Clinical Investigation

Clinical Investigation is the systematic investigation or study of one or more medical devices in human subjects, undertaken to assess the safety and performance of those devices. Under EU MDR (Regulation 2017/745), clinical investigations must follow stringent requirements outlined in Chapter VI and ISO 14155 standards.

Regulatory framework:
EU Medical Device Regulation (MDR 2017/745) Chapter VI establishes comprehensive requirements for clinical investigations of medical devices. Unlike pharmaceuticals, not all medical devices require clinical investigations - they are conducted when existing clinical evidence is insufficient to demonstrate conformity with safety and performance requirements. The regulation mandates ethics committee approval, competent authority notification, and adherence to Good Clinical Practice (GCP) principles.

When clinical investigations are required:
Clinical investigations become necessary under several circumstances:
- Class III and implantable devices - Generally required unless equivalence to existing device can be demonstrated
- Devices with new technology or novel intended purpose - When no equivalent device exists for clinical data reference
- Significant device modifications - Design changes affecting safety or performance may trigger investigation requirements
- Insufficient clinical evidence - When literature review and existing data cannot adequately support Clinical Evaluation Report (CER)
- PMCF studies - Post-market clinical follow-up investigations to gather long-term safety and performance data

Key differences from US clinical trials:
While similar in principle, EU clinical investigations differ from FDA-regulated clinical trials:
- Pre-approval requirement - US requires IDE approval before trials; EU has coordinated assessment through competent authorities
- Regulatory pathway - FDA uses IDE (Investigational Device Exemption); EU uses MDR Chapter VI procedures
- Ethics oversight - Both require ethics approval, but EU explicitly requires ethics committee as part of approval process
- Consent requirements - Both mandate informed consent, but EU has specific MDR requirements
- Serious incident reporting - EU requires reporting to competent authorities within specified timeframes per MDR Article 80

ISO 14155 requirements:
ISO 14155 "Clinical investigation of medical devices for human subjects - Good clinical practice" provides internationally recognized standards for clinical investigation conduct:
- Investigator responsibilities and qualifications
- Sponsor obligations for monitoring and oversight
- Ethics committee review procedures
- Informed consent processes
- Investigational plan requirements
- Data management and statistical analysis
- Documentation and record retention
- Adverse event reporting and safety monitoring

Clinical Investigation Plan (CIP):
The CIP is the foundational protocol document that outlines the complete investigation methodology. Essential CIP components include:
- Rationale and objectives - Scientific justification, research questions, hypotheses
- Device description - Technical specifications, intended purpose, instructions for use
- Study design - Randomized controlled trial, single-arm study, observational study design
- Subject selection - Inclusion/exclusion criteria, sample size justification, recruitment strategy
- Primary and secondary endpoints - Clearly defined safety and performance outcomes
- Risk mitigation - Identified risks and monitoring procedures
- Statistical analysis plan - Statistical methods, interim analyses, stopping rules
- Data management - Case report forms, data collection procedures, quality control
- Safety monitoring - Adverse event definitions, reporting procedures, Data Safety Monitoring Board
- Ethical considerations - Benefit-risk assessment, informed consent process, subject protection measures

Ethics Committee approval:
Before initiating any clinical investigation in the EU, manufacturers must obtain approval from an independent Ethics Committee (EC). The EC reviews:
- Scientific validity and methodological soundness
- Justification of risks in relation to anticipated benefits
- Suitability of investigators and facilities
- Adequacy of informed consent documentation
- Subject safety protection measures
- Compliance with ethical principles (Declaration of Helsinki, GCP)

Competent Authority notification:
EU MDR requires notification to the competent authority (regulatory body) in each member state where the investigation will be conducted. The notification includes:
- Clinical Investigation Plan (CIP)
- Investigator's Brochure with device information
- Proof of insurance/indemnity coverage
- Ethics Committee approval documentation
- Informed consent forms
- If coordinated assessment applies (multi-country studies), a single assessment coordinated across member states

Informed consent requirements:
Informed consent is mandatory before enrolling any subject in a clinical investigation. The consent process must:
- Provide comprehensive written and verbal information about the investigation
- Explain potential risks and anticipated benefits in understandable language
- Clarify voluntary nature of participation and right to withdraw
- Describe data privacy and confidentiality protections
- Allow adequate time for subject consideration and questions
- Document consent with signed, dated consent forms
- Comply with GDPR for data protection

Investigation monitoring and oversight:
Sponsors must implement monitoring systems to ensure investigation integrity:
- Regular site monitoring visits to verify data accuracy and protocol compliance
- Source data verification against case report forms
- Protocol deviation tracking and corrective action
- Continuous safety surveillance and adverse event monitoring
- Quality assurance audits of investigation processes
- Data Safety Monitoring Board for high-risk investigations

Serious incident reporting:
MDR Article 80 mandates strict timelines for reporting serious adverse events:
- Death or serious deterioration of health: Report to competent authorities and ethics committee within 7 calendar days
- Serious public health threat: Immediate notification (within 2 days)
- Other serious adverse events: Report within specified timeframes based on severity

Documentation and record retention:
Clinical investigation documentation must be retained for specified periods:
- Investigation records: Minimum 5 years after investigation completion, or longer if required by member state
- For implantable and Class III devices: At least 15 years
- Documentation includes: CIP, amendments, ethics approvals, informed consents, case report forms, adverse event reports, monitoring logs, final clinical investigation report

Clinical Investigation Report:
Upon investigation completion, sponsors must prepare a comprehensive Clinical Investigation Report containing:
- Summary of investigation objectives, design, and methodology
- Subject accountability and demographic characteristics
- Safety results: Adverse events, serious adverse events, device deficiencies
- Performance results: Primary and secondary endpoint analyses
- Statistical analysis and interpretation
- Discussion of findings in context of existing knowledge
- Conclusions regarding device safety and performance
- The report becomes integral evidence for the Clinical Evaluation Report (CER)

Post-Market Clinical Follow-up (PMCF) investigations:
PMCF studies are clinical investigations conducted after device CE marking to:
- Confirm long-term safety and performance in real-world settings
- Identify previously unknown adverse events or side effects
- Monitor emerging risks from device-device or device-drug interactions
- Gather data on rare complications requiring larger populations
- Evaluate performance in broader patient populations than pre-market studies

Regulatory compliance and inspections:
Competent authorities conduct inspections to verify compliance with:
- MDR Chapter VI requirements
- ISO 14155 Good Clinical Practice standards
- Approved Clinical Investigation Plan adherence
- Proper informed consent procedures
- Accurate and complete documentation
- Timely serious adverse event reporting

A well-conducted clinical investigation following EU MDR Chapter VI and ISO 14155 requirements generates high-quality clinical evidence essential for demonstrating device safety and performance, supporting regulatory approval, and building confidence among healthcare providers and patients.