Overview

Good clinical practice standard for clinical investigations of medical devices ensuring ethical conduct, subject safety, and reliable data collection

ISO 14155:2020 "Clinical investigation of medical devices for human subjects — Good clinical practice" represents the internationally-recognized standard specifying comprehensive good clinical practice (GCP) requirements for designing, conducting, recording, and reporting clinical investigations of medical devices involving human subjects. Published by ISO Technical Committee ISO/TC 194 (Biological and clinical evaluation of medical devices) on July 28, 2020, this third edition of the standard provides the global framework ensuring ethical conduct of medical device clinical studies, protection of human subjects' rights and well-being, scientific rigor and credibility of investigation results, and data integrity and reliability. Clinical investigations are essential components of medical device development and regulatory approval, providing critical clinical evidence demonstrating device safety and clinical performance or effectiveness, supporting regulatory submissions to authorities such as FDA (United States), European Competent Authorities under MDR (European Union), PMDA (Japan), NMPA (China), Health Canada, and TGA (Australia), developing evidence-based instructions for use and clinical labeling, evaluating device performance in real-world clinical settings across diverse patient populations, and identifying unanticipated adverse device effects and use-related risks.

Unlike pharmaceutical clinical trials governed by ICH E6 Good Clinical Practice guidelines designed primarily for drug development, medical device clinical investigations face unique challenges, complexities, and considerations including **device learning curves** (clinical performance often improves as clinicians gain experience with the device through repeated use, creating temporal performance variations), **procedural dependencies** (outcomes depending substantially on operator skill, technique, and training rather than device characteristics alone), **iterative device refinement** (medical devices frequently undergo design modifications during clinical development based on clinical feedback and performance data, requiring protocol amendments and regulatory submissions), **diverse device types and risk profiles** (ranging from simple, low-risk instruments and disposable products to complex, high-risk implantable devices, life-sustaining equipment, and sophisticated software algorithms including AI/ML-based devices), **combination of hardware, software, and procedure** (device performance depending on integrated system of physical device, software controls, and clinical technique), **shorter development timelines** (market pressures and competitive dynamics often demanding faster clinical evidence generation than typical pharmaceutical development), **post-market evidence expectations** (growing regulatory emphasis on post-market clinical follow-up and real-world evidence continuing after initial market approval), and **device-specific outcome measures** (clinical endpoints often device-specific and requiring validation, unlike standardized drug efficacy measures). ISO 14155 addresses these distinctive characteristics providing tailored GCP framework appropriate for medical device clinical investigation context while maintaining fundamental ethical principles and scientific rigor comparable to pharmaceutical clinical trials.

The 13 Principles of Good Clinical Practice

ISO 14155:2020 introduced a major enhancement by explicitly articulating 13 foundational GCP principles (in Section 4 of the standard) aligned with ICH E6(R2) Good Clinical Practice guidelines and the Declaration of Helsinki, establishing philosophical and ethical foundation for all clinical investigation requirements. These principles are: **(1) Clinical investigations should be conducted in accordance with ethical principles** originating in the Declaration of Helsinki and consistent with GCP and applicable regulatory requirements; **(2) Before a clinical investigation is initiated, foreseeable risks and inconveniences should be weighed against anticipated benefits** for individual subjects and society, with investigation proceeding only if anticipated benefits justify risks and protecting subject rights, safety, and well-being over interests of science and society; **(3) The rights, safety, dignity, and well-being of investigation subjects are the most important considerations** and shall prevail over interests of science and society; **(4) Available non-clinical and clinical information on the investigational device should be adequate** to support proposed clinical investigation through comprehensive risk analysis.

**(5) Clinical investigations should be scientifically sound and described in a clear, detailed protocol** ensuring study design appropriately addresses research questions with adequate statistical power, defined endpoints, and prospective analysis plan; **(6) Clinical investigations should be conducted in compliance with the protocol** that has received prior ethics committee approval/favorable opinion and regulatory authorization where required; **(7) Medical care provided to subjects and medical decisions made on their behalf should always be the responsibility of a qualified physician** or qualified dentist when appropriate, with clinically-trained investigators overseeing subject care; **(8) Each individual involved in conducting a clinical investigation should be qualified by education, training, and experience** to perform their respective tasks with documented evidence of qualification and training; **(9) Freely given informed consent should be obtained from every subject prior to clinical investigation participation** with comprehensive disclosure of investigation nature, risks, benefits, alternatives, and rights; **(10) All clinical investigation information should be recorded, handled, and stored** in a way that allows accurate reporting, interpretation, and verification while protecting confidentiality of records identifying subjects in accordance with applicable data protection requirements.

**(11) The confidentiality of records that could identify subjects should be protected** respecting privacy and confidentiality rules in accordance with applicable regulatory requirements; **(12) Investigational devices should be manufactured in accordance with applicable good manufacturing practice** or equivalent quality system ensuring device quality, safety, and performance consistency; **(13) Systems with procedures** that assure the quality of every aspect of the clinical investigation should be implemented ensuring adherence to GCP principles and investigation protocol. These 13 principles permeate all ISO 14155 requirements and guide interpretation and implementation of specific provisions, emphasizing that ethical conduct and subject protection are not merely regulatory compliance obligations but fundamental moral imperatives underlying all clinical research with human subjects.

Ethical Framework and Human Subject Protection

ISO 14155 establishes comprehensive ethical framework centered on protecting human subjects participating in clinical investigations. **Research Ethics Committee (REC) or Institutional Review Board (IRB) review and approval** is mandatory before initiating any clinical investigation, ensuring independent, competent review of clinical investigation plan (protocol), informed consent documents and process, investigator qualifications and facilities, risk-benefit assessment and acceptability, subject recruitment procedures and materials, compensation arrangements for subjects and investigators, provisions for subjects injured as result of investigation participation, subject privacy and confidentiality protections, and adequacy of oversight and monitoring. Ethics committees must include members with diverse expertise (clinical, scientific, ethical, legal, lay/patient perspectives) ensuring comprehensive evaluation from multiple viewpoints, operate independently from sponsors and investigators avoiding conflicts of interest, review investigations according to applicable standards and regulations, and maintain appropriate documentation of deliberations and decisions with clear rationale for favorable opinions or concerns requiring modification.

**Informed consent** represents cornerstone of ethical clinical research, requiring that competent subjects voluntarily agree to participate after receiving comprehensive, understandable information about investigation. ISO 14155 specifies detailed informed consent requirements including provision of written informed consent form in language understandable to subject, adequate time and opportunity for subjects to consider participation without pressure or coercion, information disclosure covering investigation purpose and scientific rationale, study procedures and subject participation requirements, duration of participation and follow-up obligations, investigational nature of device and that it is under clinical investigation, foreseeable risks, discomforts, and inconveniences reasonably expected, anticipated benefits for subject and/or society (acknowledging when subject may not receive direct benefit), alternative treatments or procedures available, provisions for treatment and compensation in case of investigation-related injury, extent of confidentiality protections and potential for data access by regulatory authorities and monitors, voluntary nature of participation and right to refuse or withdraw at any time without penalty or loss of benefits, circumstances under which participation might be terminated by investigator, contact information for questions and concerns including independent ethics committee, and number of subjects planned for enrollment. Informed consent process must allow opportunity for subjects to ask questions and receive satisfactory answers, be documented through signed and dated informed consent form with copy provided to subject, and be continuous process with obligation to inform subjects of new information arising during investigation that might affect willingness to continue participation.

**Vulnerable populations** including children and minors, pregnant women and nursing mothers, prisoners and institutionalized persons, persons with mental disabilities or cognitive impairment, economically or educationally disadvantaged persons, persons in subordinate positions (students, employees, military personnel), and critically ill patients require additional protections and safeguards. For pediatric investigations, informed consent must be obtained from legally authorized representative (parent or guardian) with assent obtained from child when developmentally appropriate, investigation must address condition affecting children where adult data is insufficient, risks must be minimized and justified by anticipated benefits or generalizable knowledge, and age-appropriate information and communication must be provided. Vulnerable populations should be included in investigations only when investigation addresses condition specific to that population or when participation offers prospect of direct benefit justifying risks, with heightened scrutiny of voluntariness and understanding, enhanced monitoring and safeguards, and ethics committee expertise relevant to vulnerable population.

**Risk minimization and benefit-risk assessment** require that investigational devices be used only when potential benefits justify foreseeable risks to individual subjects and society, risk assessment integrates pre-clinical testing, bench testing, animal studies, simulated use testing, and previous clinical experience if available, risk management throughout clinical investigation includes safety monitoring, adverse event tracking and analysis, Data Safety Monitoring Board (DSMB) oversight for high-risk studies, interim analyses permitting early stopping for safety concerns or overwhelming efficacy, protocol modifications to address emerging safety signals, and study suspension or termination when risks outweigh benefits. **Privacy and confidentiality protection** require compliance with applicable data protection regulations (GDPR in European Union, HIPAA in United States, national data protection laws globally), subject data coding/pseudonymization removing direct identifiers while permitting linkage, secure data storage and transmission with access controls and audit trails, confidentiality obligations for all investigation personnel, subject notification of data processing activities and rights, and data retention and destruction policies balancing regulatory requirements with privacy rights.

Clinical Investigation Planning and Study Design

ISO 14155 requires rigorous scientific study design documented in comprehensive **Clinical Investigation Plan (CIP)** serving as protocol for investigation. The CIP must specify **general information** (protocol title and version with date, sponsor identification and contact information, investigator identification for all sites, protocol approval signatures and dates, protocol amendment history); **investigation rationale and objectives** (background including disease/condition background and unmet clinical need, device description and intended use, pre-clinical and previous clinical data summary, investigation rationale and scientific justification, primary objective and hypothesis clearly stated, secondary objectives if applicable); **investigation design** (investigation design type—randomized controlled trial, single-arm study, observational study, registry, prospective/retrospective, overall investigation structure and phases, randomization and blinding procedures if applicable, control group and comparator if used, investigation duration and subject follow-up schedule, subject visit schedule and procedures at each visit).

The CIP must define **subject selection** (target population description and rationale, inclusion criteria ensuring appropriate subject selection, exclusion criteria protecting subject safety and data integrity, recruitment strategies and materials, screening procedures and informed consent timing, enrollment targets by site and overall with justification); **interventions and procedures** (investigational device specifications and description, device implantation, use, or administration procedures, concomitant treatments and procedures permitted/prohibited, subject instructions and training if applicable, device accountability and tracking procedures, protocol for device failures or malfunctions); **outcome measures and endpoints** (primary endpoint precisely defined and measurable, secondary endpoints and their definitions, safety endpoints and monitoring parameters, endpoint assessment timing and methods, endpoint validation if novel or device-specific, clinical relevance and regulatory acceptance of endpoints).

Critical CIP elements include **sample size and statistical analysis** (sample size calculation with assumptions (effect size, variability, power, significance level), justification for sample size particularly for single-arm studies, statistical analysis plan defining populations (intention-to-treat, per-protocol, safety), statistical methods for primary and secondary endpoints, handling of missing data and withdrawals, interim analyses plan and stopping rules if applicable, multiplicity adjustments if multiple endpoints or comparisons, subgroup analyses if planned), **safety monitoring** (adverse event definitions and classification, serious adverse event criteria and reporting timelines, device deficiency definitions and reporting, unanticipated adverse device effect procedures, safety review and monitoring plan, Data Safety Monitoring Board if applicable with charter, stopping rules for safety concerns); **data management and quality** (data collection methods and tools (case report forms, electronic data capture), data quality control and validation procedures, database specifications and validation, audit trail requirements, data handling and confidentiality, source data requirements and verification); **monitoring and oversight** (monitoring plan including frequency and scope of monitoring visits, risk-based monitoring strategy if applicable, on-site monitoring procedures, central monitoring activities, investigator oversight responsibilities, audit provisions).

The CIP must address **ethical and regulatory considerations** (ethics committee approval requirements, regulatory notifications and approvals needed, informed consent process and documentation, privacy and confidentiality protections, subject compensation and reimbursement, provisions for investigation-related injury, protocol deviation management, protocol amendment procedures); **investigation management** (roles and responsibilities of sponsor, investigators, monitors, committees, coordinating center if multi-center investigation, communication plan among investigation parties, investigator meetings and training, device training for clinical users, documentation and record-keeping requirements, publication and data sharing policy, investigation timeline and milestones). Well-designed CIP ensures scientific rigor, ethical conduct, subject safety, data quality, regulatory compliance, and successful investigation completion yielding credible clinical evidence.

Sponsor and Investigator Responsibilities

ISO 14155 delineates detailed responsibilities for sponsors and investigators ensuring clear accountability for investigation conduct and subject protection. **Sponsor responsibilities** (the individual, company, institution, or organization taking responsibility for initiation, management, and financing of clinical investigation) include **investigation planning and design** (developing clinical investigation plan with scientific and statistical rigor, ensuring investigation design addresses regulatory and clinical evidence requirements, conducting pre-investigation device development and non-clinical testing, performing clinical investigation risk assessment per ISO 14971 principles, engaging clinical and statistical experts in protocol development); **investigator and site selection** (selecting qualified investigators with appropriate expertise, experience, and facilities, assessing site capabilities and resources adequacy, conducting site feasibility assessments, executing investigation agreements defining roles and responsibilities, providing investigators with comprehensive device information and investigation materials).

Sponsors must ensure **investigator training and support** (comprehensive investigator meetings before investigation initiation, device training for investigators and clinical users, protocol training ensuring understanding of requirements and procedures, ongoing support and guidance during investigation conduct, regular communication and updates to investigators); **device provision and accountability** (manufacturing devices per applicable quality system requirements, providing adequate device quantities for investigation, establishing device accountability systems tracking distribution and use, managing device storage and handling requirements, implementing device recall procedures if necessary); **ethics and regulatory submissions** (obtaining ethics committee approval before investigation initiation, submitting regulatory notifications/applications to competent authorities, providing continuing safety and progress reports to ethics committees and authorities, submitting protocol amendments for approval before implementation, responding to ethics committee and regulatory authority inquiries).

Critical sponsor duties include **monitoring and oversight** (developing and implementing monitoring plan, conducting initiation visits before subject enrollment, regular monitoring visits during investigation conduct, reviewing investigation progress and data quality, verifying informed consent process and documentation, assessing protocol compliance and investigating deviations, reviewing source data and case report form accuracy, central monitoring of data trends and safety signals, conducting close-out visits upon investigation completion); **safety management** (establishing adverse event and device deficiency reporting systems, reviewing and assessing all adverse events and device deficiencies, determining expectedness and severity of events, expedited reporting of serious adverse events and serious adverse device effects to ethics committees and authorities per regulatory timeframes, periodic safety reporting and aggregate safety analyses, Data Safety Monitoring Board coordination if applicable, implementing risk mitigation measures and protocol modifications for safety concerns, device recall or field safety corrective actions if required); **data management and quality assurance** (developing and maintaining investigation databases, implementing data quality control procedures, conducting data validation and query resolution, maintaining investigation essential documents and records, conducting internal audits of investigation quality and compliance, preparing for regulatory inspections, implementing corrective and preventive actions for deficiencies).

Sponsors must manage **reporting and disclosure** (registration of clinical investigation in publicly accessible database (ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP) before first subject enrollment per transparency requirements, posting of investigation results upon completion typically within one year, preparing clinical investigation report summarizing investigation conduct and results, submitting final reports to ethics committees and regulatory authorities, supporting regulatory submissions with clinical data, publications in peer-reviewed journals following investigation completion, data sharing consistent with applicable requirements and sponsor policy). **Principal Investigator responsibilities** (physician or dentist with appropriate qualifications conducting clinical investigation at site) include **investigation preparation** (reviewing and understanding clinical investigation plan thoroughly, assessing site capability and resources to conduct investigation per protocol, obtaining local ethics committee approval if required, ensuring adequate and qualified investigation staff, completing sponsor-required training and device training, preparing site for investigation conduct including facilities, equipment, and supplies).

Investigators must manage **subject enrollment and informed consent** (recruiting subjects according to protocol selection criteria without coercion, conducting informed consent process providing comprehensive information, ensuring subjects have adequate time and opportunity to consider participation, answering subject questions and addressing concerns, obtaining written informed consent before any investigation procedures, documenting informed consent in subject records and investigation documentation, providing signed informed consent copy to subjects, maintaining subject confidentiality and privacy throughout investigation); **investigation conduct and subject care** (conducting investigation in strict accordance with approved protocol, ensuring subjects receive appropriate medical care and monitoring, performing protocol-specified procedures and assessments, administering investigational device according to instructions and protocol, managing concomitant medications and treatments per protocol requirements, ensuring subject safety through vigilant monitoring, making medical decisions in subjects' best interest, withdrawing subjects when medically indicated or at subject request, ensuring adequate subject follow-up per protocol schedule).

Investigators are accountable for **data collection and documentation** (maintaining accurate, complete, and contemporaneous source documentation, recording all investigation data in case report forms accurately and timely, reviewing and signing case report forms attesting to accuracy, responding to data queries from sponsor monitors, reporting all adverse events and device deficiencies to sponsor per protocol timelines, maintaining subject identification logs and investigation documents, permitting monitoring, audits, and regulatory inspections with direct access to source data, retaining investigation records per regulatory requirements); **compliance and quality** (following GCP principles and ISO 14155 requirements, adhering to protocol without unauthorized deviations, seeking sponsor approval and ethics committee notification for protocol deviations when necessary, maintaining device accountability records, implementing sponsor instructions and corrective actions, reporting serious adverse events to ethics committee and sponsor immediately, participating in monitoring visits and audits cooperatively, attending investigator meetings and complying with sponsor communications, conducting investigation with scientific integrity and ethical responsibility). Effective partnership between sponsor and investigators ensures investigation success with shared commitment to subject protection, data quality, regulatory compliance, and generation of credible clinical evidence.

Data Integrity, Quality Management, and Risk-Based Monitoring

ISO 14155:2020 significantly enhanced requirements for data integrity and quality management, introducing risk-based approaches to monitoring aligned with evolving regulatory expectations. **Data integrity** requires that clinical investigation data be accurate (correct, free from errors), complete (all required data collected and recorded), consistent (data concordant across different sources and time points), legible (readable and comprehensible), contemporaneous (recorded at or close to time of observation), original or certified copy (source data preserved), attributable (traceable to person responsible for generation), and secure (protected from unauthorized access, modification, or deletion). ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate plus Complete, Consistent, Enduring, Available) guide data integrity ensuring trustworthy data supporting regulatory submissions and scientific conclusions.

**Risk-based quality management** applies ISO 14971 risk management principles to clinical investigation processes identifying critical to quality factors (subject safety protection, reliability of investigation results, adherence to fundamental ethical and regulatory requirements), assessing risks to these quality factors from investigation design, site capabilities, device characteristics, subject population, conducting risk assessment determining likelihood and impact of potential issues, developing risk mitigation strategies targeting highest risks, implementing proportionate monitoring and oversight focused on critical areas, monitoring effectiveness of risk mitigation measures. This risk-based approach enables efficient resource allocation focusing intensive monitoring on high-risk aspects while reducing effort on low-risk elements, moving beyond prescriptive 100% source data verification to targeted verification of critical data, critical processes, and high-risk sites.

**Risk-based monitoring** (RBM) combines central monitoring (systematic assessment of accumulating data using statistical methods, data analytics, and visualization to identify data anomalies, protocol deviations, safety signals, and site performance issues) and on-site monitoring (targeted site visits focused on high-risk sites, sites with performance concerns identified through central monitoring, verification of critical data and processes, assessment of informed consent process quality, evaluation of device storage and accountability, investigator training and oversight). RBM benefits include earlier detection of systematic issues through continuous central monitoring, more efficient use of monitoring resources, enhanced data quality through proactive issue identification, reduced burden on sites from less frequent visits, maintained assurance of subject protection and data integrity. Implementation requires robust electronic data capture systems enabling central monitoring, statistical monitoring plans defining triggers and thresholds, qualified personnel experienced in data analytics and investigation conduct, documented monitoring plans explaining risk assessment and strategy, and flexibility to adapt monitoring intensity based on emerging issues.

**Quality assurance and auditing** include sponsor internal audits (systematic, independent examination of investigation-related activities and documents determining whether activities comply with GCP, protocol, and regulatory requirements, assessing whether data are recorded, analyzed, and accurately reported, evaluating effectiveness of quality systems, conducted by personnel independent from investigation conduct, planned based on importance of investigation and identified risks, documented in audit reports with findings and recommendations); regulatory inspections (inspections by FDA, European Competent Authorities, or other regulators, may inspect sponsor facilities, investigator sites, ethics committees, or service providers, assess GCP compliance, data integrity, subject protection, and regulatory submission accuracy, may occur during investigation, after submission, or triggered by concerns, require cooperation providing access to facilities, personnel, and documentation, findings documented in inspection reports potentially requiring corrective actions); essential documents and record-keeping (sponsor must maintain investigation master file containing protocol and amendments, investigator brochure and device information, ethics committee approvals and correspondence, regulatory submissions and approvals, investigator agreements and CVs, monitoring reports, safety reports, laboratory certifications, and source data); investigators must maintain investigation site files containing protocol and amendments, investigator brochure, ethics committee approval documentation, informed consent forms, subject identification logs and screening logs, source documents and case report forms, device accountability records, adverse event reports, correspondence with sponsor and ethics committee, delegation of authority logs; retention periods typically 5-25 years depending on jurisdiction, longer if required by applicable regulations or if device remains on market).

Regulatory Framework and Global Harmonization

ISO 14155 harmonizes with and is recognized by major regulatory frameworks worldwide facilitating global clinical investigations and regulatory submissions. In the **European Union**, the Medical Device Regulation (EU MDR 2017/745) and In Vitro Diagnostic Regulation (EU IVDR 2017/746) explicitly reference ISO 14155 as good clinical practice standard for clinical investigations, requiring investigations be conducted per harmonized standards or equivalent GCP principles, clinical evaluation under MDR mandating clinical evidence from investigations for high-risk devices or novel devices lacking equivalence data, Notified Body assessment including review of clinical investigation compliance with ISO 14155, Competent Authority authorization required before initiating investigations in EU member states, serious adverse event reporting to Competent Authorities and sponsor national authority, clinical investigation requirements increasingly stringent under MDR versus previous directives (MDD/AIMDD), and post-market clinical follow-up (PMCF) requirements for continuous clinical evidence gathering. The EU Clinical Trials Information System (CTIS) serves as single entry point for clinical investigation applications across EU starting 2025, streamlining multi-country submissions.

In the **United States**, FDA recognizes ISO 14155:2011 (recognition of 2020 version anticipated) as consensus standard compatible with US GCP requirements, accepting clinical data from studies conducted per ISO 14155 from non-US sites for regulatory submissions. 21 CFR Part 812 Investigational Device Exemption (IDE) regulations govern US clinical investigations requiring IDE submission for significant risk devices (SR-IDE requiring FDA approval before investigation initiation) while abbreviated requirements apply to non-significant risk devices (NSR-IDE with IRB approval sufficient). FDA requirements include IRB approval, informed consent per 21 CFR 50, investigator responsibilities per 21 CFR 812, monitoring and records, financial disclosure reporting, and sponsor responsibilities. FDA issued final rule (2018) accepting data from clinical investigations conducted outside US when investigations comply with GCP (ISO 14155 meets this requirement) and FDA can validate data through inspections. FDA emphasizes risk-based approaches consistent with ISO 14155:2020, encouraging innovative study designs, adaptive designs, and real-world evidence generation.

**Global regulatory convergence** is increasing with **Japan** (PMDA recognizes ISO 14155 with clinical investigation requirements under Pharmaceuticals and Medical Devices Act aligned with GCP principles), **Canada** (Health Canada Medical Devices Regulations reference GCP with ISO 14155 compatibility, investigational testing authorization required for clinical investigations), **Australia** (Therapeutic Goods Administration applies clinical investigation requirements aligned with ISO 14155, clinical investigation exemption required for unapproved devices), **China** (NMPA regulations increasingly aligned with international GCP standards, clinical investigation requirements under Medical Device Supervision and Administration Regulation), **Brazil** (ANVISA clinical investigation requirements reference GCP principles compatible with ISO 14155), and **other jurisdictions** progressively adopting or recognizing ISO 14155. International Council for Harmonisation of Technical Requirements for Medical Devices (IMDRF) promotes global convergence including clinical investigation harmonization, essential principles of safety and performance including clinical evidence requirements, and single audit program facilitating mutual recognition of audits and inspections.

2020 Updates and Recent Developments

ISO 14155:2020 (third edition, published July 28, 2020) introduced significant updates from ISO 14155:2011 including **13 GCP principles** explicitly articulated aligning with ICH E6(R2) and Declaration of Helsinki providing philosophical foundation, **enhanced risk-based approaches** integrating risk management throughout investigation lifecycle and risk-based monitoring strategies, **clinical investigation registration requirements** mandating registration in publicly accessible databases before first subject enrollment enhancing transparency, **results posting obligations** requiring investigation results posting upon completion addressing publication bias and transparency expectations, **strengthened informed consent requirements** reflecting contemporary ethical standards and regulatory requirements including electronic consent provisions, **enhanced investigator responsibilities and accountability** clarifying investigator obligations and oversight requirements, **data integrity and quality management emphasis** addressing data reliability and ALCOA+ principles, **cybersecurity and data protection considerations** reflecting digitalization and data privacy regulations (GDPR, HIPAA), **post-market clinical follow-up (PMCF) guidance** supporting EU MDR PMCF requirements and post-market evidence generation, **real-world evidence (RWE) accommodation** recognizing RWE role in regulatory decisions and device evaluation, **software as medical device (SaMD) considerations** addressing unique aspects of software-based devices including algorithm validation and software updates, **harmonization with ISO 14971** ensuring consistent risk management approach between device development and clinical investigation.

**Amendment ISO 14155:2020/Amd 11:2024** published in 2024 introduced additional updates addressing emerging requirements including enhanced clinical risk management provisions aligning with evolving MDR interpretations, improved guidance on clinical study design particularly for adaptive designs and novel endpoints, strengthened emphasis on clinical evidence role in regulatory submissions and post-market surveillance, updated serious adverse event definitions and reporting clarifications, and digital health and decentralized trial considerations reflecting COVID-19 pandemic impacts and future trial conduct evolution. The standard continues evolving through ongoing revision activities within ISO/TC 194, stakeholder feedback from regulators, industry, ethics committees, and investigators, alignment with emerging technologies (AI/ML devices, digital therapeutics, combination products, personalized devices), and regulatory landscape changes (EU MDR implementation experience, FDA modernization initiatives, global convergence efforts).

Post-Market Clinical Follow-Up and Real-World Evidence

Beyond pre-market clinical investigations, ISO 14155 increasingly applies to **post-market clinical follow-up (PMCF)** studies required under EU MDR Article 61 to proactively and systematically gather, assess, and analyze clinical data from marketed devices, confirming device safety and clinical performance throughout expected lifetime and in actual conditions of use, identifying previously unknown or emerging side effects, adverse events, or risks, evaluating long-term safety and performance in broader, more diverse patient populations than pre-market studies, assessing performance in different clinical settings and user environments, and generating evidence for ongoing clinical evaluation and benefit-risk determination. PMCF plans (required for each device or device family) must specify objectives, methods, and procedures, subject identification and enrollment, data collection timeframes and endpoints, statistical analysis approaches, and reporting and evaluation procedures. PMCF methods include prospective studies (registries tracking device use and outcomes in routine practice, observational cohort studies following patients longitudinally, comparative effectiveness studies versus alternative treatments), retrospective studies (analysis of existing medical records or databases, electronic health record data mining), case series and surveillance (systematic collection of device use and outcome data), and patient surveys and questionnaires (patient-reported outcomes and satisfaction).

**Real-world evidence (RWE)** from real-world data (RWD) collected during routine clinical practice (electronic health records, claims databases, patient registries, patient-generated data from wearables and apps, product and disease registries) provides valuable complementary evidence to traditional prospective clinical investigations. RWE benefits include large, diverse patient populations including underrepresented groups, long-term follow-up beyond typical investigation durations, actual clinical practice conditions versus controlled trial settings, rapid evidence generation leveraging existing data sources, cost-effectiveness compared to traditional prospective trials, and ongoing monitoring enabling timely safety signal detection. ISO 14155 principles apply to RWE generation ensuring scientific rigor in study design and analysis plan, appropriate data quality and validation for intended purpose, protection of patient privacy and confidentiality, ethical conduct and applicable oversight, and transparency in methods and reporting. Challenges include potential for selection bias, confounding, and missing data, data quality and completeness variability, inability to control exposures or interventions, difficulties establishing causation versus association, and regulatory acceptance requiring demonstration of data reliability and analytical validity. Regulatory frameworks increasingly incorporate RWE with FDA Real-World Evidence Framework providing guidance for RWE use in regulatory decisions, EU MDR requiring PMCF and real-world performance evidence, and IMDRF guidance on RWD for regulatory purposes establishing international principles.

Specialized Applications and Future Directions

ISO 14155 application extends to specialized device types and emerging technologies. **Software as Medical Device (SaMD)** including diagnostic algorithms, clinical decision support, treatment planning software, and AI/ML-based devices requires algorithm validation and performance assessment across diverse datasets and populations, software version control managing updates and modifications during investigations, cybersecurity and data privacy protections for connected devices and cloud-based systems, and unique performance endpoints relevant to software functionality (diagnostic accuracy, predictive performance, clinical impact on decision-making). **Artificial Intelligence and Machine Learning (AI/ML) devices** present novel challenges including algorithm transparency and interpretability (understanding AI/ML decision-making and identifying features), bias detection and mitigation ensuring representative training data and equitable performance, continuous learning algorithms potentially changing during deployment, and validation across diverse populations and clinical settings preventing algorithmic bias.

**Digital therapeutics** (software-based interventions treating medical conditions) require endpoints demonstrating therapeutic efficacy not just device functionality, patient engagement and adherence measurement critical to effectiveness, data privacy and security for personal health data, and regulatory classification varying by jurisdiction (medical device, pharmaceutical, wellness product). **Decentralized and hybrid trials** accelerated by COVID-19 pandemic employ remote data collection and telemedicine visits, wearable sensors and home monitoring devices, electronic consent and remote consent processes, direct-to-patient device shipping, virtual study visits and remote monitoring, reduced site visits and patient burden, expanded geographic reach and diverse recruitment, and data security for remote collection. **Personalized and 3D-printed devices** customized for individual patients require demonstrating safety and performance across range of customizations, limited sample sizes when devices are patient-specific, regulatory pathways for personalized manufacturing, and quality management for variable manufacturing processes.

**Future directions** for ISO 14155 and medical device clinical investigations include greater regulatory harmonization reducing duplicative requirements across jurisdictions, broader acceptance of RWE and innovative study designs, patient engagement and patient-centered endpoints incorporating patient perspectives and priorities, pragmatic trial designs embedded in clinical practice, adaptive platform trials evaluating multiple devices or indications, Bayesian methods and continuous learning enhancing efficiency, data standards and interoperability enabling data sharing and integration, global collaboration and data sharing accelerating evidence generation, precision medicine approaches targeting device therapy to patient characteristics, sustainability considerations in device design and lifecycle, and health equity ensuring diverse populations benefit from device innovations. ISO 14155 will continue evolving ensuring medical device clinical investigations uphold fundamental ethical principles, protect human subjects, generate credible scientific evidence, support regulatory decisions, and ultimately advance patient care through safe, effective medical device innovations that address unmet clinical needs and improve health outcomes worldwide.

Purpose

To establish good clinical practice requirements for clinical investigations of medical devices, ensuring ethical conduct, subject safety, data integrity, and regulatory compliance in device clinical research

Key Benefits

• International standard ensuring consistent GCP across global clinical investigations
• Regulatory recognition by FDA, EU, and major authorities worldwide facilitating global studies
• Comprehensive ethical framework protecting human subjects and ensuring ethical conduct
• Scientific rigor requirements ensuring credible, reliable clinical evidence generation
• Clear roles and responsibilities for sponsors, investigators, and ethics committees
• Enhanced subject safety through systematic adverse event monitoring and risk management
• Data integrity and quality assurance producing reliable evidence for regulatory decisions
• Risk-based monitoring approaches improving efficiency while maintaining oversight
• Harmonization with EU MDR, FDA IDE, and global regulations reducing compliance burden
• Support for innovative study designs including adaptive trials and real-world evidence
• Post-market clinical follow-up (PMCF) framework for ongoing evidence generation
• Standardized documentation and reporting facilitating regulatory submissions
• Protection of subject privacy and confidentiality per data protection regulations
• Quality management systems ensuring investigation excellence and compliance
• Transparency through clinical trial registration and results disclosure
• Guidance for emerging technologies (SaMD, AI/ML, digital therapeutics, personalized devices)
• Global harmonization reducing duplicative requirements across jurisdictions
• Credibility and acceptance of clinical data by regulatory authorities worldwide
• Cost-efficiency through risk-based approaches and optimized monitoring strategies
• Professional development providing GCP framework for clinical research workforce

Key Requirements

• Adherence to 13 foundational GCP principles aligned with ICH E6(R2) and Declaration of Helsinki
• Research Ethics Committee (REC) or IRB approval before investigation initiation
• Written informed consent from all subjects or legally authorized representatives
• Comprehensive Clinical Investigation Plan (CIP/protocol) with scientific rationale
• Clearly defined investigation objectives, endpoints, and success criteria
• Appropriate subject selection criteria (inclusion/exclusion) ensuring suitable population
• Sample size justification with statistical rationale for adequacy
• Prospective statistical analysis plan defining analysis methods and populations
• Risk assessment and risk management throughout investigation lifecycle per ISO 14971
• Qualified investigators with appropriate medical expertise, training, and facilities
• Sponsor responsibilities for investigation oversight, monitoring, and safety management
• Investigator responsibilities for protocol compliance, subject care, and data integrity
• Adverse event and device deficiency monitoring, reporting, and management
• Serious adverse event expedited reporting to ethics committees and authorities
• Data Safety Monitoring Board (DSMB) for high-risk investigations when appropriate
• Monitoring plan with on-site and/or central monitoring ensuring quality and compliance
• Risk-based monitoring approaches focused on critical data and processes
• Source documentation requirements ensuring accurate, complete, contemporaneous records
• Data management and quality control with validation and query resolution
• Essential document retention and investigation file maintenance per regulations
• Clinical investigation registration in publicly accessible database before enrollment
• Investigation results posting upon completion ensuring transparency
• Compliance with data protection regulations (GDPR, HIPAA, national laws)
• Device quality assurance through GMP or equivalent quality systems
• Protocol amendments submitted for ethics committee and regulatory approval
• Final clinical investigation report documenting conduct, results, and conclusions
• Preparation for regulatory inspections and audits with documentation access
• Post-market clinical follow-up (PMCF) for ongoing evidence generation where applicable
• Special protections for vulnerable populations (pediatric, pregnant, impaired)
• Cybersecurity and data security measures for digital devices and data systems

Who Needs This Standard?

Medical device manufacturers conducting clinical studies, clinical research organizations (CROs), clinical investigators, research institutions, regulatory affairs professionals, ethics committees, and sponsors of device clinical investigations.

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