
│ • IRT records return │
└────────────────┬────────────────────┘
│
▼
┌─────────────────────────────────────┐
│ EMERGENCY UNBLINDING (Rare) │
│ │
│ ONLY for true medical emergency: │
│ • Life-threatening event │
│ • Serious adverse event │
│ • Treatment info needed for care │
│ │
│ IRT provides code: │
│ • Cannot be hidden │
│ • Documented immediately │
│ • Reason recorded │
│ • Sponsor/IRB notified │
└────────────────┬────────────────────┘
│
▼
┌────────────────────────────────────────────────┐
│ STUDY CLOSEOUT (IRT Final Accounting) │
│ │
│ Final Reconciliation: │
│ • Total received │
│ • Total dispensed │
│ • Total returned │
│ • Total destroyed │
│ • Total remaining → destroyed per sponsor │
│ │
│ Equation must BALANCE: │
│ Received = Dispensed + Destroyed + Remaining │
│ │
│ 21 CFR Part 11 Compliance: │
│ • Complete electronic records │
│ • Audit trail of every action │
│ • User access logs │
│ • 2+ years records retention │
└────────────────────────────────────────────────┘
═════════════════════════════════════════════════════════════════
IRT ADVANTAGES OVER MANUAL SYSTEMS:
✓ Eliminates selection bias
✓ Prevents allocation manipulation
✓ Maintains blinding integrity
✓ Real-time inventory management
✓ Eliminates human error
✓ Complete audit trail
✓ 21 CFR Part 11 compliant
7. DRUG ACCOUNTABILITY CHAIN OF CUSTODY VISUAL
COMPLETE CHAIN OF CUSTODY: RECEIPT TO DESTRUCTION
═════════════════════════════════════════════════════════════════
SPONSOR SHIPS PRODUCT
│
▼ [VERIFY: Temperature logs, manifest]
┌─────────────┐
│ RECEIPT │────────→ Document:
│ │ • Date received
└─────────────┘ • Lot #, expiration
│ • Quantity
│ • Condition
│ • Signature
▼
┌──────────────────┐
│ STORAGE │────────→ Requirements:
│ (Locked, │ • Temperature control (2-8°C, etc.)
│ Temperature │ • Humidity monitoring
│ Controlled) │ • Daily temp logs
│ │ • Access delegation log
└──────────────────┘ • Separated from commercial drugs
│
├─────────────┬──────────────┐
│ │ │
▼ ▼ ▼
NORMAL TEMPERATURE EXPIRED
DISPENSING EXCURSION PRODUCT
│ │ │
│ QUARANTINE │
│ └→ NOTIFY SPONSOR │
│ └→ DESTROY │
│ (per sponsor) │
│ │
▼ │
┌──────────────┐ │
│ DISPENSING │ │
│ │ │
│ Record: │ │
│ • Date │ │
│ • Subject ID │ │
│ • Visit # │ │
│ • Lot # │ │
│ • Expiration │ │
│ • Qty │ │
│ • Signature │ │
└──────────────┘ │
│ │
├─────────────┬──────────┘
│ │
▼ ▼
SUBJECT [Expired]
TAKES DRUG DESTROYED
│ (with
│ sponsor
▼ auth)
┌──────────────┐
│ RETURNS │────────→ Record:
│ UNUSED │ • Date
│ │ • Quantity
└──────────────┘ • Condition
│
▼
STORE SEPARATELY
FROM REMAINING
│
├──────────────┬──────────────┐
│ │ │
▼ ▼ ▼
[Used] [Destroyed] [Remaining]
58 units 40 units 22 units
│ │ │
│ │ │
│ Sponsor Auth END OF STUDY
│ Certificate │
│ of Destruction │
│ Required Remaining
│ Destroyed
│ (final
│ accounting)
│ │
└────────────┬───────────────┘
│
▼
┌────────────────────────────┐
│ FINAL RECONCILIATION │
│ │
│ Received = 100 units │
│ Dispensed = 70 units │
│ Destroyed = 48 units │
│ Remaining = 22 units │
│ │
│ VERIFY: │
│ Used (58) + Returned (12) │
│ + Destroyed (40) + Remaining(22)
│ = 132? │
│ NO - DISCREPANCY! │
│ │
│ → Investigate │
│ → Document │
│ → Report to sponsor │
└────────────────────────────┘
═════════════════════════════════════════════════════════════════
MASTER EQUATION (MUST BALANCE):
Received = Dispensed + Destroyed + Remaining
100 = 70 + 8 + 22
KEY CHECKPOINTS:
✓ Receipt: Verify contents, temperature, condition
✓ Storage: Daily temperature logging, access control
✓ Dispensing: Every dose logged with detail
✓ Returns: Count and verify returned product
✓ Destruction: Sponsor authorization, witness, certificate
✓ Closeout: Equation balanced or discrepancy investigated
8. RECONCILIATION CALCULATION TEMPLATE WORKSHEET
DRUG ACCOUNTABILITY RECONCILIATION WORKSHEET
═════════════════════════════════════════════════════════════════
Study Name: ________________________ Site: __________________
Report Date: _______________________ Period: ________________
STEP 1: RECEIVED (Incoming Product)
─────────────────────────────────────────────────────────────────
Receipt Date(s): _________________
Shipment 1: _____ units, Lot #_______, Expiration: ________
Shipment 2: _____ units, Lot #_______, Expiration: ________
Shipment 3: _____ units, Lot #_______, Expiration: ________
TOTAL RECEIVED: ____________ units [A]
STEP 2: DISPENSING (Product Given to Subjects)
─────────────────────────────────────────────────────────────────
Total dispensed to subjects: ____________ units [B]
Dispensing breakdown (optional):
Visit 1: _____ units to _____ subjects
Visit 2: _____ units to _____ subjects
Visit 3: _____ units to _____ subjects
Other: _____ units
STEP 3: SUBJECT RETURNS (Unused Product from Subjects)
─────────────────────────────────────────────────────────────────
Total returned by subjects: ____________ units [C]
Actually USED by subjects: B - C = _____ units [D]
(Calculation: _____ - _____ = _____)
STEP 4: DESTRUCTION (Product Destroyed per Protocol)
─────────────────────────────────────────────────────────────────
Temperature excursion destroyed: _____ units
Expired product destroyed: _____ units
Damaged product destroyed: _____ units
End-of-study destroyed: _____ units
Other destruction: _____ units
TOTAL DESTROYED: ____________ units [E]
(Each with sponsor authorization and certificate?)
□ Yes □ No (if no, document why)
STEP 5: REMAINING (Physical Inventory Count)
─────────────────────────────────────────────────────────────────
Physical count of remaining product: ____________ units [F]
Verify count by:
□ Bottle/kit count
□ Weight verification
□ Other: _________________________
STEP 6: RECONCILIATION EQUATION
─────────────────────────────────────────────────────────────────
METHOD 1 (Using Remaining):
Received = Dispensed + Destroyed + Remaining
[A] = [B] + [E] + [F]
_____ = _____ + _____ + _____
═════════════════════════════════
BALANCED? □ YES □ NO
═════════════════════════════════
METHOD 2 (Verification):
Received = Used + Returned + Destroyed + Remaining
[A] = [D] + [C] + [E] + [F]
_____ = _____ + _____ + _____ + _____
═════════════════════════════════
BALANCED? □ YES □ NO
═════════════════════════════════
STEP 7: DISCREPANCY ANALYSIS (IF NOT BALANCED)
─────────────────────────────────────────────────────────────────
If equation does not balance:
Expected Remaining = Received - Dispensed - Destroyed
= _____ - _____ - _____ = _____
Actual Remaining = _____
DISCREPANCY = Expected - Actual = _____ units
Possible causes (check all that apply):
□ Undocumented temperature excursion
□ Documented but uncounted destroyed units
□ Data entry error in dispensing records
□ Spillage or accidental loss
□ Recount needed (count again)
□ Other: _________________________
Investigation findings:
________________________________________
________________________________________
Resolution:
________________________________________
________________________________________
STEP 8: INVESTIGATOR SIGN-OFF
─────────────────────────────────────────────────────────────────
Investigator Name (print): _________________________________
Investigator Signature: ____________________________________
Date: _____________________________
Comments:
________________________________________
________________________________________
STEP 9: SPONSOR APPROVAL
─────────────────────────────────────────────────────────────────
Sponsor Representative: ____________________________________
Signature: _____________________________________
Date: _____________________________
Approved: □ Yes □ Conditional □ Requires Further Action
If conditional or requires action:
________________________________________
________________________________________
═════════════════════════════════════════════════════════════════
KEEP: Original copy in trial files, electronic copy in database
SUBMIT: Copy to sponsor per protocol requirements
9. AMENDMENT IMPLEMENTATION TIMELINE
PROTOCOL AMENDMENT TIMELINE
═════════════════════════════════════════════════════════════════
DAY 0: PROBLEM IDENTIFIED
│
▼
┌─────────────────────────────┐
│ DRAFT AMENDMENT │
│ (Sponsor prepares) │
│ │
│ Content: │
│ • Amended protocol pages │
│ • Rationale for change │
│ • Safety assessment │
│ • Impact statement │
└──────────────┬──────────────┘
│
▼
┌──────────────────────────────┐
│ DAY 1-2: SPONSOR SUBMITS │
│ TO FDA │
│ │
│ Submission: │
│ • IND Amendment (312.30) │
│ • Complete amendment │
│ • Cover letter │
│ │
│ FDA receives and LOGS │
│ (doesn't mean approved) │
└──────────────┬───────────────┘
│
┌──────────────────┴──────────────────┐
│ │
▼ ▼
┌──────────────────┐ ┌──────────────────┐
│ SIMULTANEOUSLY: │ │ SIMULTANEOUSLY: │
│ FDA REVIEWS │ │ IRB REVIEWS │
│ (Background) │ │ (Active review) │
│ │ │ │
│ • Evaluates │ │ • Meeting/ballot │
│ • May question │ │ • Determines if │
│ • Issues letter? │ │ full/expedited │
│ (Usually none) │ │ • Votes approval │
└──────────────────┘ └────────┬─────────┘
│ │
│ ┌─────────────▼────────────┐
│ │ IRB APPROVAL OBTAINED │
│ │ (Usually 1-2 weeks) │
│ │ │
│ │ Investigator receives: │
│ │ • IRB approval letter │
│ │ • Approved amendment │
│ │ • Effective date │
│ └────────────┬─────────────┘
│ │
└─────────────────────┬───────────┘
│
▼
┌─────────────────────────┐
│ IMPLEMENTATION CONDITIONS│
│ MET: │
│ ✓ FDA received amend │
│ ✓ IRB approved amend │
└────────────┬────────────┘
│
▼
┌──────────────────────────┐
│ AMENDMENT IMPLEMENTED │
│ (Begin using new version)│
│ │
│ Actions: │
│ • Distribute to sites │
│ • Train staff │
│ • Update procedures │
│ • Start new practices │
│ • Document implementation
│ • File amendment copies │
└────────────┬─────────────┘
│
▼
┌──────────────────────────┐
│ ONGOING: │
│ FDA may ask questions │
│ (Reviewed while in use) │
│ │
│ Schedule: │
│ • FDA review during │
│ study conduct │
│ • Usually no approval │
│ letter needed │
│ • Just acknowledgment │
└──────────────────────────┘
═════════════════════════════════════════════════════════════════
CRITICAL POINTS:
✓ Sponsor submission to FDA = Day 1-2
✓ IRB review = 1-2 weeks (can be expedited)
✓ Implementation = After BOTH conditions met
✗ Cannot implement before BOTH approvals
✗ FDA does NOT approve amendments (pre-approval authority only)
✗ FDA reviews amendments while study ongoing
EXCEPTION:
Immediate hazard elimination:
→ Implement immediately
→ Notify FDA/IRB within 15 days