• adverse event related to the use of an investigational medical device

NOTE 1 This definition includes adverse events resulting from insufficient or inadequate instructions for use, deployment, implantation, installation, or operation, or any malfunction of the investigational medical device.

NOTE 2 This definition includes any event resulting from use error or from intentional misuse of the investigational medical device.

-ISO14155 3.1

• In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). -ICH E6(R2) 1.1

• Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). -ICH E6(R2) 1.2

• any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device

NOTE 1 This definition includes events related to the investigational medical device or the comparator.

NOTE 2 This definition includes events related to the procedures involved.

NOTE 3 For users or other persons, this definition is restricted to events related to investigational medical devices.

-ISO14155 3.2

• See Protocol Amendment.  -ICH E6(R2) 1.3

• Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.   -ICH E6(R2) 1.4

• The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements.   -ICH E6(R2) 1.5

• A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).    -ICH E6(R2) 1.6

• systematic independent examination of activities and documents related to clinical investigation to determine whether these activities were conducted, and the data recorded, analysed and accurately reported, according to the CIP, standard operating procedures, this International Standard and applicable regulatory requirements  -ISO14155 3.3

• A declaration of confirmation by the auditor that an audit has taken place.     -ICH E6(R2) 1.7

• A written evaluation by the sponsor's auditor of the results of the audit.   -ICH E6(R2) 1.8

• Documentation that allows reconstruction of the course of events.   -ICH E6(R2) 1.9

• procedure in which one or more parties to the clinical investigation are kept unaware of the treatment assignment(s)

NOTE Single blinding usually refers to the subject(s) being unaware of the treatment assignment(s). Double blinding usually refers to the subject(s), investigator(s), monitor and, in some cases, centralized assessors being unaware of the treatment assignment(s). -ISO14155 3.4

• set of printed, optical or electronic documents for each subject on which information to be reported to the sponsor is recorded, as required by the CIP -ISO14155 3.5

• A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original.  -ICH E6(R2) 1.63

• systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a medical device

NOTE “Clinical trial” or “clinical study” are synonymous with “clinical investigation”.  

-ISO14155 3.6

• document that state(s) the rationale, objectives, design and proposed analysis, methodology, monitoring, conduct and record-keeping of the clinical investigation

NOTE The term “protocol” is synonymous with “CIP”. However, protocol has many different meanings, some not related to clinical investigation, and these can differ from country to country. Therefore, the term CIP is used in this International Standard.    

-ISO14155 3.7

• document describing the design, execution, statistical analysis and results of a clinical investigation  -ISO14155 3.8

• behaviour of a medical device or response of the subject(s) to that medical device in relation to its intended use, when correctly applied to appropriate subject(s)    -ISO14155 3.9

• Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.   -ICH E6(R2) 1.12

• A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).    -ICH E6(R2) 1.13

• medical device, therapy (e.g. active control), placebo or no treatment, used in the reference group in a clinical investigation  -ISO14155 3.10

• Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements.  -ICH E6(R2) 1.15

• Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity.  -ICH E6(R2) 1.16

• A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.   -ICH E6(R2) 1.17

• person or organization contracted by the sponsor to perform one or more of the sponsor's clinical investigation-related duties and functions  -ISO14155 3.11

• A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.   -ICH E6(R2) 1.18

• investigator who is appointed by the sponsor to coordinate work in a multicentre clinical investigation  ISO14155 3.12

• independent committee that may be established by the sponsor to assess, at intervals, the progress of the clinical investigation, the safety data or the critical performance endpoints and to recommend the sponsor whether to continue, suspend, modify, or stop the clinical investigation

NOTE Examples of DMCs are “data safety monitoring board (DSMB)” or “data safety monitoring committee (DSMC)”.   

-ISO14155 3.13

• instance(s) of failure to follow, intentionally or unintentionally, the requirements of the CIP   -ISO14155 3.14

• inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or performance

NOTE Device deficiencies include malfunctions, use errors, and inadequate labelling.  

-ISO14155 3.15

• Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.     -ICH E6(R2) 1.21

• All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.   -ICH E6(R2) 1.22

• 〈primary〉 principal indicator(s) used for assessing the primary hypothesis of a clinical investigation   -ISO14155 3.16

• 〈secondary〉 indicator(s) used for assessing the secondary hypotheses of a clinical investigation   -ISO14155 3.17

• Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial).   -ICH E6(R2) 1.23

• independent body whose responsibility it is to review clinical investigations in order to protect the rights, safety and well-being of human subjects participating in a clinical investigation

NOTE For the purposes of this International Standard, “ethics committee” is synonymous with “research ethics committee”, “independent ethics committee” or “institutional review board”. The regulatory requirements pertaining to ethics committees or similar institutions vary by country or region.   

-ISO14155 3.18

• A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.  -ICH E6(R2) 1.24

• testable statement, resulting from the objective, regarding the investigational medical device safety or performance that is used to design the clinical investigation and that can be accepted or rejected based on results of the clinical investigation and statistical calculations

NOTE The primary hypothesis is the determinant of the investigational medical device safety or performance parameters and is usually used to calculate the sample size. Secondary hypotheses concerning other points of interest can also be evaluated.  

-ISO14155 3.19

• A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.   -ICH E6(R2) 1.26

• not involved in the conduct of a clinical investigation, except for their specifically assigned responsibilities, in order to avoid bias or a conflict of interest  -ISO14155 3.20

• An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.  -ICH E6(R2) 1.25

• An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.   -ICH E6(R2) 1.27

• A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.   -ICH E6(R2) 1.28

• process by which an individual is provided information and is asked to voluntarily participate in a clinical investigation  

NOTE Informed consent is documented by means of a written, signed and dated informed consent form.

 -ISO14155 3.21

• The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).   -ICH E6(R2) 1.29

• Any public or private entity or agency or medical or dental facility where clinical trials are conducted.    -ICH E6(R2) 1.30

• An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.    -ICH E6(R2) 1.31

• A report of intermediate results and their evaluation based on analyses performed during the course of a trial.    -ICH E6(R2) 1.32

• institution or site where the clinical investigation is carried out

NOTE For the purpose of this International Standard, “investigation site” is synonymous with “investigation centre”.   

 -ISO14155 3.22

• medical device being assessed for safety or performance in a clinical investigation

NOTE 1 This includes medical devices already on the market, that are being evaluated for new intended uses, new populations, new materials or design changes.

NOTE 2 In this International Standard, the terms “investigational medical device” and “investigational device” are usedinterchangeably.     

 -ISO14155 3.23

• A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.     -ICH E6(R2) 1.33

• individual member of the investigation site team designated and supervised by the principal investigator at an investigation site to perform critical clinical-investigation-related procedures or to make important clinical investigation- related decisions

NOTE An individual member of the investigation site team can also be called “sub-investigator” or “co-investigator”.  

 -ISO14155 3.24

• An expression meaning "the investigator and/or institution, where required by the applicable regulatory requirements".    -ICH E6(R2) 1.35

• compilation of the current clinical and non-clinical information on the investigational medical device(s), relevant to the clinical investigation   -ISO14155 3.25

• An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.    -ICH E6(R2) 1.37, ISO14155 3.26

• failure of an investigational medical device to perform in accordance with its intended purpose when used in accordance with the instructions for use or CIP -ISO14155 3.27

• any instrument, apparatus, implement, machine, appliance, implant, software, material, or other similar or related article

a) intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the specific purpose(s) of

   1) diagnosis, prevention, monitoring, treatment or alleviation of disease,

   2) diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury,

   3) investigation, replacement, modification, or support of the anatomy or of a physiological process,

   4) supporting or sustaining life,

   5) control of conception,

   6) disinfection of medical devices, and

b) which does not achieve its primary intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its intended function by such means

NOTE The term “medical device” is usually defined by national regulations. For the purposes of this International Standard, this definition does not list “in vitro diagnostic medical devices” (see ISO 13485:2003, definition 3.7[1]).

 -ISO14155 3.28

• act of overseeing the progress of a clinical investigation and to ensure that it is conducted, recorded, and reported in accordance with the CIP, written procedures, this International Standard, and the applicable regulatory requirements  -ISO14155 3.29

• A document that describes the strategy, methods, responsibilities, and requirements for monitoring the trial.     -ICH E6(R2) 1.64

• A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs.     -ICH E6(R2) 1.39

• A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator   -ICH E6(R2) 1.39, ISO14155 3.30

• Biomedical studies not performed on human subjects.    -ICH E6(R2) 1.41

• main purpose for conducting the clinical investigation   -ISO14155 3.31

• The judgement and/or the advice provided by an Independent Ethics Committee (IEC).    -ICH E6(R2) 1.42

• See Source Documents.    -ICH E6(R2) 1.43

• time at which, following recruitment, a subject signs and dates the informed consent form    -ISO14155 3.32

• qualified person responsible for conducting the clinical investigation at an investigation site

NOTE 1 If a clinical investigation is conducted by a team of individuals at an investigation site, the principal investigator is responsible for leading the team.

NOTE 2 Whether this is the responsibility of an individual or an institution can depend on national regulations.   

 -ISO14155 3.33

• A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments.    -ICH E6(R2) 1.44

• A written description of a change(s) to or formal clarification of a protocol.    -ICH E6(R2) 1.45

• All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).    -ICH E6(R2) 1.46

• The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.    -ICH E6(R2) 1.47

• process of assigning subjects to the investigational medical device or comparator groups using an established recognized statistical methodology to determine the assignment in order to reduce bias    -ISO14155 3.34

• active efforts to identify subjects who may be suitable for enrolment into the clinical investigation    -ISO14155 3.35

• Bodies having the power to regulate. In the ICH GCP Guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29). These bodies are sometimes referred to as competent authorities.    -ICH E6(R2) 1.49

• adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event   -ISO14155 3.36

• adverse event that

a) led to death,

b) led to serious deterioration in the health of the subject, that either resulted in

   1) a life-threatening illness or injury, or

   2) a permanent impairment of a body structure or a body function, or

   3) in-patient or prolonged hospitalization, or

   4) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function,

c) led to foetal distress, foetal death or a congenital abnormality or birth defect

NOTE Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious deterioration in health, is not considered a serious adverse event.  -ISO14155 3.37

• All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). -ICH E6(R2) 1.51,  ISO14155 3.38

• printed, optical or electronic document containing source data 

EXAMPLES Hospital records, laboratory notes, device accountability records, photographic negatives, radiographs, records kept at the investigation site, at the laboratories and at the medico-technical departments involved in the clinical investigation.   -ISO14155 3.39

• individual or organization taking responsibility and liability for the initiation or implementation of a clinical investigation

NOTE When an investigator initiates, implements and takes full responsibility for the clinical investigation, the investigator also assumes the role of the sponsor and is identified as the sponsor-investigator.   -ISO14155 3.40

• An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.  -ICH E6(R2) 1.54

• Detailed, written instructions to achieve uniformity of the performance of a specific function.   -ICH E6(R2) 1.55

• Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.   -ICH E6(R2) 1.56

• individual who participates in a clinical investigation

NOTE A subject can be either a healthy volunteer or a patient.    -ISO14155 3.41

• A unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial related data.    -ICH E6(R2) 1.58

• The location(s) where trial-related activities are actually conducted.    -ICH E6(R2) 1.59

• An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).     -ICH E6(R2) 1.60

• serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the current version of the risk analysis report

NOTE Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or outcome has been identified in the risk analysis report.      -ISO14155 3.42

• act or omission of an act that results in a different medical device response than intended by the manufacturer or expected by the user

NOTE 1 Use error includes slips, lapses, and mistakes.

NOTE 2 An unexpected physiological response of the subject does not in itself constitute a use error.

[ISO 14971:2007, definition 2.27]     -ISO14155 3.43

• A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.     -ICH E6(R2) 1.65

• individual whose willingness to volunteer in a clinical investigation could be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of retaliatory response from senior members of a hierarchy in case of refusal to participate

EXAMPLE Individuals with lack of or loss of autonomy due to immaturity or through mental disability, persons in nursing homes, children, impoverished persons, subjects in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, and those incapable of giving informed consent. Other vulnerable subjects include, for example, members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the sponsor, members of the armed forces, and persons kept in detention. -ISO14155 3.44

The physical and mental integrity of the subjects participating in a clinical trial.    -ICH E6(R2) 1.62