ISO 14155 is the international standard for good clinical practice in clinical investigations of medical devices for human subjects. It describes the planning, conduct, recording, and reporting of such investigations with the aim of protecting the rights, safety, and well-being of participants and generating scientifically robust data. The third edition was published in July 2020 and is structured into ten chapters and ten annexes, including the normative Annex A on the clinical investigation plan and Annex B on the investigator’s brochure. For investigations within the scope of Regulation (EU) 2017/745, the standard supplements the legal requirements; Articles 62 to 82 and Annex XV of the Regulation are binding.
Scope and Structure of the Standard
The standard applies to pre-market clinical investigations and is to be applied analogously to post-market investigations insofar as their nature permits. Following an introductory chapter on good clinical practice, subsequent chapters address ethical considerations, clinical investigation planning including risk-benefit assessment and study design, conduct, termination, and the responsibilities of the sponsor and investigator. The annexes provide the structure of the key documents: Annex A defines the minimum content of the clinical investigation plan, Annex B that of the investigator’s brochure. Further annexes address, among other topics, the clinical investigation report, case report forms, the attribution of adverse events, and the handling of investigational devices.
Core Requirements for the Sponsor
The sponsor is responsible for the qualification of investigation sites, the risk-based monimonitoring plan, ensuring data integrity, the traceability of investigational devices from dispatch to return or destruction, and the evaluation and reporting of safety-relevant events.
Core Requirements for the Investigator
The investigator is responsible for informed consent, medical care, complete and timely documentation in source data, and the reporting of adverse events to the sponsor. Characteristic of device investigations is the close integration with risk management: the clinical investigation plan must address the hazards identified in the risk analysis, and events are classified not only by severity but also by their relationship to the device, the interventional procedure, and any device deficiency.
Relationship to the Medical Device Regulation
Article 62 of Regulation (EU) 2017/745 governs the general requirements for clinical investigations conducted as part of clinical evaluation for conformity assessment purposes; design, authorization, conduct, recording, and reporting follow Articles 62 to 80 and Annex XV. Annex XV Chapter I contains the general requirements, Chapter II the documentation to be submitted with the application for authorization, and Chapter III further obligations of the sponsor. ISO 14155 is not currently listed among the harmonized standards for the MDR; nevertheless, it is recognized as the state of the art and is used as a reference by authorities, ethics committees, and notified bodies. For post-market investigations within the framework of post-market clinical follow-up, the standard likewise provides the methodological framework.
Distinction from ICH E6 and Pharmaceutical Investigations
ISO 14155 is the counterpart to ICH E6 for medical devices, but not a translation. The differences arise from the investigational product: a device is applied, implanted, or operated, not dosed. Consequently, the standard addresses user training, investigators’ learning curves, device handling, calibration, and traceability of individual device units, whereas blinding and randomization are often limited in feasibility. Instead of an investigational medicinal product dossier, the investigator’s brochure with preclinical data, risk analysis, and biological evaluation is central. Reporting pathways also differ: safety reports from device investigations are submitted under Article 80 of the Regulation via the electronic system designated for medical devices, not through the systems established for medicinal products under Regulation (EU) No 536/2014. It is also essential that authorization is granted on a device-specific basis and that the term medical device determines the applicability of the entire regulatory framework.
Relevance for clinical trials
In practice, ISO 14155 serves as a blueprint for the study documentation package: the clinical investigation plan follows Annex A, the investigator’s brochure follows Annex B, and the standard operating procedures for monitoring, data management, event assessment, and device management are derived from the responsibility chapters. Consistent application of the standard fulfills a large part of the requirements of Annex XV, but must be supplemented by the additional procedural requirements of the Regulation and national provisions for the authorization and ethics review process.
The standard does not replace a study strategy: whether a clinical investigation is required at all, which endpoints support the demonstration of performance, and how the data will later be incorporated into the clinical evaluation remain planning decisions. Full-service CROs such as Mediconomics support sponsors in setting up the investigation plan, investigator’s brochure, and standard operating procedures in compliance with the standard and aligning the study documentation with the subsequent conformity assessment.
Frequently Asked Questions (FAQ)
Is the application of ISO 14155 legally mandatory?
Articles 62 to 82 and Annex XV of Regulation (EU) 2017/745 are binding. The standard is not listed as a harmonized standard, but is recognized as the state of the art; any deviation from it should be justified and documented.
Does the standard also apply to post-market studies?
Yes, analogously. For investigations within the framework of post-market clinical follow-up, its principles are to be applied insofar as the nature of the investigation permits.
What distinguishes the investigator’s brochure from an investigational medicinal product dossier?
The investigator’s brochure according to Annex B summarizes the device description, preclinical investigations, risk analysis, biological evaluation, and handling instructions. It is device-specific and does not contain pharmaceutical-qualitative information on active substance and dosage form.
Regulatory References
- ISO 14155:2020, third edition, including normative Annexes A and B
- Regulation (EU) 2017/745, Articles 62 to 82
- Regulation (EU) 2017/745, Annex XV Chapters I to III
- Regulation (EU) 2017/745, Article 80 on the reporting of events in clinical investigations
- Implementing Decision (EU) 2021/1182 as amended, list of harmonized standards for the MDR
