Comprehensive Exam Preparation Guide

Week: 9 of 12
Topic: Study Conduct and Subject Management
Exam Relevance: Domain 2 (Study Implementation) - 50% of SOCRA CCRP Exam
Target Exam Date: December 2025 / January 2026

Learning Objectives

By the end of Week 9, you will be able to:

1. Describe regulatory requirements for subject recruitment materials and IRB oversight
2. Apply screening and enrollment procedures in compliance with 21 CFR 50 and ICH E6(R3)
3. Calculate visit windows and identify protocol deviations
4. Differentiate between withdrawal types and lost to follow-up (LTFU)
5. Implement compliance monitoring strategies and retention best practices
6. Document subject management activities according to GCP requirements

Part 1: Subject Recruitment Strategies

1.1 Regulatory Framework for Recruitment

KEY PRINCIPLE: FDA considers advertising to be the START of informed consent.

"Direct advertising for study subjects is considered the start of the informed consent and subject selection processes."
— FDA Guidance: Recruiting Study Subjects (1998)

Materials Requiring IRB Review (21 CFR 56.109(a))

Acceptable vs. Unacceptable Recruitment Content

✅ ACCEPTABLE:

• Investigator name and facility address
• Condition under study and research purpose
• Summary eligibility criteria
• Brief participation benefits (e.g., "no-cost health examinations")
• Time commitment
• Statement that treatment is investigational
• "Compensation available for participation"

❌ UNACCEPTABLE (PROHIBITED):

• Claims drug/device is "safe" or "effective"
• Superiority claims over existing treatments
• "New treatment" without clarifying investigational status
• "FREE medical treatment" (implies value beyond research)
• Exculpatory language (violates 21 CFR 50.20)
• Excessive emphasis on payment (bold fonts, enlarged text)
• Certainty of favorable outcomes
• "Guaranteed cure"

1.2 Recruitment Planning and Feasibility

Screen Failure Rate Planning:

• Typical Phase II/III trials: 20-30% screen failure rate
• Complex conditions (e.g., Alzheimer's): 70-80% screen failure rate
• Planning formula: Need X subjects → Plan to screen X ÷ (1 - failure rate)

Example Calculation:

Need to enroll: 50 subjects
Screen failure rate: 30%
Subjects to screen: 50 ÷ 0.70 = 72 subjects needed

1.3 Key Regulatory Citations

Part 2: Screening and Enrollment Procedures

2.1 Pre-Screening Activities: What's Allowed Without Consent?

WITHOUT informed consent, sites MAY:

• Discuss study availability in general terms
• Ask general, non-sensitive questions (age, general health status)
• Use procedures performed as standard medical care
• Review existing medical records as part of normal clinical practice
• Answer logistical questions (location, time commitment)

Informed consent IS REQUIRED for:

• Clinical screening procedures performed solely for research eligibility
• Laboratory tests specifically for eligibility determination
• Medication wash-out periods
• Invasive procedures
• Collection of sensitive personal information
• Any procedure not part of routine clinical care

2.2 Eight Basic Elements of Informed Consent (21 CFR 50.25(a))

MEMORY AID: "R-R-B-A-C-C-C-V" (Remember Really Bold Adventures Can Create Careful Volunteers)

2.3 Six Additional Elements When Appropriate (21 CFR 50.25(b))

1. Unforeseeable risks (including to embryo/fetus if applicable)
2. Circumstances for termination without subject's consent
3. Additional costs to subject from participation
4. Consequences of withdrawal and termination procedures
5. Significant new findings will be provided to subjects
6. Approximate number of subjects in study

2.4 ClinicalTrials.gov Statement Requirement

For applicable clinical trials initiated on or after March 7, 2012, consent forms must include a statement that:

• A description of the trial will be available on ClinicalTrials.gov
• The website will not include personally identifying information
• At most, study results will be posted after completion

Citation: 21 CFR 50.25(c)

2.5 Eligibility Verification Requirements

Documentation Requirements:

• Each inclusion criterion must be documented as MET
• Each exclusion criterion must be documented as NOT MET
• Source documentation must support each determination
• Independent verification by qualified staff
• Eligibility checklist signed and dated by PI or delegate before randomization

Critical Points:

• Subject ID numbers should NEVER be re-used (even after screen failure)
• Screen failure reason must be documented
• Randomization occurs ONLY after eligibility AND consent confirmed

2.6 Enrollment Sequence

1. Eligibility Verification ✓
       ↓
2. Consent Documentation ✓
   - Current IRB-approved form
   - All signatures complete
   - Comprehension verified
   - Original stored in regulatory binder
   - Copy provided to subject
       ↓
3. Randomization (if applicable)
   - Using IRT/IWRS or specified methods
   - Maintain allocation concealment
   - Document date/time and assignment
       ↓
4. Subject ID Assignment
   - Unique identifier
   - Never re-used

Part 3: Visit Scheduling and Protocol Windows

3.1 Visit Window Calculations

FORMULA: Target Date ± X days = Window Range

• Earliest acceptable day = Target Day - Window
• Latest acceptable day = Target Day + Window

CRITICAL: Windows should specify calendar days (not workdays/business days)

3.2 Visit Window Examples

3.3 Out-of-Window Visits

Visits outside protocol windows constitute protocol deviations.

Required Documentation:

1. Reason for out-of-window visit
2. Assessment of impact on subject safety
3. Assessment of impact on data integrity
4. PI review and signature
5. Reporting per sponsor/IRB requirements

Visit Recovery Strategy:

Schedule subsequent visits from ORIGINAL target dates rather than from the actual missed/late visit date to avoid cascading deviations.

3.4 Missed Visit Procedures

Documentation Requirements:

• Date of scheduled visit
• Date determined to be missed
• Reason (if known)
• All contact attempts with dates/times/outcomes
• Impact assessment

Best Practice: Minimum 3 or more contact attempts using multiple strategies:

• Phone (different times of day)
• Email (if authorized)
• Certified letter
• Emergency contacts (per consent)

3.5 Primary Endpoint Visits

Primary endpoint visits typically have STRICTER windows than routine follow-up visits because data integrity at critical timepoints directly impacts study validity.

Part 4: Informed Consent as an Ongoing Process

4.1 Consent is Continuous, Not a Single Event

"Informed consent is an ongoing exchange of information throughout participation."
— FDA Guidance (2023)

Per 21 CFR 50.25(b)(5): Subjects must be informed of significant new findings that may relate to their willingness to continue participation.

4.2 Re-Consent Triggers

Protocol Amendments Require Re-Consent When:

• Changes significantly affect safety, scope, or scientific quality
• New or modified procedures are added
• Eligibility criteria change
• Risk/benefit ratio materially changes

New Safety Information:

• IND Safety Reports impacting informed consent
• New adverse event patterns discovered
• Updated Investigator's Brochure with significant changes

Status Changes:

• Subject turns 18 during pediatric study → Adult consent required
• Subject loses capacity → LAR consent required
• Subject regains capacity → Subject re-consent required

4.3 Short Form Consent Process

For subjects who cannot read English, the short form consent requires:

• Impartial witness present during entire oral presentation
• Witness signature on both short form AND full consent
• Interpreter if needed
• Copy of IRB-approved short form in subject's language

Part 5: Subject Compliance and Retention

5.1 Compliance Assessment Methods

5.2 Managing Non-Compliance

Approach Sequence:

1. Assess the extent and pattern of non-compliance
2. Counsel the subject on importance of compliance
3. Implement corrective actions (reminders, adherence aids)
4. Document all interventions
5. Consider discontinuation only if safety/data integrity compromised

Key Principle: Counseling and corrective actions should precede discontinuation decisions.

5.3 Retention Strategies

Should Begin at Protocol DESIGN (not after problems occur)

Effective Strategies:

• Provide consistent point of contact for subjects
• Flexible scheduling within protocol windows
• Transportation assistance (if protocol permits)
• Reimbursement for actual expenses (travel, parking, meals)
• Regular communication and appreciation
• Patient-friendly visit reminders
• Minimize visit burden where possible
• Build rapport through active listening

Payment Guidelines:

• Payments should be prorated based on participation
• Should NOT be contingent wholly on completion
• Should compensate for time and inconvenience
• Excessive payment = potential coercion

Part 6: Subject Withdrawal and Discontinuation

6.1 Four Types of Withdrawal

6.2 Withdrawal Types: Critical Distinctions

Withdrawal FROM TREATMENT:

• Subject stops study intervention
• May continue follow-up visits
• Data collection continues if subject agrees

PARTIAL Withdrawal:

• Subject withdraws from some components
• Continues agreed-upon activities
• Scope clarified and documented

COMPLETE Withdrawal (Withdrawal of Consent):

• Ends all study activities
• No further data collection
• But: Data already collected typically remains in database

6.3 Subject's Absolute Right to Withdraw

21 CFR 50.25(a)(8) requires consent to state:

• Participation is voluntary
• Refusal involves no penalty
• No loss of benefits to which subject is otherwise entitled
• May discontinue at any time without penalty

PROHIBITED:

• Language limiting withdrawal rights
• Coercion or undue influence
• Penalties for withdrawal

6.4 Data Retention After Withdrawal

FDA-Regulated Research:

Data collected before withdrawal cannot be removed from the study database.

Rationale:

• Required for complete safety profile
• Essential for scientific validity
• ITT analysis requires all randomized subjects
• Selective removal creates bias

Non-FDA Research (OHRP guidance):

• Investigators may honor destruction requests if permitted by funder and law

6.5 Intent-to-Treat (ITT) Analysis

Definition: All randomized subjects analyzed per original assignment regardless of:

• Actual treatment received
• Protocol compliance
• Early withdrawal or completion status

Impact of High Withdrawal Rates:

• May jeopardize trial validity
• Creates missing data requiring imputation
• Can introduce selection bias
• May trigger FDA questions about study conduct

6.6 Early Termination Visit Documentation

Required Documentation:

• Date of withdrawal/termination
• Reason for discontinuation (if provided)
• Safety assessments performed
• Adverse events status
• Study drug accountability
• Instructions for follow-up care
• Source document notation

Part 7: Lost to Follow-Up (LTFU)

7.1 Definition and Distinction

Lost to Follow-Up (LTFU): Subjects who were actively participating but become unreachable at follow-up points despite documented contact attempts.

LTFU is DIFFERENT from:

7.2 LTFU Impact on Studies

Threshold Concerns:

• <5% LTFU: Generally acceptable
• 5-20% LTFU: May adversely impact validity
• >20% LTFU: Likely introduces serious bias

Example: ATLAS ACS 2-TIMI 51 trial

• 7.2% LTFU (1,117 patients) exceeded total primary endpoints (1,002)
• Raised significant validity concerns

7.3 LTFU Due Diligence Requirements

Per 21 CFR 312.62(b): Investigators must maintain adequate case histories requiring reasonable efforts to maintain subject follow-up.

SWOG Guidelines for LTFU Declaration:

• Interval since last contact exceeds 2 years
• At least 3 telephone attempts documented
• Certified letter returned or not answered

7.4 Contact Attempt Documentation

Each attempt must document:

• Date
• Time
• Method (phone, email, mail, in-person)
• Person contacted (name, voicemail, no answer)
• Outcome
• Staff initials

7.5 HIPAA Considerations for LTFU

Permitted WITHOUT additional authorization:

• Consulting public records (death indices, obituaries)
• Using contact information per original consent
• Contacting emergency contacts (per consent provisions)
• Primary care physician contact (if consent obtained)

NOT Permitted:

• Accessing medical records without prior authorization
• If HIPAA authorization revoked: cannot access new PHI

7.6 LTFU Status Can Be Rescinded

If a subject declared LTFU is later located, the site should:

1. Rescind LTFU status
2. Attempt re-engagement per protocol
3. Update documentation accordingly

Part 8: Protocol Compliance Monitoring

8.1 Coordinator Daily Responsibilities

• Review enrolled patient status
• Track upcoming visits and approaching window deadlines
• Review pending queries
• Check drug accountability
• Document contact attempts for overdue subjects

8.2 Principal Investigator Responsibilities

Per ICH GCP (ICH E6(R3) Section 2):

• Overall responsibility for protocol compliance
• Review all deviations with documented explanations
• Implement recurrence prevention
• Sign off on major protocol decisions

8.3 Protocol Deviation vs. Violation

8.4 Medical Monitor Consultation

Appropriate for:

• SAE assessment
• Unblinding decisions
• Eligibility waiver considerations
• Safety concerns

NOT appropriate for:

• Routine scheduling questions
• Administrative paperwork
• Standard recruitment activities

Part 9: Special Populations

9.1 Pediatric Subjects (21 CFR 50 Subpart D)

Parental Permission Requirements:

Child Assent:

• Required for children capable of assent
• IRB determines capability based on age, maturity, condition
• Can be waived in specific circumstances

When Child Turns 18: → Adult informed consent REQUIRED

9.2 Pregnant Women (45 CFR 46 Subpart B)

• Risk minimized to fetus
• Consent cannot be obtained under coercive circumstances
• Father's consent may be required depending on circumstances

9.3 Prisoners (45 CFR 46 Subpart C)

IRB Composition Requirements:

• Majority of members have no prison association
• At least one member must be prisoner representative

If Enrolled Subject Becomes Incarcerated: → Immediately notify IRB and suspend activities pending review

9.4 Cognitively Impaired Subjects

Capacity Assessment:

• Protocol-specific and situation-specific
• NOT a one-time evaluation
• Legally Authorized Representative (LAR) consent required when capacity lacking

If Subject Loses Capacity During Study: → Notify IRB and plan for LAR consent

Part 10: ICH E6(R3) Updates for Decentralized Trials

10.1 Remote/Decentralized Trial Provisions

ICH E6(R3) (effective January 6, 2025) introduces:

eConsent Requirements:

• Participant identity verification
• Audit trail for electronic signatures
• Accessibility considerations
• Process for answering questions remotely

Remote Monitoring Provisions:

• Risk-based monitoring approaches
• Centralized monitoring capabilities
• Source data verification methods

Data Integrity in Decentralized Settings:

• ALCOA+C principles apply
• Direct data capture from wearables/devices
• Quality management systems for data governance

10.2 Participant-Centric Approaches

ICH E6(R3) emphasizes:

• Reducing participant burden
• Flexibility in visit conduct
• Enhanced informed consent processes
• Retention through convenience

Part 11: Key Regulatory Citations Quick Reference

Part 12: High-Yield Exam Topics

12.1 Most Frequently Tested Concepts

1. Visit window calculations - Know the formula!
2. Withdrawal vs. LTFU distinction - Active decision vs. unable to contact
3. Eight basic consent elements - 21 CFR 50.25(a)
4. Exculpatory language prohibition - 21 CFR 50.20
5. Data retention after withdrawal - Cannot remove from FDA-regulated studies
6. Subject's absolute right to withdraw - 21 CFR 50.25(a)(8)
7. Re-consent triggers - Amendments, new safety info, status changes
8. IRB review of recruitment materials - Advertising = start of consent

12.2 Common Exam Traps

TRAP 1: "The subject withdrew consent, so their data must be destroyed."

• FALSE for FDA-regulated research

TRAP 2: "ClinicalTrials.gov listings require IRB approval."

• FALSE for basic listings only

TRAP 3: "Sponsor approval is sufficient for enrolling an ineligible subject."

• FALSE - IRB approval always required

TRAP 4: "One unreturned phone call = lost to follow-up."

• FALSE - Multiple documented attempts required

TRAP 5: "Visit windows should use business days."

• FALSE - Calendar days to avoid confusion

Memory Aids and Mnemonics

Eight Basic Consent Elements: "R-R-B-A-C-C-C-V"

• Research statement
• Risks
• Benefits
• Alternatives
• Confidentiality (FDA may inspect)
• Compensation for injury
• Contact information
• Voluntary participation

LTFU Due Diligence: "3-2-1"

• 3 telephone attempts minimum
• 2 years since last contact
• 1 certified letter returned/unanswered

Visit Window Formula: "TED"

• Target day
• Earliest = Target - Window
• Datest (Latest) = Target + Window

Withdrawal Types: "T-P-C"

• Treatment withdrawal (stop drug, continue visits)
• Partial withdrawal (stop some activities)
• Complete withdrawal (stop everything)

Summary: Week 9 Key Takeaways

1. Subject safety and rights ALWAYS prevail over scientific interests (ICH GCP Principle 1)

2. FDA considers recruitment advertising the start of informed consent - IRB review required

3. Visit windows must be in calendar days; calculate using Target ± Window

4. Informed consent is ongoing - re-consent for amendments affecting risk/benefit

5. Withdrawal ≠ LTFU: Withdrawal is subject's active decision; LTFU is inability to contact

6. Data collected before withdrawal cannot be removed in FDA-regulated research

7. Subject may withdraw at any time without penalty (21 CFR 50.25(a)(8))

8. LTFU requires documented due diligence - multiple attempts over extended period

9. Compliance assessment should use multiple methods; biomarkers most objective

10. Special populations require additional protections per 21 CFR 50 Subpart D and 45 CFR 46

Preparation for Week 10: Study Closeout

Next week covers:

• Study completion procedures
• Closeout visit requirements
• Drug accountability finalization
• Essential documents review and archiving
• Record retention requirements
• Final reporting to FDA and IRB
• Clinical Study Report (CSR) overview

Homework: Review ICH E6(R2) Sections 4.8-4.10 and 21 CFR Part 50 (subject rights emphasis)

Week 9: Study Conduct and Subject Management
Version 1.0 - January 2026