Definitions for clinical studies / investigations involving medical devices

Do you want to understand and use the most important MDR, IVDR and ISO14155 definitions for your project?

The EU Regulation on medical devices with the number 2017/745, the so-called Medical Device Regulation (MDR), defines and explains terms that are also relevant for clinical investigations (medical device clinical trial) and are therefore briefly explained here. The full list can be found in Article 2 of the EU Regulation MDR. Other definitions are deducted from te ISO14144. In the EU, further national laws are to be considered. Germany is subjected to the Medical Device Law Implementation Act (MPDG), for which translations of the respective terminology are also listed below.

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‍Active medical device: Depends on an energy source, excluding energy produced by the human body or gravity. It works by changing the density or converting this energy. Software is also considered an active medical device.

Adverse Event (AE): Any untoward medical occurrence, inappropriate decision regarding patient treatment, unintended illness or injury, or any untoward clinical sign, including an abnormal laboratory finding, in subjects, users, or other individuals in the context of a performance study, regardless of whether it is related to the product under investigation or not. See MDR Art. 2(58) or IVDR Article 2(60).

‍Alpha Level: The significance threshold set by researchers for statistical significance tests to reject the null hypothesis in favor of the alternative hypothesis.

Benefit-Risk Assessment: The analysis of all evaluations of benefits and risks relevant to the intended use of a product as specified by the manufacturer. This assessment is also conducted by physicians before initiating a clinical investigation and is carefully reviewed by ethics committees and regulatory authorities.

‍CE marking of conformity: A marking indicating that a product complies with the relevant requirements of this regulation or other Union legislation. Clinical investigations of medical devices with a CE mark are structured differently and involve less regulatory effort compared to those without this marking.

Clinical Data: Information on safety or performance obtained from clinical investigations or from the scientific literature either with the product in question or a product whose equivalence to the product in question has been demonstrated, or from post-market surveillance.

‍Clinical Evaluation: A systematic process to assess clinical data of a medical device to verify its safety and performance, including clinical benefit, when used as intended by the manufacturer. This may require a clinical investigation if there is no comparability with another product for which literature results are available. For more details, see also here.

‍Clinical Evidence: Clinical data and results that are sufficient to qualitatively assess whether a product is safe and effective when used as intended.

Clinical Benefit: Positive effects of a medical device on an individual's health, measured by meaningful, measurable and patient-relevant clinical results, including diagnostic results. This also includes positive effects on patient management or public health. Often referred to as medical use, see also here.

‍Clinical Investigation Plan: A document that describes the objectives, methodology, monitoring, and conduct of a clinical trial. See also more here.

Clinical Performance: The ability of a product to fulfill its intended purpose based on its technical or functional characteristics, including diagnostic features, to achieve a clinical benefit for patients.

‍Clinical Investigation: A systematic investigation in human subjects to assess the safety or performance of a medical device, see also here.

Clinical Investigation Procedure: Any procedure planned in a performance study (e.g., sample collection oder medical intervention) with the goal of testing the device.

‍Common Specifications (CS): Technical and/or clinical requirements that are not standards but enable compliance with legal obligations for a product, procedure, or system.

Companion Diagnostic (CDx): A product essential for the safe and effective application of a corresponding medicinal product to:

(a) identify individuals who are most likely to benefit from the corresponding medicinal product before and/or during treatment, or

(b) identify individuals at increased risk of serious adverse reactions during treatment with the corresponding medicinal product. See IVDR Article 2(7).

Comparison Wise Error Rate (CWER): The probability of rejecting a null hypothesis that is actually true.

Conformity Assessment: A process to determine whether a product meets the requirements of the applicable regulation. A clinical trial may be carried out as part of a conformity assessment process or after its completion. The objectives, the applicable laws and thus the costs of the clinical trial then depend decisively on this.

Consent for Data Processing: All trial participants must consent to the processing of their data, especially health data, in written or electronic form after being informed. This includes pseudonymization, anonymization, storage, purpose of use, and the right to revoke this consent.

Coordinated Network: MEDIACC works as an independent company within a dynamic, fluid network with other stakeholders that together form the network. Depending on the contractual tasks, MEDIACC coordinates the entire system or subsystems. The mission to make scientific evidence through optimal patient-centered clinical studies for significant innovative medical products accessible to all stakeholders unites everyone in this network.

Corrective Action: An action to eliminate the cause of a potential or existing nonconformity or other undesirable situation.

Data Lifecycle: All processes related to the creation, recording, processing, verification, modification, analysis, reporting, transmission, storage, migration, archiving, querying, and deletion of data.

Data Integrity: The reliability and trustworthiness of data throughout their lifecycle. Data integrity is a cornerstone of data quality, significantly impacting the quality of the study.

Decentralized Clinical Trial (DCT): Studies conducted using telemedicine and mobile/local healthcare services, employing procedures and technologies that differ from traditional clinical trial models. Digital elements are used at different times for different tasks and scopes.

Device Deficiency, DD: Any inadequacy regarding the identity, quality, durability, reliability, usability, safety, or performance of a product for a performance study, including functional failures, application errors, or inadequate information from the manufacturer. See IVDR Article 2(62).

Device for Performance Study: A device intended by the manufacturer for use in a performance study. A device used for research purposes without a medical objective does not qualify as a device for performance studies. See IVDR Article 2(45).

Direct Comparison: Comparison of treatments either through a single comparative study or a pairwise meta-analysis or another method synthesizing comparative studies without indirect comparisons.

Dynamic Data Formats: Dynamic files involve automatic processing and/or enable interactive relationships with the user. An authenticated electronic copy can be stored in electronic data formats that differ from the original dataset but should retain the dynamic nature (including metadata) of the original dataset.

Effectiveness: Describes how well a treatment works in patients; includes efficacy and safety.

Effect Modifier: A variable that modifies a treatment effect, i.e., a variable that changes the relative efficacy between two treatments.

Electronic Data Capture (EDC) System: A computerised system for capturing clinical data in electronic form, primarily used in clinical investigations or performance studies. It replaces traditional manual data capture to make data collection faster, more efficient, and safer.

‍Ethics Committee: An independent body established in accordance with respective European and national laws with the authority to to provide opinions on clinical trials (drug studies), investigations (medical devices) or performance studies (in vitro diagnostic medical devices) or “other clinical investigations” (medical devices) before they start. This includes taking into account the views of laypeople, in particular patients or patient organizations. NO clinical study involving patients may be started or even carried out before this statement and approval by the Ethics Committee has been received.

Evidence: Empirical information from scientific studies on a specific question.

Evidence Synthesis: A broad term for combining the results of multiple studies investigating the same topic.

Family Wise Error Rate (FWER) in the weak sense: The probability of rejecting at least one of k null hypotheses when all null hypotheses are true; also known as the global level.

Family Wise Error Rate (FWER) in the strong sense: The probability of rejecting at least one of k null hypotheses when this null hypothesis is true, regardless of which and how many other null hypotheses are true; also known as the multiple testing level.

Field Safety Corrective Action: Measures taken by the manufacturer to prevent or reduce the risk of serious incidents related to a product placed on the market.

Field Safety Notice: A communication from the manufacturer to users or customers regarding a field safety corrective action.

‍Healthcare institution: An organisation whose primary purpose is to care for or treat patients or promote public health. In general, this includes hospitals, research clinics or practices.

Health Technology: Health technologies include medicinal products, medical devices, in vitro diagnostics, and medical procedures, as well as measures for prevention, diagnosis, or treatment of diseases.

Incident: Any malfunction or deterioration of the characteristics/performance of a device made available on the market, including user errors due to ergonomic features, any inadequacy of the information provided by the manufacturer, and any harm resulting from a medical decision or action taken or not taken based on the information or results provided by the product. See MDR Article 2(64) and IVDR Article 2(67).

Indirect Comparison: A broad term referring to any evidence synthesis comparing treatment groups from different studies. This includes synthesizing evidence to infer the relative efficacy of two treatments without directly comparing them in studies; indirect comparisons are also performed using more general methods of network meta-analysis, even when direct studies are available for the comparison of interest.

Informed consent: The voluntary and free consent of subjects who participate in a clinical investigation after they have been fully informed about all relevant aspects of the clinical investigation. In the case of minors or persons unable to give consent, approval is given by legal representatives.

In-house devices: An IVD manufactured and used within the same healthcare institution, as described in IVDR Article 5(5). The healthcare institution is defined in IVDR Article 2(29).

‍Insurance Coverage: In a clinical investigation, performance study, or other clinical investigation, study participants must be insured for injuries to health or body or in case of death. On a national Eiuropean level, in Germany exceptions apply if the investigational product is CE-marked and tested within its intended use in another investigation, there are no additional burdensome or invasive measures for the study, no additional personal visits occur, and the sponsor or investigator has alternative insurance (§26 MPDG).

Intended Purpose: Refers to the intended purposeof a product as specified by the manufacturer on the labeling, in the instructions for use, or in promotional materials.

‍Interchangeability: When patients in one treatment group are replaced by another, expecting the same treatment effect; includes components of similarity, homogeneity, and consistency in indirect comparisons.

Intercurrent Event (ICE): An event occurring after the start of treatment that affects the interpretation or presence of measurements related to the clinical question of interest.

Interim or Intermediate Analysis: Any analysis of study data regarding efficacy at a point before the formal completion of a study (hereinafter collectively referred to as final analysis).

‍Interoperability: The ability of two or more devices to share information, communicate with each other, or collaborate, regardless of manufacturer.

Interventional Clinical Performance Study: A clinical performance study whose test results influence decisions about patient management and/or can be used to control treatment. See IVDR Article 2(46).Labeling: written, printed, or graphical information on the product, packaging, or in sales materials.

Investigational Device: A device being evaluated in the context of a clinical investigation.

Investigator: A person responsible for conducting a performance study at a study site. See IVDR Article 2(48). Also referred to as the study physician. Investigators are responsible for conducting a clinical investigation or performance study or "other clinical investigation" at a study site (also known as a study center) and must be "appropriately qualified." In exceptional cases, individuals from other professional groups with sufficient qualifications can assume the role of investigator. This is regulated by the MDR and national law, and in for Germany by § 30 MPDG.

‍Labeling: Written, printed, or graphic information on the product, packaging, or in sales materials.

Lay person: A person without formal training in healthcare or a medical specialty who uses a device. This can include patients, relatives, or others without training in the medical or nursing field.

Lead Clinical Investigator: Physicians who must be at least sufficiently qualified and have at least two years of experience in clinical investigations of medical devices or in conducting interventional clinical performance studies with in vitro diagnostics (regulated in Germany by § 30 MPDG).

Malfunction: Any malfunction of a product in a performance study that occurs during intended use according to the instructions for use or the performance study plan. See ISO 20916, Section 3.27.

Manufacturer: A natural or legal person who manufactures or fully prepares a product or has a product designed, manufactured, or fully prepared and places it on the market under their name or trademark. See IVDR Article 2(23).

MEDIACC Study Platform: Enables the conduct of hybrid (analog and digital) to fully digital decentralized clinical trials (DDCTs). This uses an electronic data capture system as a basis and additional digital elements such as electronic signatures, web-based calendars, or physician video conferencing software.

Medical device: broad collective term for instruments, apparatus, appliances, software, implants or other objects that are used for medical purposes on humans and fulfil certain medical purposes alone or in combination. The main intended action in or on the human body is not intended to be achieved by pharmacological, immunological or metabolic means. See more here.

‍Meta-Analysis: The synthesis of two or more comparative studies with a common intervention and comparator to obtain a pooled estimate of the relative treatment effect. Sometimes referred to as pairwise meta-analysis to distinguish it from network meta-analysis.

Metadata: Data become information through context. Without the context provided by metadata, data have no meaning. The loss of metadata can lead to a lack of data integrity, rendering the data unusable. Essential for clinical trials of medicinal products and possibly medical devices under Article 62 or 82 MDR (authorization studies) or for the safety of medical devices Class IIb to III or as required by regulatory authorities.

Multiplicity: The performance of multiple statistical analyses for a research question.

Network Meta-Analysis (NMA): An extension of meta-analysis to evidence networks involving more than two treatments, which can include both direct and indirect evidence. NMA encompasses other terms used in the literature to describe the synthesis of both direct and indirect evidence, such as mixed treatment comparisons and indirect treatment comparisons.

‍Notified body: A conformity assessment body designated in accordance with the Medical Devices Regulation (EU MDR 2017/745). It may be involved as part of the clinical investigation process.

Pairwise Meta-Analysis: The synthesis of two or more head-to-head studies with a common intervention and comparator to obtain a pooled estimate of the relative treatment effect.

Participant: Individuals involved in the conception, planning, execution, data management, analysis, and publication of a clinical investigation, such as physicians, study assistants, project managers, Lead Clinical Investigator (LCI), IT developers, laboratory staff, or personnel in practices or clinics. These individuals cannot be considered "active participants."

Performance: The ability of a product to fulfill its intended purpose.

Performance Study (PS): A study conducted to establish or confirm the analytical or clinical performance of a product. See IVDR Article 2(42).

Pilot Test: The first series of tests of all digital and analog elements of a DDCT by test persons who are not included in the study. Part of the validation process in a DDCT. Successful pilot tests and complete resolution of all technically necessary and safety-related weaknesses or problems are prerequisites for the system's release by MEDIACC, LKP, and sponsor for the pilot run. [DDCT]

Pilot Run: The first series of inclusions of active participants recruited for the study. Part of the validation process in a DDCT. The pilot run can generally only take place after receiving a positive vote from the ethics committee and after successful pilot test . [DDCT]

‍Planned or pre-specified analysis: A statistical analysis planned according to a study protocol or statistical analysis plan (SAP).

Population-adjusted method for indirect comparisons: A method for indirect comparisons using a mix of individual patient data (IPD) from one or more studies and aggregated data from other studies to adjust for relevant population characteristics that differ between studies to estimate a treatment effect.

Post-hoc Analysis: A statistical analysis not planned within the framework of a study protocol or statistical analysis plan (SAP).

Power or Statistical Power: The conditional probability that a significance test will detect an effect if the alternative hypothesis is true.

Predictive Factor: A patient characteristic that modifies the relative efficacy between two treatments (also known as an effect modifier).

Principal investigator: If several doctors (investigators) at a study center are involved in a clinical investigation, a performance study, "PMCF investigation" or an “other clinical investigation”, one of these investigators is appointed by the sponsor as the principal investigator. For Germany, this is regulated in § 30 MPDG. Principal investigators may also be persons from other professions if their education entitles them to pursue a profession that qualifies for a clinical investigation, performance study, "PMCF investigation" or "other clinical investigation". See also “Investigator” or more here. For the duties and duties of principal investigators, see here.

Product shortage: An insufficiency in the identification, quality, durability, reliability, safety, or performance of a test device, including malfunctions, application errors, or insufficient information from the manufacturer.

Prognostic Factor: A patient characteristic that affects the outcome of interest, regardless of the treatment received.

‍p-Value: The conditional probability of obtaining a result equal to or more extreme than the one actually observed, given that the null hypothesis is true.

Risk: The combination of the probability of occurrence of harm and the severity of that harm.

Sample: Any separate part of a body fluid or tissue taken for examination, study, or analysis to determine the characteristics of the entire body fluid or tissue. See ISO 20916, Section 3.47.

Sensitivity Analysis: A series of analyses that estimate the same effect but use different methodologies to evaluate the impact of different decisions compared to the primary assumptions of the analysis.

Serious Public Health Threat: An event with an immediate risk of death, severe health deterioration, or serious illness that can cause significant morbidity or mortality and is unusual or unexpected for a specific location and time.

Serious Adverse Event: An adverse event with serious consequences such as death, life-threatening illness or injury, permanent damage, or hospitalisation. Foetal distress or congenital anomalies are also considered serious adverse events. Immediate corrective actions are required for such events. More about this can be found here.

Serious incident: An incident with serious consequences, such as death, serious deterioration of health, or a serious threat to public health.

Source Data: Permanent data from electronic data generation/capture should be defined as electronic source data. This process should be validated to ensure that the generated/captured source data are representative of the original observation and should include metadata, including an audit trail, to ensure compliance with ALCOA++ principles. The location where the source data were first obtained should be part of the metadata. If processing is an integral part of the solution used and is recognizable as such in the solution features, there is no need to extract and store the unprocessed data. It must be possible to validate the correct functioning of the processing. Generally, source data should be processed as little as necessary and as much as needed.

Sponsor: A person or organization responsible for initiating, managing, and financing a clinical investigation. See IVDR Article 2(57). See also more here.

Static Data Formats: Static files containing information or data that are unchangeable and do not allow dynamic interaction.

Study Infrastructure: Study platform and analogous elements. [DDCT]

Study Phases: Typically include strategy development, conception, planning, setup of digital elements, study conduct, data management, analysis, and publication for scientifc or research work, including clinical investigations of medical devices. While these phases are linear in conventional studies, they form a non-linear complex arrangement in decentralized clinical trials (DCTs). Not to be mixed up with phases I - IV of clinical trials of medicinal product (drugs).

Subgroup or Subpopulation: A subgroup of the study/population defined by one or more specific patient characteristics (e.g., age, gender) measured at the start of the study. Subgroup analyses within a joint clinical assessment (JCA) are conducted within a specific PICO framework.

Subgroup Analysis: The estimation and comparison of treatment effects in the (disjoint) subgroups of a potential effect modifier.

Subpopulation: A subset of the study/population covered by the therapeutic indication. Subpopulations in the context of a JCA lead to separate PICOs for each subpopulation.

Subject: A person participating in a clinical investigation or performance study whose sample(s) are subjected to examination by the investigational product and/or a control device used for comparison purposes. See IVDR Article 2(47).

Treatment: A health technology being evaluated. Health technologies include medicinal products, medical devices, in vitro diagnostics, and medical procedures.

‍User: Any healthcare professional or layperson who uses a medical device. In addition to lay person (see below), this also includes people who have medical or nursing education.

Validation: The performance of a risk assessment that considers the intended use of the system and its potential impact on the protection of study participants and the reliability of study results. Validation ensures that systems work fully, accurately, reliably, and consistently, with documentation of validation steps and adherence to quality standards being crucial.

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References: https://eur-lex.europa. eu/legal- content/EN/TXT/HTML/?uri=CELEX :32017R0745 and https://eur -lex.europa.eu/legal-content /EN/TXT/HTML/?uri=CELEX :32017R0746 (Please delete lblanks for link)

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