Gap Analysis: ISO 14155:2026 (GCP), the leading international standard for global medical device clinical research, vs. the 2020 edition

This revision of the international standard ISO 14155 for medical device clinical trials is a major update following the 2020 edition (Edition 4)

This document specifies Good Clinical Practice (GCP) for the design, conduct, recording, and reporting of clinical investigations in human subjects to evaluate the clinical performance, safety, and effectiveness of medical devices. For post-market clinical investigations, given the nature of the study, the principles set out in this document should be followed to the relevant extent (see Annex A). The general requirements set out in this document are intended to:

Protect the rights, safety, and well-being of human subjects, users, or other persons;
Ensure the scientific validity of the clinical investigation and the credibility of its results;
Clarify the responsibilities of the sponsor and principal investigator;
Provide guidance for sponsors, investigators, ethics committees, regulatory authorities, and other bodies involved in medical device conformity assessment.

I. The following is the scope and contents of the updated ISO 14155:2026

Table  of Contents	Title
	Foreword
	Introduction
1	Scope
2	Normative references
3	Terms and definitions
4	Summary of good clinical  practice principles
5	Ethical considerations
5.1	General
5.2	Improper influence or  inducement
5.3	Compensation and additional  health care
5.4	Registration in publicly  accessible database
5.5	Responsibilities
5.6	Communication with the ethics  committee
5.7	Vulnerable populations
5.8	Informed consent
6	Clinical investigation  planning
6.1	General
6.2	Risk management
6.3	Justification for the design  of the clinical investigation
6.4	Clinical investigation plan
6.5	Investigator's brochure
6.6	Case report forms
6.7	Monitoring plan
6.8	Investigation site selection
6.9	Agreement(s)
6.10	Labelling
6.11	Data monitoring committee
6.12	Clinical events committee
7	Clinical investigation conduct
7.1	General
7.2	Investigation site initiation
7.3	Investigation site monitoring
7.4	Adverse events and device  deficiencies
7.5	Clinical investigation  documents and documentation
7.6	Additional members of the  investigation site team
7.7	Subject privacy and  confidentiality of data
7.8	Document and data control
7.9	Investigational device  accountability
7.10	Accounting for subjects
7.11	Auditing
8	Suspension, termination and  close-out of the clinical investigation
8.1	Completion of the clinical  investigation
8.2	Suspension or premature  termination of the clinical investigation
8.3	Routine close-out
8.4	Clinical investigation report
8.5	Risk assessment and  conclusions
8.6	Document retention
9	Responsibilities of the  sponsor
9.1	Clinical quality management
9.2	Clinical investigation  planning and conduct
9.3	Outsourcing of duties and  functions
9.4	Communication with regulatory
10	Responsibilities of the  principal investigator
10.1	General
10.2	Qualification of the principal  investigator
10.3	Qualification of investigation  site
10.4	Communication with the EC
10.5	Informed consent process
10.6	Compliance with the CIP
10.7	Medical care of subjects
10.8	Safety reporting
Annex A	Clinical investigation plan
A.1	General
A.2	Identification and description  of the investigational device
A.3	Justification for the design  of the clinical investigation
A.4	Benefits and risks
A.5	Objectives and hypotheses
A.6	Design of the clinical  investigation
A.7	Statistical design and  analysis
A.8	Data management
A.9	Amendments to the CIP
A.10	Deviations from clinical  investigation plan
A.11	Device accountability
A.12	Statements of compliance
A.13	Informed consent process
A.14	Adverse events
A.15	Vulnerable population
A.16	Suspension or termination
A.17	Publication policy
A.18	Bibliography
Annex B	Investigator's brochure
B.1	General
B.2	Device information
B.3	Preclinical testing
B.4	Existing clinical data
B.5	Risk management
B.6	Regulatory references
Annex C	Case report forms
C.1	General
C.2	Content and format
C.3	Procedural issues
Annex D	Clinical investigation report
D.1	General
D.2	Cover page
D.3	Table of contents
D.4	Summary
D.5	Introduction
D.6	Methods
D.7	Results
D.8	Discussion
D.9	Terms
D.10	Ethics
D.11	Investigators
D.12	Signature
D.13	Annexes
Annex E	Essential documents
Annex F	Adverse event categorization
Annex G	EC responsibilities
Annex H	ISO 14971 application
Annex I	Clinical development stages
Annex J	Audits
Annex K	Design considerations
	Bibliography

2. Interpretation of the key revisions in ISO 14155 Fourth Edition: clinical trial governance is moving from “mere compliance completion” to more granular risk management

Based on the source excerpt provided here, the strongest signal the ISO 14155 Fourth Edition sends to the industry is not that the framework has been torn up and rewritten, but that, while preserving continuity with the existing GCP framework, the standard is further clarifying, grounding, and making executable a number of key issues that were previously handled too broadly.

The most noteworthy change is the revision to the definition of “clinical performance.” Clinical performance is no longer just an abstract discussion of whether a device functions; it is now more explicitly linked to the device’s technical/functional characteristics, the manufacturer’s claimed intended use, and whether it can ultimately deliver clinical benefit. This means that, when designing clinical trials, defining endpoints, and drafting protocols and reports, companies can no longer stop at the level of “function achieved” and must more clearly demonstrate why the device can produce meaningful outcomes in the target clinical setting--This signal is perfectly aligned with the key elements of EU clinical evaluation and is interconnected with them—they reinforce one another.

The second notable change:

is the further refinement of subject protection requirements. The source specifically emphasizes that, where applicable, informed consent should be obtained by the subject’s legally designated representative; subjects should also be given the opportunity to discuss participation in the trial with others, such as family members. Although this appears to be a wording change, it in fact reflects the standard’s greater emphasis on the authenticity, sufficiency, and human-centered nature of the informed consent process, rather than merely the completion of a signed form.

The third change:

is a further breakdown and clarification of the risk management logic. The standard now clearly distinguishes between two types of risk: one related to device use, and another related to clinical procedures required by the clinical trial plan but not part of routine clinical practice; it also adds a requirement to assess residual risk. The direct impact of this revision on sponsors is that the risk management file, CIP, subject information materials, and adverse event determination pathways must achieve true consistency, and a single generic risk description can no longer be used to cover all scenarios.

The fourth direction worth attention:

is the strengthening of the clinical trial governance structure. The Fourth Edition adds provisions for Clinical Event Committees (CEC) and reinforces the role of Data Monitoring Committees (DMC), for example by requiring the DMC to confirm the conditions for pausing or stopping a trial; if no DMC is established, the reason must be explained. This shows that the standard is placing increasing emphasis on consistency in critical event adjudication and on independent oversight during study conduct.

Fifth:

This revision clearly strengthens requirements for protocol design and statistical rigor. The source adds requirements for non-inferiority margins, missing data, estimands and their attributes, and updates the methods and timing for variable assessment, recording, and analysis in the CIP, while also adding device calibration requirements.For companies, this means that clinical trials can no longer focus only on site-level execution; they must also address statistical assumptions, endpoint definitions, data integrity, and measurement consistency upfront.

Sixth:

The fourth edition also provides more granular requirements for safety reporting and clinical investigation suspension/termination management. The standard clarifies the circumstances in which less stringent adverse event reporting requirements may be applied, introduces additional adverse event categories related to device deficiencies, and further aligns the relationship among suspension, early termination, and the corresponding flowcharts. This will directly affect sponsors’ safety management SOPs, event escalation pathways, and communication interfaces with ethics committees/regulatory authorities.

Seventh:

This revision also reflects a trend toward better alignment with real-world regulatory requirements, for example by clarifying local representative-related content and adding implant card requirements. From a regulatory practice perspective, these changes indicate that ISO 14155 is further strengthening its interoperability with national/regional requirements, making the standard not merely a set of high-level principles, but increasingly an implementation-oriented framework that can directly support regulatory submission and review communications.

In summary, this revision can be distilled into three key points:

First, subject protection requirements are more detailed;

Second, the boundaries of risk management are clearer;

Third, requirements for clinical investigation governance and statistics are more stringent.

For companies, CROs, investigators, and ethics committees, this means that future clinical investigation documentation must not only be “complete,” but also “consistent, traceable, executable, and interpretable.”

III. Overview of Changes in This Revision (Based on the Original Change List)

No.	Key revision point
1	Revised“the definition of clinical performance (3.12）”.
2	Clarified that deviations from subject eligibility criteria are not permitted; if changes are needed, they should be handled through revision of the Clinical Investigation Plan (CIP) (see 5.6.4）。
3	Clarified that, where applicable, informed consent should be obtained from the subject’s legally designated representative (see 5.8.1）。
4	Clarified that subjects should be given the opportunity to discuss participation in the investigation with others (e.g., family members) (see 5.8.2）。
5	Clarified risk management by explicitly distinguishing between two categories of risk: one related to device use, and the other arising from procedures required by CIP but not part of routine clinical practice (see 6.2.1）。
6	Added a requirement to assess residual risk (see 6.2.2）。
7	Corrected the reference wording relating to risks associated with use of the investigational device (see 6.2.1、7.4.4、8.2, Annex F, Annex H and 3.2）。
8	moved certain requirements previously located in Annex A into 6.4.
9	new requirement: the Data Monitoring Committee (DMC) should confirm the conditions for suspending or stopping the clinical investigation (see  6.11）。
10	added a “Clinical Events Committee (CEC）” section (see  3.8、6.12 and A.14）。
11	clarified the circumstances in which reduced adverse event reporting requirements may apply (see  7.4.2）。
12	added requirements for managing risks associated with  CIP clinical procedures required as part of the clinical investigation (see  7.4.5）。
13	in conjunction with the updated  7.4.4  and Figure  H.1, further clarified the process for suspension or early termination of a clinical investigation (see  8.2）。
14	updated    CIP In the“procedures”section, supplemented the methods and timing for variable assessment, recording, and analysis, and added equipment calibration requirements (see A.6.4）。
15	Clarified the requirements for the non-inferiority margin and missing data handling (see A.7）。
16	Added a requirement: if no DMCis set, the rationale should be explained (see A.14）。
17	Added a requirement that subject follow-up and ongoing care should include elements that differ from routine practice (see A.16）。
18	Clarified the“local representative”related content to better align with national regulatory requirements (see 9.2.1）。
19	Added implant card requirements (see 9.2.2）。
20	Consolidated the general requirements for study objectives and study design into 6.4(see A.5）。
21	Updated the adverse event classification and clarified terminology in Figure F.1.
22	Appendix H was updated according to 6.2.1, and Figure H.1 was updated accordingly.
23	Introduced principles for the estimand and its attributes (see 6.4, A.5, A.6, A.7, and Appendix   K).
24	Added notes (see B.5), training information for use of the investigational device (see B.2), and in-silico   testing (see B.3).
25	Added the category of “adverse events related to device deficiencies” — Figures F.1 and F.2 now both apply.

IV. The following is a summary of the key updates or revisions:

4.1 “Major changes” in the foreword

The fourth edition supersedes and replaces the third edition (ISO 14155:2020) and has been technically revised. The principal changes are as follows:

The definition of “clinical performance (3.12)” has been revised.
It has been clarified that deviations from subject eligibility criteria are not permitted; if changes are needed, they shall be handled through a Clinical Investigation Plan (CIP) amendment (see 5.6.4).
It has been clarified that, where applicable, informed consent should be obtained by the subject’s legally designated representative (see 5.8.1).
It has been clarified that subjects should be given the opportunity to discuss whether to participate in the study with others, such as family members (see 5.8.2).
Risk management has been clarified by explicitly distinguishing between two types of risk: risks associated with the use of the device, and risks arising from procedures required by the CIP but not part of routine clinical practice (see 6.2.1).
A requirement to assess residual risk has been added (see 6.2.2).
Reference wording relating to risks associated with the use of the investigational device has been corrected (see 6.2.1, 7.4.4, 8.2, Annex F, Annex H, and 3.2).
Some requirements previously located in Annex A have been moved to 6.4.
New requirement: the Data Monitoring Committee (DMC) shall confirm the conditions for pausing or stopping the clinical trial (see 6.11).
A new “Clinical Events Committee (CEC)” section has been added (see 3.8, 6.12, and A.14).
The circumstances under which reduced adverse event reporting requirements may apply have been clarified (see 7.4.2).
A requirement has been added to manage risks associated with clinical procedures required by the CIP(see 7.4.5).
The process for pausing or early terminating a clinical trial has been further clarified in conjunction with the updated 7.4.4 and Figure H.1 (see 8.2).
The “procedures” section in the CIP has been updated to add methods and timing for assessing, recording, and analyzing variables, and a new equipment calibration requirement has been added (see A.6.4).
The requirements for non-inferiority margins and handling missing data have been clarified (see A.7).
A new requirement has been added: if no DMC is established, the rationale shall be stated (see A.14).
A new requirement has been added: subject follow-up and ongoing care should include elements that differ from routine practice (see A.16).
The provisions related to the “local representative” have been clarified to better align with national regulatory requirements (see 9.2.1).
A new implant card requirement has been added (see 9.2.2).
General requirements on study objectives and study design have been moved into 6.4 (see A.5).
Updated adverse event classification and clarified terminology in Figure F.1.
Appendix H was updated in accordance with 6.2.1, and Figure H.1 was updated accordingly.
Introduced the principles for the estimand (estimand) and its attributes (see 6.4, A.5, A.6, A.7, and Annex K).
Added notes (see B.5), information on training in the use of the investigational device (see B.2), and in-silico testing (see B.3).
Added a new category of “adverse events related to device deficiencies” — Figures F.1 and F.2 now both apply.

4.2 Introduction

For the purposes of this document, the term “compliance” is used when the clinical trial requirements and Good Clinical Practice specified in this document are required to be met; the term “conformance with” is used when referring to requirements specified in regulatory documents or other standards.

4.3 Scope

This document specifies Good Clinical Practice (GCP) for the design, conduct, recording, and reporting of clinical trials in human subjects to evaluate the clinical performance or effectiveness and safety of medical devices.

For post-market clinical trials, the principles set out in this document should be followed, to the relevant extent, taking into account the nature of the trial (see Annex I).

The general requirements specified in this document are intended to:

protect the rights, safety, and well-being of subjects, users, or other persons;
ensure the scientific conduct of the clinical trial and the credibility of the clinical trial results;
define the responsibilities of the sponsor and the principal investigator;
assist sponsors, investigators, ethics committees, regulatory authorities, and other bodies involved in device conformity assessment.

Other standards or national requirements may also apply to the investigational device or clinical trial under study.

Note: For software as a medical device (SaMD), where appropriate, evidence of its analytical validity (i.e. that the SaMD outputs are accurate for a given input), scientific validity (i.e. that the SaMD outputs are relevant to the intended clinical condition/physiological state), and clinical performance (i.e. that there is a clinically meaningful association between the SaMD outputs and the intended use) may be demonstrated in the relevant scope of this document (see Reference [5]). Where certain requirements of this document are not applicable, the rationale for exemption may take into account the unique nature of the “indirect contact” between the subject and the SaMD.

This document does not apply to in vitro diagnostic medical devices. However, in certain cases, depending on the characteristics of the device and national/regional requirements, users of this document may consider whether specific clauses, specific requirements, or both in this document are applicable.

4.4 Normative references

The following documents, through normative reference in this document, constitute part of the requirements of this document. For dated references, only the edition cited applies; for undated references, the latest edition (including all amendments) applies.

ISO 14971, Medical devices — Application of risk management to medical devices

4.5 Terms and definitions

The following terms and definitions apply in this document. ISO and IEC maintain terminology databases for standardization at the following addresses:

— ISO Online Browsing Platform: https://www.iso.org/obp

— IEC Electropedia：https://www.electropedia.org/

3.1 Adverse device effect (ADE)

An adverse event (3.2) related to the use of an investigational medical device (3.30).

Note: This definition includes adverse events resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, operation, or any malfunction (3.34) of the investigational medical device.

Note: This definition includes any event resulting from use error (3.53) or intentional misuse of the investigational medical device.

Note: If the comparator (3.13) is a medical device, this definition also applies to the “comparator.”

3.2 Adverse event (AE)

Any untoward medical occurrence, unintended disease or injury, or any unfavorable clinical sign (including an abnormal laboratory finding) occurring in a subject (3.51), user, or other person, whether or not related to the use of an investigational medical device (3.30) and whether or not expected.

Note: This definition includes events related to the use of the investigational medical device or comparator (3.13), as well as events resulting from clinical procedures required by the clinical investigation plan (CIP) (3.10) that are beyond routine clinical practice but are not related to the use of the device itself.

Note: For users or other persons, this definition is limited to events related to the use of the investigational medical device or comparator.

3.3 Audit

A systematic examination by independent (3.27) persons of activities and documents related to a clinical investigation (3.9) to determine whether those activities were conducted in accordance with the clinical investigation plan (CIP) (3.10), standard operating procedures, this document, and applicable regulatory requirements, and whether the relevant data were recorded, analyzed, and accurately reported.

3.4 Audit trail

A documented record that can reconstruct the sequence of events.

3.5 Blinding/masking

A procedure that prevents one or more parties to the clinical investigation (3.9) from knowing the treatment assignment.

Note: Single blinding usually means that the subject (3.51) does not know the treatment assignment; double blinding usually means that the subject, investigator (3.31), monitor, and, in some cases, the central assessor do not know the treatment assignment.

Note: If assessment of at least the primary endpoint (3.23) is performed without knowing whether the subject received the investigational medical device (3.30) or the comparator (3.13), the clinical investigation is described as “observer-blinded.”

3.6 Case report form (CRF)

A paper, optical, or electronic set of documents designed for each subject (3.51) to record the information required by the clinical investigation plan (CIP) (3.10) to be reported to the sponsor (3.50).

3.7 Certified copy

A copy, regardless of the medium used, of the original record that has been verified, for example by dated signature or by a validated process, to have the same information as the original record, including data describing the context, content, and structure of the original record.

3.8 Clinical Event Committee (CEC) / Central Event Committee / Clinical Adjudication Committee (CAC) / Endpoint Adjudication Committee (EAC)

An independent (3.27) committee of clinical experts established by the sponsor (3.50) to ensure consistent assessment of events across participating centers and to reduce the risk of underreporting.

3.9 Clinical investigation / clinical trial / clinical study

A systematic investigation conducted in one or more subjects (3.51) to evaluate the clinical performance (3.12), effectiveness (3.20), or safety of a medical device (3.35).

3.10 Clinical investigation plan (CIP) / protocol

A document stating the rationale, objectives (3.38), design, and predefined analysis, methodology, organization, monitoring (3.36), conduct, and record-keeping of a clinical investigation (3.9).

Note: Because the term “protocol” has multiple meanings and may differ from country to country, this document uses the term “CIP.”

3.11 Clinical investigation report

A document describing the design, conduct, statistical analysis, and results of a clinical investigation (3.9).

3.12 Clinical performance

The ability of a medical device (3.35), when used in accordance with the manufacturer’s intended use, to achieve the intended purpose claimed by the manufacturer through any direct or indirect medical effect derived from its technical or functional characteristics, including diagnostic characteristics, thereby providing a clinical benefit to the subject (3.51).

Note: Clinical performance may be defined by national regulations.

Note: Not all clinical investigations provide a clinical benefit to the subject, for example studies in healthy volunteers, clinical investigations that collect data only, and the like.

3.13 Comparator

A medical device (3.35), therapeutic measure (such as active treatment or routine clinical practice), placebo, sham procedure, or no treatment used in the control group (3.15) of a clinical investigation (3.9).

3.14 Contract research organization (CRO)

An individual or organization contracted by the sponsor (3.50) to perform one or more sponsor duties and functions related to clinical investigations.

3.15 Control group

The group of subjects (3.51) receiving the comparator (3.13).

Note: The control group may be a concurrent control, historical control, or the subjects themselves may serve as controls.

3.16 Coordinating investigator / national investigator / global investigator

An investigator (3.31) designated by the sponsor (3.50) to assist in coordinating activities in a multicenter clinical investigation (3.9).

3.17 Data Monitoring Committee (DMC/DSMB/IDMC/DSMC)

An independent (3.27) committee established by the sponsor (3.50) to assess at intervals the progress of the clinical investigation (3.9), safety data, or key clinical performance (3.12)/effectiveness (3.20) endpoints (3.23, 3.24), and to recommend to the sponsor whether to continue, suspend, modify, or stop the clinical investigation.

3.18 Deviation

An intentional or unintentional failure to comply with the requirements of the clinical investigation plan (CIP) (3.10).

3.19 Device deficiency

An insufficiency in a medical device (3.35) with respect to identity, quality, durability, reliability, usability, safety, or performance, including malfunction (3.34), use error (3.53), or insufficiency of information provided by the manufacturer (including labeling).

Note: This definition includes device deficiencies related to the investigational medical device (3.30) or comparator (3.13).

3.20 Effectiveness

The degree to which, in a proportion of the target population under the intended conditions of use, and when the investigational medical device (3.30) is used for its intended purpose in accordance with the instructions for use, the Investigator's Brochure (IB), and the Clinical Investigation Plan (CIP) (3.10), the clinically meaningful expected results identified on the basis of documented scientific evidence are achieved.

3.21 Electronic clinical data system

Hardware and software, including related documentation such as user manuals, that create, modify, maintain, archive, retrieve, or transmit in digital form information related to the conduct of a clinical investigation (3.9).

3.22 Electronic record

Any combination of text, graphics, data, audio, images, or other information, in digital form, that is created, modified, maintained, archived, retrieved, or distributed by an electronic clinical data system (3.21).

Example: electronic case report form (CRF).

3.23 Endpoint — primary endpoint

The main variable used to provide evidence of clinical performance (3.12), effectiveness (3.20), or safety in a clinical investigation (3.9).

3.24 Endpoint — secondary endpoint

A variable used to assess the secondary objective(s) (3.38) of a clinical investigation (3.9).

3.25 Ethics committee (EC)/research ethics committee/independent ethics committee/institutional review board

An independent (3.27) body responsible for reviewing a clinical investigation (3.9), with the purpose of protecting the rights, safety, and well-being of human subjects (3.51) participating in the clinical investigation.

Note: Regulatory requirements for ethics committees or similar bodies differ across countries or regions.

3.26 Hypothesis

A testable statement derived from the objective(s) (3.38) of a clinical investigation (3.9), based on a prespecified statistical test and used to draw conclusions regarding that objective.

Note: The primary hypothesis is based on a predefined primary endpoint (3.23) and is typically used for sample size calculation.

3.27 Independent

Not involved in the development of the investigational device or the conduct of the clinical investigation (3.9), except as necessary to fulfill a specific responsibility, in order to avoid bias or conflicts of interest.

3.28 Informed consent

The process by which an individual voluntarily confirms willingness to participate in a clinical investigation (3.9), after having been informed of all aspects relevant to the decision on whether to participate.

3.29 Investigational site/study site

The institution or site where a clinical investigation (3.9) is conducted.

3.30 Investigational medical device

A medical device (3.35) whose safety, clinical performance (3.12), or effectiveness (3.20) is being evaluated in a clinical investigation (3.9).

Note: This includes marketed medical devices being evaluated for a new intended use, a new population, a new material, or a design change.

Note: This includes marketed medical devices being evaluated within their established intended use in a post-market clinical investigation (interventional or non-interventional).

3.31 Investigator

An individual member of the investigational site (3.29) study team who is designated and supervised by the principal investigator (3.40) to perform clinical investigation-related procedures or to make important clinical investigation and medical decisions.

Note: Members of the investigational site team may also be referred to as "sub-investigators" or "co-investigators."

3.32 Investigator's Brochure (IB)

A compilation of the current clinical and non-clinical information on the investigational medical device (3.30) relevant to the clinical investigation (3.9).

3.33 Legally designated representative

An individual, judicial body, or other body authorized under applicable law to consent, on behalf of a prospective subject (3.51), to that subject's participation in a clinical investigation (3.9).

Note: "Legally authorized representative" or "legally acceptable representative" are other terms used in national regulations for this concept, but this document does not use those terms.

3.34 Malfunction

Failure of the investigational medical device (3.30) to perform as intended when used in accordance with the instructions for use, the Clinical Investigation Plan (CIP) (3.10), or the Investigator's Brochure (IB) (3.32).

3.35 Medical device

An instrument, apparatus, implement, machine, implant, reagent for in vitro use, software, material, or other similar or related article intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the following specific purposes: diagnosis, prevention, monitoring, treatment, or alleviation of disease; diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury; investigation, replacement, modification, or support of the anatomy or of a physiological process; life support or life-sustaining; control of conception; disinfection of medical devices; providing information by means of in vitro examination of specimens derived from the human body; and which does not achieve its primary intended action in or on the human body by pharmacological, immunological, or metabolic means, but may be assisted in its function by such means.

Note: Products that can be considered medical devices in some jurisdictions, but not necessarily in others, include disinfecting substances, aids for persons with disabilities, devices incorporating animal and/or human tissues, and devices for in vitro fertilization or assisted reproductive technologies.

Source: modified from ISO 13485:2016, 3.11.

3.36 Monitoring

The act of overseeing the progress of a clinical investigation (3.9) to ensure that it is conducted, recorded, and reported in accordance with the Clinical Investigation Plan (CIP) (3.10), written procedures, this document, and applicable regulatory requirements.

Note: Centralized monitoring can provide additional monitoring capability through remote assessment of aggregated data and overall study compliance, and can supplement or reduce the scope and frequency of on-site monitoring.

3.37 Multicentre study

A clinical investigation (3.9) conducted according to a single Clinical Investigation Plan (CIP) (3.10) and carried out at two or more investigational sites (3.29).

3.38 Objective

The main purpose for conducting a clinical investigation (3.9).

3.39 Enrolment time point

The time point at which the subject (3.51) signs and dates the informed consent form (3.28), after completion of recruitment (3.44) and before any clinical investigation-related procedures are performed.

3.40 Principal investigator

A qualified individual responsible for conducting a clinical investigation (3.9) at a given investigational site (3.29).

NOTE If a clinical investigation at an investigational site is conducted by a team, the principal investigator is responsible for leading that team.

NOTE Whether this responsibility is assumed by an individual or an institution can depend on national regulations.

3.41 Quality assurance

Planned and systematic actions established to ensure that a clinical investigation (3.9) is conducted and that the related data are generated, documented (recorded), and reported in compliance with this document and applicable regulatory requirements.

3.42 Quality control

Operational techniques and activities undertaken within the quality assurance (3.41) system to verify that the quality requirements for clinical investigation-related activities have been fulfilled.

3.43 Randomization

The process of assigning subjects (3.51) to the investigational medical device (3.30) group or the control group (3.15) on the basis of chance, using predetermined and accepted statistical methods, in order to achieve unpredictable allocation and reduce bias.

3.44 Recruitment

Activities to actively identify subjects (3.51) who are suitable for inclusion in a clinical investigation (3.9).

3.45 Serious adverse device effect (SADE)

An adverse device effect (3.1) that has resulted in consequences characteristic of a serious adverse event (3.46).

3.46 Serious adverse event (SAE)

An adverse event (3.2) that resulted in any of the following: a) death; b) serious deterioration in the health of the subject (3.51), user, or other person, as evidenced by one or more of the following: 1) a life-threatening illness or injury; 2) permanent impairment of a body structure or a body function, including chronic disease; 3) hospitalization or prolongation of hospitalization; 4) medical or surgical intervention to prevent a life-threatening illness or injury, or permanent impairment to a body structure or a body function; c) fetal distress, fetal death, congenital abnormality, or birth defect, including physical or mental impairment.

NOTE Planned hospitalization for a pre-existing condition, or a procedure required by the Clinical Investigation Plan (CIP) (3.10), without serious deterioration in health, is not considered a serious adverse event.

3.47 Serious health threat

Any adverse event (3.2) or device deficiency (3.19) that signals an imminent risk of death or serious deterioration in health among subjects (3.51), users, or other persons, and requires prompt remedial action to protect other subjects, users, or other persons.

NOTE A serious health threat includes events of significant and unexpected nature whose severity is sufficient to cause alarm, constituting a potential major public health hazard or the possibility of multiple deaths occurring within a short period of time.

3.48 Source data

All information in original records, or certified copies (3.7) thereof, relating to clinical findings, observations, or other activities in a clinical investigation (3.9), which is necessary for the reconstruction and evaluation of that clinical investigation.

NOTE This definition includes source data initially recorded in electronic format.

3.49 Source documents

Original documents, or certified copies (3.7), of paper, optical, or electronic files containing source data (3.48).

EXAMPLE Medical records, laboratory records, device accountability records, photographic negatives, X-ray films, and records maintained at investigational sites (3.29), laboratories, and biomedical engineering technical departments participating in the clinical investigation (3.9).

3.50 Sponsor

An individual, company, institution, or organization that assumes responsibility and liability for the initiation and management of a clinical investigation (3.9) and arranges financial support.

NOTE When an investigator (3.31) initiates, conducts, and assumes full responsibility for a clinical investigation, that investigator also assumes the role of sponsor and is referred to as a "sponsor-investigator."

3.51 Subject

An individual who is or is about to become a participant in a clinical investigation (3.9), taking part in the study as a recipient of the investigational medical device (3.30) or the control article (3.13).

NOTE A subject can be a healthy volunteer.

3.52 Unanticipated serious adverse device effect (USADE)

A serious adverse device effect (3.45) whose nature, incidence, severity, or outcome has not been identified in the current risk assessment.

NOTE An anticipated serious adverse device effect (ASADE) is an effect whose nature, incidence, severity, or outcome has been identified in the risk assessment.

3.53 Use error

An act or omission by the user while using a medical device (3.35) that leads to a different result from that intended by the manufacturer or expected by the user.

NOTE Use error includes the user's failure to complete a task.

NOTE Use error can be caused by a mismatch between user characteristics, the user interface, the task, or the use environment.

NOTE The user can be aware or unaware that a use error has occurred.

NOTE An unexpected physiological response by the patient is not, by itself, considered a use error.

NOTE A medical device malfunction that leads to an unintended result is not considered a use error.

Source: ISO 14971:2019, 3.30.

3.54 Validation

Confirmation, through examination and the provision of objective evidence, that the specific requirements for a particular intended use can be consistently fulfilled.

3.55 Verification

Confirmation, through examination and the provision of objective evidence, that specified requirements have been fulfilled.

3.56 Vulnerable subject

An individual who, due to physical, social, economic, or environmental factors or processes, is in a disadvantaged position, expects to benefit or fears retaliation, and is therefore unable to fully understand all aspects relevant to the decision of whether to participate in a clinical investigation, or who can be manipulated or subjected to undue influence.

The above is the interpretation and summary of the main changes and updates in this ISO4155 revision, Compliance PathManman, “Global medical-device regulation is shifting from ‘compliance is enough’ to ‘evidence is king,’ and clinical trial andclinical evaluationcapabilities, are becoming a core competitive advantage for companies expanding overseas.”

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Reference:

[1]	ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process
[2]	ISO 13485:2016, Medical devices — Quality management systems — Requirements for regulatory purposes
[3]	ISO 15223-1, Medical devices — Symbols to be used with information to be supplied by the manufacturer — Part 1: General requirements
[4]	ISO/TR 24971, Medical devices — Guidance on the application of ISO 14971
[5]	Software as a Medical Device (SaMD): Clinical Evaluation [IMDRF/ SaMD WG/ N41 FINAL:2017], available at: https://www.imdrf.org/docs/imdrf/final/technical/imdrf-tech-170921-samd-n41-clinical-evaluation_1.pdf
[6]	International Medical Device Regulators Forum. Clinical Evaluation [MDCE WG/N56 FINAL:2019], available at: https://www.imdrf.org/documents/clinical-evaluation
[7]	International Medical Device Regulators Forum. Essential Principles of Safety and Performance of Medical Devices and IVD medical devices [GRRP WG/ N47 FINAL:2018], available at: https://www.imdrf.org/sites/default/files/docs/imdrf/final/technical/imdrf-tech-181031-grrp-essential-principles-n47.pdf
[8]	Declaration of Helsinki. available at: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
[9]	MEDDEV 2.7.1, Clinical Evaluation: A Guide for Manufacturers and Notified Bodies, available at: https://ec.europa.eu/docsroom/documents/17522/attachments/1/translations/
[10]	Design considerations for pivotal clinical investigations for medical devices – guidance for industry, clinical investigators, institutional review boards and Food and Drug Administration staff, November 7, 2013, available at: https://www.fda.gov/media/87363/download
[11]	Exemptions I.D. (IDEs) for early feasibility medical device clinical studies, including certain first in human (FIH) studies, guidance for industry and Food and Drug Administration staff, October 1, 2013, available at: https://www.fda.gov/training-and-continuing-education/ cdrh-learn/ transcript-ides-early-feasibility-medical-device-clinical-studies-including-first-human-fih-studies
[12]	Oversight of clinical investigations — A risk-based approach to monitoring, August 2013, available at: https://www.fda.gov/downloads/Drugs/Guidances/UCM269919.pdf
[13]	A risk based approach to monitoring clinical investigations – questions and answers, April 2023. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ A Risk-Based-Approach- to-Monitoring-of-Clinical-Investigations-Questions-and-Answers
[14]	FDA guidance for industry; Electronic Source Data in Clinical Investigations; September 2013, available at: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm328691.pdf
[15]	MHRA Guidance on legislation; clinical investigations of medical devices – statistical guidance; May 2021, available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1097800 /Statistical_considerations_clinical_investigations_-_May_2021.pdf
[16]	Guideline on data monitoring committees, available at: https://www.ema.europa.eu/documents/scientific-guideline/guideline-data-monitoring-committees_en.pdf
[17]	Patient Engagement in the Design and Conduct of Medical Device Clinical Studies. Guidance for Industry, Food and Drug Administration Staff, and Other Stakeholders Document issued on January 26, 2022). Available from: https://www.fda.gov/regulatory-information/ search-fda-guidance-documents /patient-engagement-design-and-conduct-medical-device-clinical-studies
[18]	E9(R1) Statistical Principles for Clinical Trials. Addendum: Estimands and Sensitivity Analysis in Clinical Trials). Available from: https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf

The “Global GCP Standard” for Medical Device Clinical Trials, ISO 14155:2026, Has Been Officially Released