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# Standard Operating Procedure: Document Control
| Document ID | SOP-001 |
|-------------|---------|
| Title | Document Control |
| Revision | 1.0 |
| Effective Date | [DATE] |
| Author | [AUTHOR] |
| Approved By | [APPROVER] |
| Department | Quality Assurance |
---
## 1. Purpose
To establish a procedure for the creation, review, approval, distribution, and control of documents within the Pediatric Clinical Research Quality Management System.
## 2. Scope
This procedure applies to all controlled documents including:
- Policies
- Standard Operating Procedures (SOPs)
- Work Instructions
- Forms and Templates
- Assent and Parental Permission forms
- Study protocols and protocol amendments
- Informed consent/assent documents
- Case Report Forms (CRFs)
- External documents of external origin
## 3. Responsibilities
### 3.1 Document Owner
- Responsible for document content and accuracy
- Initiates document creation and revision
- Ensures periodic review is performed
- Ensures pediatric-specific requirements are addressed
### 3.2 Quality Assurance
- Maintains the document control system
- Assigns document numbers
- Manages document distribution
- Archives obsolete documents
- Ensures regulatory compliance
### 3.3 Approvers
- Review and approve documents before release
- Ensure documents are adequate for intended purpose
- Verify pediatric-appropriateness where applicable
### 3.4 Pediatric Research Specialist (where applicable)
- Reviews assent/consent documents for age-appropriateness
- Verifies developmental considerations are addressed
- Ensures compliance with 45 CFR 46 Subpart D and 21 CFR 50 Subpart D
## 4. Procedure
### 4.1 Document Creation
1. Identify the need for a new document
2. Request document number from Quality Assurance
3. Draft document using appropriate template
4. Include all required header information
5. For pediatric-specific documents:
- Specify applicable age ranges
- Include developmental considerations
- Reference appropriate pediatric regulations
6. Submit for review and approval
### 4.2 Document Review and Approval
1. Route document to appropriate reviewers:
- Content expert reviewers
- Quality Assurance
- Pediatric specialist (for child-specific documents)
- Regulatory affairs (for regulatory documents)
2. Reviewers provide comments within 5 business days
3. Author addresses all comments
4. For assent/consent documents, ensure:
- Age-appropriate language and reading level
- Developmentally appropriate explanations
- IRB/Ethics Committee requirements met
5. Final approval by designated approver
6. Quality Assurance releases document
### 4.3 Document Numbering
Documents shall be numbered according to the following convention:
| Type | Prefix | Example |
|------|--------|---------|
| Policy | POL | POL-001 |
| SOP | SOP | SOP-001 |
| Pediatric SOP | SOP-PED | SOP-PED-001 |
| Clinical SOP | SOP-CL | SOP-CL-001 |
| Regulatory SOP | SOP-REG | SOP-REG-001 |
| Data Management SOP | SOP-DM | SOP-DM-001 |
| Safety SOP | SOP-SAF | SOP-SAF-001 |
| Work Instruction | WI | WI-001 |
| Form | FRM | FRM-001 |
| Assent Form | ASF | ASF-001 |
| Parental Permission Form | PPF | PPF-001 |
| Informed Consent Form | ICF | ICF-001 |
### 4.4 Revision Control
1. All changes require documented justification
2. Changes follow same review/approval process as new documents
3. Revision number increments with each approved change
4. Major revisions: Change integer (e.g., 1.0 → 2.0)
5. Minor revisions: Change decimal (e.g., 1.0 → 1.1)
6. Revision history maintained in document footer
7. For assent/consent forms:
- IRB/Ethics Committee re-approval required for substantive changes
- Version date clearly displayed on forms
### 4.5 Document Distribution
1. Current versions available in electronic document control system
2. Obsolete versions clearly marked "OBSOLETE" and archived
3. Training on new/revised documents as needed
4. For assent/consent documents:
- Site investigators notified immediately of updates
- Process for transitioning participants to new versions documented
### 4.6 Periodic Review
1. Documents reviewed at least every 2 years
2. Pediatric-specific documents reviewed annually or when regulations change
3. Review documented even if no changes made
4. Reviews may result in revision or reaffirmation
5. Quality Assurance tracks review due dates
### 4.7 External Documents
1. External documents (regulations, standards) identified and controlled
2. Updates to external documents monitored
3. Impact of updates assessed and communicated
## 5. Special Considerations for Pediatric Documents
### 5.1 Assent and Consent Forms
- Age-appropriate language verified (reading level assessment)
- Visual aids and graphics used where appropriate
- Multiple versions for different age groups as needed
- Parent and child versions clearly distinguished
- Compliance with OHRP and FDA pediatric assent guidance
### 5.2 Study Materials
- Developmental appropriateness assessed
- Child life specialist input obtained where applicable
- Age ranges clearly specified
## 6. Related Documents
- FRM-001 Document Change Request Form
- FRM-002 Document Review Record
- SOP-PED-001 Pediatric Assent Process
- SOP-PED-002 Parental Permission Requirements
## 7. Definitions
| Term | Definition |
|------|------------|
| Controlled Document | Document managed under document control system |
| Obsolete | Document no longer valid for use |
| Revision | Updated version of a document |
| Assent | A child's affirmative agreement to participate in research |
| Parental Permission | Permission obtained from parent(s) or guardian(s) for child's participation |
## 8. References
- 45 CFR 46.116, 46.408 (Assent and Parental Permission)
- 21 CFR 50.55 (Parental Permission)
- ICH-GCP E6(R2) Section 4.8 (Informed Consent)
- OHRP Guidance on Assent and Permission
---
## Revision History
| Rev | Date | Description | Author |
|-----|------|-------------|--------|
| 1.0 | [DATE] | Initial release | [AUTHOR] |

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# Standard Operating Procedure: Corrective and Preventive Action (CAPA)
| Document ID | SOP-002 |
|-------------|---------|
| Title | Corrective and Preventive Action |
| Revision | 1.0 |
| Effective Date | [DATE] |
| Author | [AUTHOR] |
| Approved By | [APPROVER] |
| Department | Quality Assurance |
---
## 1. Purpose
To establish a systematic process for identifying, investigating, correcting, and preventing nonconformities and potential nonconformities in pediatric clinical research operations.
## 2. Scope
This procedure applies to:
- Product and process nonconformities
- Protocol deviations and violations
- Adverse events requiring corrective action
- Audit findings (internal, sponsor, regulatory)
- Customer/sponsor complaints
- Process deviations
- IRB/Ethics Committee findings
- Potential nonconformities identified through risk analysis
- Child safety concerns requiring systemic response
## 3. Definitions
| Term | Definition |
|------|------------|
| Corrective Action | Action to eliminate the cause of a detected nonconformity |
| Preventive Action | Action to eliminate the cause of a potential nonconformity |
| Root Cause | Fundamental reason for a nonconformity |
| Effectiveness Check | Verification that implemented actions achieved desired results |
| Protocol Deviation | Unplanned departure from protocol requirements |
| Protocol Violation | Serious protocol deviation that may impact participant safety or data integrity |
## 4. Responsibilities
### 4.1 CAPA Owner
- Investigates the issue
- Identifies root cause
- Develops and implements corrective/preventive actions
- Verifies effectiveness
- For pediatric safety issues, escalates immediately
### 4.2 Quality Assurance
- Manages CAPA system
- Assigns CAPA numbers
- Tracks CAPA status
- Reviews and approves CAPAs
- Reports CAPA metrics to management
- Monitors trends affecting pediatric participant safety
### 4.3 Principal Investigator
- Reviews CAPAs related to study conduct
- Determines if protocol deviations/violations require CAPA
- Reports to sponsor and IRB/Ethics Committee as required
- Ensures child safety concerns are addressed
### 4.4 Management
- Provides resources for CAPA implementation
- Reviews CAPA trends
- Ensures timely closure
- Escalates pediatric safety concerns to appropriate authorities
## 5. Procedure
### 5.1 CAPA Initiation
1. Identify nonconformity or potential nonconformity through:
- Internal/external audits
- Protocol deviations
- Adverse events
- Sponsor monitoring
- IRB findings
- Participant/family complaints
- Quality metrics
2. Document issue on CAPA Form (FRM-003)
3. Classify severity and priority:
- **Critical**: Immediate threat to child safety or data integrity
- **Major**: Significant impact on quality or compliance
- **Minor**: Limited impact, easily correctable
4. For pediatric safety concerns:
- Immediate interim measures implemented
- Principal Investigator and Medical Monitor notified
- IRB/Ethics Committee notification per requirements
5. Assign CAPA owner
### 5.2 Investigation
1. Gather relevant data and evidence:
- Study records and source documents
- Interview personnel and families involved
- Review environmental factors
- Consider age-specific factors
2. Review related documents and records:
- Protocol and protocol amendments
- Informed consent/assent documents
- Training records
- Prior CAPAs
3. Use appropriate investigation tools:
- 5 Whys
- Fishbone (Ishikawa) Diagram
- Failure Mode and Effects Analysis (FMEA)
- Timeline analysis
### 5.3 Root Cause Analysis
1. Identify potential root causes, considering:
- Human factors (training, fatigue, workload)
- Process failures
- Equipment or facility issues
- Communication breakdowns
- Pediatric-specific factors (age-appropriateness, family dynamics)
2. Verify root cause through evidence
3. Document root cause determination
4. Consider systemic implications:
- Impact on other studies or sites
- Need for system-wide changes
- Regulatory reporting requirements
### 5.4 Action Development
1. Develop corrective/preventive actions that address root cause
2. For pediatric research CAPAs, consider:
- Impact on child participants (current and future)
- Changes to assent/consent processes
- Age-appropriateness modifications
- Family communication needs
- IRB/Ethics Committee approval requirements
3. Assign responsibilities and due dates
4. Assess actions for:
- Appropriateness to problem severity
- Impact on other processes and studies
- Resource requirements
- Regulatory implications
5. Obtain necessary approvals:
- Quality Assurance
- Principal Investigator
- Sponsor (if applicable)
- IRB/Ethics Committee (if required)
### 5.5 Implementation
1. Execute approved actions per timeline
2. Document implementation evidence
3. Update affected documents/processes:
- Revise SOPs
- Update training materials
- Modify study documents (with IRB approval)
4. Provide training as needed:
- Staff training on changes
- Refresher training if knowledge gaps identified
5. Communicate changes to:
- Study team members
- Sponsor
- IRB/Ethics Committee
- Participants/families (if applicable)
### 5.6 Effectiveness Verification
1. Define effectiveness criteria (measurable outcomes)
2. Establish verification timeframe:
- Minimum 30 days for routine CAPAs
- Shorter for critical safety issues with ongoing monitoring
3. Collect and analyze data:
- Review metrics
- Monitor for recurrence
- Audit compliance
4. Document verification results
5. If ineffective:
- Reopen CAPA for further action
- Perform additional root cause analysis
- Develop alternative actions
### 5.7 Closure
1. Review all CAPA documentation for completeness
2. Verify all actions completed
3. Confirm effectiveness verified
4. Obtain Quality Assurance approval for closure
5. Document lessons learned
6. Update risk assessments if applicable
## 6. Special Considerations for Pediatric Research
### 6.1 Child Safety Issues
- Immediate action required for any threat to child safety
- Principal Investigator and Medical Monitor notification
- IRB/Ethics Committee and regulatory authority notification per timelines
- Parental notification process activated
- Consider Data Safety Monitoring Board (DSMB) review if applicable
### 6.2 Assent/Consent Issues
- Any CAPA affecting informed consent or assent requires IRB approval
- Age-appropriateness concerns addressed by pediatric specialist
- Updated documents require re-consent/re-assent per regulations
### 6.3 Family Communication
- Transparent communication with affected families
- Age-appropriate explanations for child participants
- Cultural sensitivity in communications
## 7. CAPA Metrics
Quality Assurance shall track and report:
- Number of open CAPAs
- CAPA aging (days open)
- On-time closure rate
- Effectiveness rate
- CAPAs by category/source:
- Protocol deviations/violations
- Adverse events
- Audit findings
- Pediatric safety concerns
- Repeat/recurring issues
## 8. Related Documents
- FRM-003 CAPA Form
- SOP-004 Internal Audit
- SOP-REG-001 Regulatory Reporting
- SOP-SAF-001 Pediatric Safety Monitoring
- SOP-PED-004 Protocol Deviation Management
## 9. References
- ICH-GCP E6(R2) Section 5.20 (Noncompliance)
- 45 CFR 46.103 (Assurance of Compliance)
- 21 CFR 312.56 (Review of Ongoing Investigations)
- ISO 13485:2016 Section 8.5 (Improvement)
---
## Revision History
| Rev | Date | Description | Author |
|-----|------|-------------|--------|
| 1.0 | [DATE] | Initial release | [AUTHOR] |

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# Standard Operating Procedure: Training and Competence
| Document ID | SOP-003 |
|-------------|---------|
| Title | Training and Competence |
| Revision | 1.0 |
| Effective Date | [DATE] |
| Author | [AUTHOR] |
| Approved By | [APPROVER] |
| Department | Human Resources / Quality |
---
## 1. Purpose
To ensure personnel performing work in pediatric clinical research are competent based on appropriate education, training, skills, and experience, with specific emphasis on pediatric research requirements and child protection.
## 2. Scope
This procedure applies to:
- All employees performing pediatric research activities
- Principal Investigators and sub-investigators
- Study coordinators and research nurses
- Contractors and temporary personnel
- Personnel requiring GCP and pediatric-specific training
- Personnel interacting with child participants and families
## 3. Responsibilities
### 3.1 Supervisors/Managers
- Identify training needs for their personnel
- Ensure pediatric-specific competencies are met
- Ensure training completed before performing tasks with children
- Evaluate competence of personnel
- Maintain department training records
### 3.2 Human Resources
- Coordinate training programs
- Maintain central training database
- Track training compliance
- Verify credentials and licenses
- Archive training records
### 3.3 Quality Assurance
- Develop QMS-related training
- Approve training curricula for pediatric research activities
- Monitor pediatric research competency requirements
- Audit training compliance
- Ensure GCP and pediatric-specific training current
### 3.4 Principal Investigator
- Ensure study team adequately trained for pediatric research
- Verify protocol-specific training completion
- Assess ongoing competence
- Document delegation of duties
### 3.5 Employees
- Complete assigned training on time
- Maintain current qualifications and certifications
- Report training needs to supervisor
- Maintain GCP certification
- Complete pediatric research ethics training
## 4. Procedure
### 4.1 Training Needs Assessment
1. Identify competence requirements for each role:
- Educational background
- Professional licenses/certifications
- Required training courses
- Pediatric experience requirements
2. Document requirements in job descriptions
3. Assess current competence of personnel
4. Identify training gaps
5. Develop training plan addressing:
- General QMS training
- GCP training
- Pediatric research-specific training
- Protocol-specific training
- Child protection and safety
### 4.2 Core Training Requirements
All personnel involved in pediatric clinical research must complete:
#### 4.2.1 Foundational Training
- Good Clinical Practice (GCP) - ICH E6(R2)
- Human Subject Protection (HSP)
- HIPAA and privacy regulations
- 21 CFR Part 11 (if applicable)
#### 4.2.2 Pediatric-Specific Training
- **45 CFR 46 Subpart D**: Additional Protections for Children
- **21 CFR 50 Subpart D**: Additional Safeguards for Children
- **ICH E11**: Pediatric Clinical Investigations
- Pediatric assent process
- Parental permission requirements
- Age-appropriate communication techniques
- Child development basics
- Child abuse recognition and reporting
- Pediatric adverse event assessment
#### 4.2.3 Role-Specific Training
- Protocol-specific procedures
- Study drug/device administration (pediatric dosing)
- Pediatric phlebotomy (if applicable)
- Medical monitoring for pediatric populations
- Regulatory submissions for pediatric studies
- Data management for pediatric trials
### 4.3 Training Curriculum Development
1. Define learning objectives appropriate for pediatric research
2. Develop training materials including:
- Pediatric research regulations
- Age-appropriate study techniques
- Child-family interaction skills
- Case studies and scenarios
3. Identify delivery method:
- Classroom/interactive sessions
- On-the-job training with experienced personnel
- Self-study modules
- Computer-based training
- Simulation/role-play (for assent discussions)
4. Define assessment criteria
5. Obtain approval from Quality (for GCP/pediatric training)
### 4.4 Training Delivery
1. Schedule training session
2. Document attendance with:
- Employee name and ID
- Training title and date
- Trainer name and qualifications
- Training duration
3. Deliver training per curriculum
4. Assess comprehension through:
- Written test (minimum 80% passing)
- Practical demonstration (e.g., assent discussion)
- Supervisor observation
- Competency checklist completion
5. For hands-on pediatric procedures:
- Observed practice before independent performance
- Competency assessment by qualified trainer
- Documentation of proficiency
### 4.5 Training Documentation
Training records shall include:
- Employee name, position, and ID number
- Training title, description, and objectives
- Training date and location
- Trainer name and qualifications
- Training materials version
- Assessment method and results
- Pass/fail determination
- Signatures (trainer and trainee)
- Remediation if applicable
### 4.6 Retraining Requirements
Retraining is required when:
- Significant document revisions occur (especially consent/assent forms)
- Performance deficiencies identified
- Extended absence from pediatric research functions (>12 months)
- Periodic requalification due:
- GCP certification: Every 3 years
- Pediatric research ethics: Every 3 years
- Protocol-specific: Per protocol requirements or annually
- Regulatory changes affecting pediatric research
- Corrective action plans require retraining
### 4.7 New Employee Orientation
All new employees involved in pediatric research shall complete:
1. **Day 1-3**: Company orientation
- Company mission and values
- Organizational structure
- Facilities and safety
2. **Week 1**: Quality system and regulatory training
- Quality Management System overview
- Document control and CAPA
- GCP and Human Subject Protection
- Privacy and confidentiality
3. **Week 1-2**: Pediatric research-specific training
- Pediatric research regulations (45 CFR 46 Subpart D, 21 CFR 50 Subpart D)
- ICH E11 guidelines
- Assent and parental permission processes
- Age-appropriate communication
- Child safety and abuse reporting
4. **Ongoing**: Job-specific training
- SOP read and understand for applicable procedures
- Protocol-specific training
- Supervised practice before independent work
- Competency assessments
### 4.8 Principal Investigator Requirements
Principal Investigators must demonstrate:
- Medical degree or equivalent qualification
- Board certification in relevant specialty (pediatrics, pediatric subspecialty)
- Active state medical license
- Current GCP certification
- Pediatric clinical experience
- Prior research experience (preferred)
- Training in pediatric research ethics
- No regulatory sanctions or clinical privileges restrictions
### 4.9 Study Coordinator Requirements
Study Coordinators must demonstrate:
- Nursing degree or equivalent healthcare background (preferred)
- Current professional license (if applicable)
- GCP certification
- Pediatric research training
- Experience working with children and families
- Protocol-specific training
- Competency in age-appropriate communication
### 4.10 Verification of Training
1. Human Resources verifies completion before research activities begin
2. Principal Investigator reviews study team training status
3. Quality Assurance audits training compliance
4. Sponsor monitors review training records during site visits
5. Training records available for regulatory inspection
## 5. Competency Assessment
### 5.1 Initial Competency
- Written assessment (minimum 80% correct)
- Practical demonstration of skills
- Observed interactions with mock participants (families/children)
- Completion of competency checklist
### 5.2 Ongoing Competency
- Annual performance reviews
- Observation of pediatric procedures
- Audit findings review
- Protocol deviation trends
- Feedback from participants/families
### 5.3 Remediation
- Additional training if competency not demonstrated
- Supervised practice with experienced personnel
- Reassessment after remediation
- Documentation of successful completion
## 6. Training Records Retention
- Training records maintained for duration of employment plus 3 years
- Study-specific training records maintained per protocol requirements
- GCP certificates maintained with personnel files
- Records available for regulatory inspection
- Electronic records maintained per 21 CFR Part 11 if applicable
## 7. Special Pediatric Populations
Additional training may be required for:
- Neonatal intensive care research
- Pediatric oncology
- Rare pediatric diseases
- Emergency research in children
- Adolescent reproductive health research
- Research with decisionally impaired children
## 8. Related Documents
- FRM-004 Training Record Form
- FRM-005 Training Assessment Form
- FRM-PED-001 Pediatric Competency Checklist
- Job Descriptions
- Delegation of Authority Log
## 9. References
- ICH-GCP E6(R2) Section 5.18 (Investigator and Institution)
- 45 CFR 46 Subpart D (Additional Protections for Children)
- 21 CFR 50 Subpart D (Additional Safeguards for Children)
- 21 CFR 312.53 (Selecting Investigators and Monitors)
- ICH E11 (Pediatric Clinical Investigations)
---
## Revision History
| Rev | Date | Description | Author |
|-----|------|-------------|--------|
| 1.0 | [DATE] | Initial release | [AUTHOR] |

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# Standard Operating Procedure: Internal Audit
| Document ID | SOP-004 |
|-------------|---------|
| Title | Internal Audit |
| Revision | 1.0 |
| Effective Date | [DATE] |
| Author | [AUTHOR] |
| Approved By | [APPROVER] |
| Department | Quality Assurance |
---
## 1. Purpose
To establish a process for conducting internal audits to verify compliance with the Quality Management System, pediatric research regulations, and study protocols, and to identify opportunities for improvement.
## 2. Scope
This procedure applies to:
- Planned audits of QMS processes and procedures
- Study-specific audits of pediatric clinical trials
- Site audits of research facilities
- Supplier/vendor audits (if applicable)
- For-cause audits triggered by quality concerns
- Pre-study readiness assessments
## 3. Definitions
| Term | Definition |
|------|------------|
| Internal Audit | Systematic, independent examination of activities and documents |
| Auditor | Qualified individual conducting the audit |
| Auditee | Individual or department being audited |
| Audit Finding | Observation of noncompliance or deficiency |
| Observation | Opportunity for improvement not constituting noncompliance |
| Critical Finding | Issue that poses immediate risk to child safety or data integrity |
## 4. Responsibilities
### 4.1 Quality Assurance Manager
- Develops annual audit program
- Selects and qualifies auditors
- Reviews and approves audit reports
- Tracks corrective actions
- Reports audit results to management
- Ensures pediatric-specific requirements audited
### 4.2 Auditors
- Conduct audits per plan and procedure
- Maintain independence and objectivity
- Document findings accurately
- Verify corrective actions
- Maintain confidentiality
- Understand pediatric research regulations
### 4.3 Auditee
- Cooperate with audit activities
- Provide requested documentation
- Respond to findings within timeframe
- Implement corrective actions
- Verify effectiveness
### 4.4 Management
- Support audit program
- Provide resources for corrective actions
- Review audit summaries
- Address systemic issues
## 5. Procedure
### 5.1 Annual Audit Program
1. Quality Assurance develops annual audit schedule considering:
- All QMS processes audited at least annually
- Risk-based prioritization
- Previous audit results
- Regulatory inspection history
- Active pediatric studies
- Changes to regulations or processes
- Sponsor/customer requirements
2. Audit schedule includes:
- QMS processes (Document Control, CAPA, Training)
- Clinical operations (protocol compliance, safety reporting)
- Regulatory affairs (submissions, communications)
- Data management
- Pediatric-specific processes (assent, parental permission, age-appropriate procedures)
3. Schedule approved by management
4. Schedule flexible to accommodate for-cause audits
### 5.2 Auditor Qualification
Auditors must demonstrate:
- Knowledge of QMS standards and regulations
- Understanding of pediatric research regulations (45 CFR 46 Subpart D, 21 CFR 50 Subpart D, ICH E11)
- Current GCP certification
- Audit training completion
- Independence from audited area
- Previous audit experience (for lead auditors)
### 5.3 Audit Planning
1. Assign auditor(s) and lead auditor
2. Ensure auditor independence (no audit own work)
3. Develop audit plan including:
- Audit objectives and scope
- Areas/processes to be audited
- Audit criteria (regulations, SOPs, protocols)
- Audit dates and estimated duration
- Personnel to be interviewed
- Documents to be reviewed
- Special pediatric considerations
4. Notify auditee at least 2 weeks in advance (except for-cause audits)
5. Request documents for pre-review:
- SOPs and work instructions
- Training records
- Study protocols and amendments
- Informed consent/assent documents
- Safety reports
- Regulatory correspondence
### 5.4 Audit Execution
#### 5.4.1 Opening Meeting
1. Introduce audit team
2. Confirm audit scope and schedule
3. Explain audit process
4. Answer questions
5. Establish logistics (workspace, access)
#### 5.4.2 Document Review
Review documents for:
- Compliance with regulations and SOPs
- Completeness and accuracy
- Proper approvals and signatures
- Traceability
- Pediatric-specific requirements:
- Age-appropriate consent/assent forms
- Proper parental permission
- Adherence to 45 CFR 46.408 categories
- Pediatric safety monitoring
- Growth/development assessments
#### 5.4.3 Interviews
- Interview key personnel
- Assess knowledge of procedures
- Verify training on pediatric requirements
- Evaluate understanding of child protection principles
- Assess competence in age-appropriate communication
#### 5.4.4 Observation
- Observe processes in action where possible
- Assess compliance with procedures
- Evaluate facility suitability for pediatric research
- Assess child-friendly environment
#### 5.4.5 Finding Documentation
For each finding, document:
- Specific noncompliance or deficiency
- Regulatory or procedural reference
- Objective evidence
- Risk level (Critical, Major, Minor)
- Location and date observed
Critical findings (immediate child safety risk):
- Report immediately to management and Principal Investigator
- Document interim actions taken
- Escalate per safety procedures
### 5.5 Closing Meeting
1. Present preliminary findings
2. Discuss observations
3. Clarify any misunderstandings
4. Establish timeframe for corrective action response
5. Thank auditee for cooperation
### 5.6 Audit Report
1. Lead auditor prepares audit report including:
- Executive summary
- Audit scope and criteria
- Areas audited
- Documents reviewed
- Personnel interviewed
- Findings (Critical, Major, Minor)
- Observations (opportunities for improvement)
- Positive practices noted
- Conclusion and overall compliance assessment
2. Report issued within 10 business days
3. Report distributed to:
- Auditee
- Auditee management
- Quality Assurance Manager
- Executive management (for critical findings)
- Principal Investigator (for study audits)
### 5.7 Corrective Action Response
1. Auditee submits CAPA response within:
- Critical findings: 3 business days
- Major findings: 10 business days
- Minor findings: 15 business days
2. Response includes:
- Root cause analysis
- Immediate corrective actions
- Long-term preventive actions
- Responsible person
- Target completion date
- Effectiveness verification plan
3. Quality Assurance reviews and approves response
4. If inadequate, response returned for revision
### 5.8 Follow-up Verification
1. Auditor verifies corrective action implementation
2. Verification methods:
- Document review
- Follow-up audit
- Process observation
- Records sampling
3. Verify effectiveness of actions
4. Document verification results
5. Close findings when satisfactorily addressed
6. If not effective, finding remains open and escalated
### 5.9 Audit Metrics and Reporting
Quality Assurance tracks and reports:
- Audits completed vs. planned
- Findings by type and severity
- Open vs. closed findings
- Overdue corrective actions
- Trends by area/process
- Repeat findings
- Pediatric-specific findings trends
## 6. Special Considerations for Pediatric Research
### 6.1 Assent and Consent Verification
- Review sample informed consent/assent forms
- Verify age-appropriate language
- Check IRB approval documentation
- Verify version control and participant records match
- Confirm proper signatures obtained
### 6.2 Pediatric Safety Monitoring
- Review adverse event documentation
- Verify growth and development monitoring
- Check pediatric-specific assessments completed
- Review DSMB reports if applicable
- Verify expedited reporting timelines met
### 6.3 Participant Protection
- Assess child-friendly environment
- Review child abuse reporting procedures
- Verify staff training on child protection
- Check privacy protections for minors
- Review parental permission documentation
### 6.4 Age-Appropriate Procedures
- Verify procedures modified for pediatric population
- Check age-specific normal ranges used
- Review accommodation for family participation
- Assess minimization of participant burden
## 7. Related Documents
- FRM-006 Audit Checklist
- FRM-007 Audit Report Template
- SOP-002 CAPA
- SOP-PED-001 Pediatric Assent Process
- SOP-SAF-001 Pediatric Safety Monitoring
## 8. References
- ICH-GCP E6(R2) Section 5.19 (Monitoring and Auditing)
- 45 CFR 46.103 (Assurance of Compliance)
- 21 CFR 312.56 (Review of Ongoing Investigations)
- ISO 19011:2018 (Guidelines for Auditing Management Systems)
---
## Revision History
| Rev | Date | Description | Author |
|-----|------|-------------|--------|
| 1.0 | [DATE] | Initial release | [AUTHOR] |

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# Standard Operating Procedure: Management Review
| Document ID | SOP-005 |
|-------------|---------|
| Title | Management Review |
| Revision | 1.0 |
| Effective Date | [DATE] |
| Author | [AUTHOR] |
| Approved By | [APPROVER] |
| Department | Quality Assurance |
---
## 1. Purpose
To establish a systematic process for top management to review the Pediatric Clinical Research Quality Management System to ensure its continuing suitability, adequacy, effectiveness, and alignment with the organization's strategic direction and commitment to child participant protection.
## 2. Scope
This procedure applies to periodic reviews of the entire Quality Management System by top management, including pediatric research operations, regulatory compliance, and continuous improvement initiatives.
## 3. Definitions
| Term | Definition |
|------|------------|
| Management Review | Periodic evaluation of QMS by top management |
| Top Management | Executive leadership with authority over QMS |
| QMS | Quality Management System |
| KPI | Key Performance Indicator |
## 4. Responsibilities
### 4.1 Chief Executive Officer / President
- Chairs management review meetings
- Ensures management review conducted
- Makes decisions on QMS improvements
- Allocates resources
- Ensures pediatric research mission alignment
### 4.2 Quality Assurance Manager
- Schedules and coordinates management reviews
- Prepares management review agenda and materials
- Compiles metrics and performance data
- Documents review proceedings
- Tracks action items
- Presents pediatric research quality metrics
### 4.3 Department Heads
- Provide input and data for their areas
- Participate in review meetings
- Implement assigned action items
- Report on pediatric research operations
### 4.4 Principal Investigators (as applicable)
- Provide study-specific updates
- Report pediatric safety trends
- Discuss challenges in pediatric recruitment and retention
## 5. Procedure
### 5.1 Management Review Frequency
1. Formal management reviews conducted at least annually
2. Additional reviews conducted when:
- Major regulatory changes occur (especially pediatric regulations)
- Significant organizational changes happen
- Critical quality issues arise
- Serious pediatric safety events occur
- Major pediatric studies initiate or complete
3. Interim quality reports provided quarterly between formal reviews
### 5.2 Review Planning
1. Quality Assurance Manager schedules review at least 4 weeks in advance
2. Identify participants:
- CEO/President
- Quality Assurance Manager
- Clinical Operations Manager
- Regulatory Affairs Manager
- Principal Investigators (as needed)
- Department Heads
- Pediatric Research Specialist
3. Distribute agenda and preparation materials 2 weeks prior
4. Request input from departments 1 week prior
### 5.3 Review Inputs
The management review shall include analysis of:
#### 5.3.1 QMS Performance
- Status of actions from previous management reviews
- Changes in internal and external issues affecting QMS
- Customer/sponsor satisfaction and feedback
- Quality objectives achievement
- Process performance metrics
- Product/service conformity
#### 5.3.2 Pediatric Research Operations
- Number and status of active pediatric studies
- Pediatric participant enrollment and retention rates
- Age distribution of participants across studies
- Protocol compliance for pediatric studies
- Assent and consent processes effectiveness
#### 5.3.3 Audit Results
- Internal audit findings and trends
- Sponsor audit results
- Regulatory inspection outcomes
- Pediatric-specific audit observations
- Compliance with 45 CFR 46 Subpart D and 21 CFR 50 Subpart D
#### 5.3.4 Nonconformities and Corrective Actions
- CAPA metrics (open, closed, overdue)
- Protocol deviations and violations
- Trending by category
- Repeat findings
- Pediatric safety-related CAPAs
- Assent/consent issues
#### 5.3.5 Monitoring and Measurement Results
- Key performance indicators (KPIs):
- Participant safety metrics (AEs, SAEs in pediatric population)
- Enrollment vs. targets for pediatric studies
- Protocol deviation rates
- Data quality metrics
- Training compliance
- Document control effectiveness
- Sponsor/customer satisfaction scores
- Family satisfaction with pediatric research experience
#### 5.3.6 Pediatric Safety Data
- Adverse events summary by severity and age group
- Serious adverse events requiring regulatory reporting
- Data Safety Monitoring Board (DSMB) recommendations
- Unanticipated problems involving risks
- Growth and development monitoring results
- Long-term safety follow-up status
#### 5.3.7 Training and Competence
- Training completion rates
- GCP certification status
- Pediatric research training completion
- Competency assessment results
- Training effectiveness
- Knowledge gaps identified
#### 5.3.8 Regulatory Compliance
- FDA/EMA/regulatory authority communications
- IRB/Ethics Committee findings
- Regulatory submissions status
- Changes to pediatric regulations (PREA, BPCA, etc.)
- Warning letters or inspectional observations (industry-wide)
#### 5.3.9 Resource Adequacy
- Staffing levels and qualifications
- Facilities and equipment suitability for pediatric research
- Technology and systems adequacy
- Budget vs. actual
- Pediatric specialist availability
- Child life support services
#### 5.3.10 Opportunities for Improvement
- Process improvement initiatives
- Technology enhancements
- Best practices identified
- Lessons learned from completed pediatric studies
- Feedback from pediatric research community
#### 5.3.11 Changes Affecting QMS
- Organizational changes
- New service offerings
- Regulatory requirement changes
- Standard updates (ICH guidelines)
- New pediatric research areas
### 5.4 Review Meeting
1. Quality Assurance Manager facilitates meeting
2. Review each input systematically using agenda
3. Discuss trends, successes, and challenges
4. Address pediatric-specific considerations:
- Adequacy of age-appropriate procedures
- Effectiveness of assent processes
- Family engagement and satisfaction
- Pediatric safety monitoring effectiveness
- Compliance with pediatric regulations
5. Identify systemic issues requiring attention
6. Make decisions on:
- QMS improvements needed
- Resource allocation
- Quality objectives revision
- Process changes
- Training needs
- Pediatric research capability enhancements
7. Document all decisions and action items
### 5.5 Review Outputs
Management review shall produce:
1. **Decisions and Actions** related to:
- Quality Management System improvements
- Pediatric research process enhancements
- Resource needs (personnel, facilities, equipment)
- Quality objectives updates
- Policy revisions
- Training initiatives
- Technology investments
2. **Action Items** with:
- Specific action description
- Responsible person assigned
- Target completion date
- Expected outcome
- Priority level
3. **Quality Objectives** for next period
4. **Resource Commitments** for improvements
### 5.6 Documentation
1. Quality Assurance Manager prepares Management Review Report including:
- Date and attendees
- Review inputs summary
- Discussion highlights
- Decisions made
- Action items (with owners and due dates)
- Updates to quality objectives
- Resource commitments
- Pediatric research strategic directions
2. Report issued within 2 weeks of meeting
3. Report distributed to:
- All attendees
- Department heads
- Board of Directors (executive summary)
4. Report retained per retention requirements
### 5.7 Follow-up
1. Quality Assurance tracks action items
2. Status updates provided in quarterly reports
3. Overdue items escalated to top management
4. Completed items verified
5. Action item status reviewed in next management review
## 6. Key Performance Indicators (KPIs)
Suggested KPIs for pediatric research operations:
### Safety and Participant Protection
- Adverse event rate by age group
- Serious adverse event rate
- Protocol violations (especially affecting child safety)
- Time to safety report submission
- DSMB recommendations implemented
### Quality and Compliance
- Audit findings by severity
- CAPA on-time closure rate
- Protocol deviation rate
- Training compliance rate
- Document control effectiveness
### Operational Efficiency
- Pediatric participant enrollment rate
- Screen failure rate by age group
- Study milestone achievement
- Query resolution time
- Family retention rate
### Regulatory and Sponsor Relations
- Regulatory submission timeliness
- Sponsor monitoring findings
- IRB approval timeliness
- Sponsor satisfaction scores
### Family Experience
- Family satisfaction survey results
- Assent comprehension assessment
- Complaints or concerns raised
- Study withdrawal reasons
## 7. Continuous Improvement
Management review drives continuous improvement through:
- Identification of improvement opportunities
- Resource allocation for improvements
- Process optimization initiatives
- Technology adoption
- Training program enhancements
- Best practice implementation
- Benchmarking against pediatric research standards
## 8. Related Documents
- FRM-008 Management Review Report Template
- Quality Objectives Document
- Annual Audit Program
- CAPA Summary Reports
- Training Compliance Reports
- Pediatric Safety Monitoring Reports
## 9. References
- ISO 13485:2016 Section 5.6 (Management Review)
- ICH-GCP E6(R2) Section 5 (Sponsor)
- 45 CFR 46.103 (Assurance of Compliance)
- 21 CFR 312.56 (Review of Ongoing Investigations)
---
## Revision History
| Rev | Date | Description | Author |
|-----|------|-------------|--------|
| 1.0 | [DATE] | Initial release | [AUTHOR] |

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