Introduction
It addresses the classifications and provides clarifications on the classification rules as set forth in Annex VIII of Regulation (EU) 2017/746. It is important to note that this classification advice also applies to diagnostic services provided to patients, information society services provided to them, and gadgets purchased online and placed into service.
This article summarises the document's key points, giving manufacturers and medical facilities advice on how to classify IVDs before releasing them onto the market.
The document itself (linked here: md_mdcg_2020_guidance_classification_ivd-md_en.pdf (europa.eu)) main goal to give manufacturers, notified organisations, and medical facilities advice on how to classify IVDs before releasing them on the market, making them accessible to the public, or putting them into use in the Union. Additionally, it is meant to assist regulators and other interested parties in determining the classification given to an IVD by a producer or a medical facility. The document also provides examples of which devices could fall under which rule, so it is most definitely a worthy read.
A device's intended use determines its classification. Devices must be classified into classes A, B, C, and D in accordance with Regulation (EU) 2017/746, taking into account their intended use and inherent dangers (Article 47).
For devices to be classified correctly in accordance with Annex VIII, strong risk-based classification rules are required because some IVDR requirements are directly related to device classification.
The conformity assessment process is heavily reliant on classification, the involvement of European Union reference laboratories for high-risk devices (Article 100), and the consultation with a national medicines agency or the European Medicines Agency (EMA) for companion diagnostics (Article 48(3)). Post-market requirements are also class-specific, such as the need to create post-market surveillance reports or periodic safety update reports (PSUR).
Image take from Annex II Guidance on Classification Rules for in vitro Diagnostic Medical Devices under Regulation (EU) 2017/746 md_mdcg_2020_guidance_classification_ivd-md_en.pdf (europa.eu)
The Rules
RULE 1
NOTE: Devices intended to be used for the following purposes are classified as class D
RULE 1 (1st Indent): Devices intended to detect the presence of, or exposure to, a transmissible agent in blood, blood components, cells, tissues, or organs, or any of their derivatives, in order to assess their suitability for transfusion, transplantation, or cell administration.
RATIONALE: All devices designed to determine whether blood, blood components, cells, tissues, or organs, or their derivatives, are suitable for transfusion, transplantation, or cell administration in terms of transmissible agents. The test's outcome will play a significant role in determining whether the donation that was studied will be put to use.
Devices that fall under this rule are typically those that are designed to detect the agents for which the EU has standardised the donor and donation testing requirements in the context of the risk of infection transmission.
RULE1 (2nd Indent): Devices intended to be used for the detection of the presence of, or exposure to, a transmissible agent that causes a life-threatening disease with a high or suspected high risk of propagation
RATIONALE: This applies to devices that are designed to be used for the detection of a transmissible agent that causes a disease with a high or presumed high risk of spreading, whether it is present or exposed. This rule applies regardless of whether the test is a first-line, confirmatory, or supplemental assay.
RULE 1 (3rd Indent): Devices intended to be used for determining the infectious load of a life-threatening disease where monitoring is critical in the process of patient management.
RATIONALE: This applies to devices designed to be used for figuring out the infectious load in the context of infectious diseases that can be fatal once the patient's disease status has been established and for which patient management choices, such as a particular course of therapy, are dependent on monitoring the infectious load.
RULE 2
Devices used for blood grouping, determining maternal blood group incompatibility, or tissue typing to assure the immunological compatibility of blood, blood components, cells, tissue, or organs intended for transfusion, transplantation, or cell administration are classified as class C devices. There are exceptions to this rule, however, such as the ABO system, the Rhesus system, the Kell system, the Kidd system, and the Duffy system.
RATIONALE: Rule 2 applies equally to donor and recipient testing. According to this rule, blood grouping devices are divided into two classes based on the possibility that a blood group marker will trigger an immune response or a severe haemolytic transfusion reaction. For the purpose of ensuring immunological compatibility and securing the transfusion of blood and blood components, the red blood cell markers specified in this rule are essential. Devices using these indicators, whether they are meant to be screening, diagnostic, confirmatory, or additional, fall within the class D category.
Other than the red blood cell markers mentioned, devices that are used to identify markers as screening, diagnostic, confirmatory, or supplemental tools for tissue typing, blood grouping, or checking the immunological compatibility of blood, blood components, cells, tissue, or organs used in transfusions, transplants, or cell administration are class C.
RULE 3
NOTE: A variety of devices are covered by Rule 3, as shown by its indents (a)–(m). Regardless of the indent used, devices falling under Rule 3 (when not classified as Class D according to Rules 1 & 2) are to be classified in Class C. A device could potentially fall under more than one Rule 3.
RULE 3a: Devices intended for detecting the presence of, or exposure to, a sexually transmitted agent
RATIONALE: Rule 3a applies to devices detecting agents whose main mode of transmission is sexual, through vaginal, oral, and anal sexual intercourse. Agents being blood, semen, vaginal, or other bodily fluids.
RULE 3b: Devices intended for detecting the presence in cerebrospinal fluid or blood of an infectious agent without a high or suspected high risk of propagation
RATIONALE: Rule 3b applies to devices intended for detecting the presence of an infectious agent in specimens derived from cerebrospinal fluid or blood. This rule does not apply to devices used to detect antibodies to the infectious agent. Regardless of the method of transmission or the origin of the infectious agent, this rule is applicable to all devices. This rule also holds true for microbiological media used to identify relevant infectious agents in blood or cerebrospinal fluid samples.
RULE 3c: Devices intended for detecting the presence of an infectious agent, if there is a significant risk that an erroneous result would cause death or severe disability to the individual, the foetus or embryo being tested, or the individual's offspring.
RATIONALE: Rule 3c applies to devices intended for detecting the presence of an infectious agent. This rule does not apply to devices used to detect antibodies to the infectious agent.
If there is a high likelihood that an incorrect result would result in death or severe disability, then this rule is applicable. The risk to a person's life or serious disability must be considered. An incorrect result in this situation does not carry the same risk as an incorrect result in, say, a pregnant, immunocompromised, or vulnerable individual, so the risk of death or severe disability to the individual must be considered. This rule also applies to a test subject's embryo, foetus, or offspring in cases where an infectious agent may harm the viability or development of the subject's embryo or foetus, resulting in death or disability, both immediate and long-term, such as developmental disability.
RULE 3d: Devices intended for prenatal screening of women in order to determine their immune status towards transmissible agents.
RATIONALE: Rule 3d applies to devices specifically intended to screen pregnant women for their immune status towards transmissible agents. The devices covered by this regulation are used to screen expectant mothers prior to delivery in order to detect the presence of an acquired, appropriately targeted immune response to transmissible agents. Absence of such acquired maternal protection is linked to a higher risk of the agent infecting the mother and spreading to the embryo or foetus. It might be suggested that these mothers take preventative measures.
RULE 3e: Devices intended for determining infective disease status or immune status, where there is a risk that an erroneous result would lead to a patient management decision resulting in a life-threatening situation for the patient or for the patient's offspring
RATIONALE: Rule 3e applies to devices for both the determination of the infectious disease status and the determination of the immune status of a patient.
The determination of the infectious disease status offers details on the nature, severity, or progression of a disease brought on by an infectious agent, including information on the efficacy of a particular treatment. In this context, measuring infectious agents, antibodies to infectious agents, surrogate markers, or analytes in patient specimens usually entails determining the infectious disease status.
The determination of immune status provides details on the patient's immune system's development in relation to a pathogen infection, including its current state or condition.
RULE 3f: Devices intended to be used as companion diagnostics
RATIONALE: Rule 3f applies to devices intended to be used as companion diagnostics.
‘Companion diagnostic’ (CDx) is defined in Article 2(7) as a device that is essential for the safe and effective use of a corresponding medicinal product to:
- identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or
- b) identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product.
RULE 3g: Devices intended to be used for disease staging, where there is a risk that an erroneous result would lead to a patient management decision resulting in a life-threatening situation for the patient or the patient's offspring
RATIONALE: Rule 3g applies to devices where the intended purpose is the staging of a disease.
Disease staging entails identifying distinct stages or intervals in a disease's progression as well as the degree of severity of a disease that can be determined, for instance, by an individual's or an organism's life history, by markers, or by any biological or physiological process. Disease staging is done in order to provide information about patient management, the suitability and accuracy of treatment choices, and/or a prognosis or prediction.
Determining the disease stage for the majority of diseases entails considering the entire clinical picture, which may include investigative procedures, reviewing the patient's medical history, and measuring markers or analytes in patient specimens.
This rule applies to devices whose information is intended to be used for disease staging and whose decision to manage the patient is solely or primarily based on an incorrect result that could put the patient in danger of losing their life.
This rule does not include:
Devices for the staging of cancer, as these devices are classified under Rule 3h.
Devices whose results are not intended to be used for disease staging, such as markers that indicate the presence of an affected health condition in general.
RULE 3h: Devices intended to be used in screening, diagnosis, or staging of cancer
RATIONALE: This applies to devices with the specific intended purpose of being used in the screening, diagnosis, or staging of cancer.
The scope of this rule is limited to cancer when the device is intended to be used in the screening, diagnosis, or staging of cancer. This regulation applies to both malignant and precancerous cancer conditions.
RULE 3i: Devices intended for human genetic testing
RATIONALE: Rule 3i applies to devices for human genetic testing. A genetic test looks for particular alleles, mutations, genotypes, karyotypes, or epigenetic changes that are linked to heritable traits, diseases, or disease predispositions for the test subject or their offspring.
An individual's medical state, the confirmation or exclusion of a suspected genetic illness, and their likelihood of contracting or passing on a genetic disorder can all be determined by the findings of a genetic test.
RULE 3j: Devices intended for monitoring levels of medicinal products, substances, or biological components when there is a risk that an erroneous result will lead to a patient management decision resulting in a life-threatening situation for the patient or for the patient's offspring
RATIONALE: Rule 3j applies to devices intended to monitor an analyte with the purpose of adjusting patient management, such as treatments or interventions.
Monitoring tests may be used to assess a person's current health and/or any changes to that person's health. This can probably be accomplished by performing repeated or multiple measurements of an analyte over time at strategic intervals. These tools are designed to assess whether outcomes meet expectations in terms of disease progression or regression, disease recurrence, minimum residual disease, therapeutic response or resistance, and/or adverse therapeutic effects.
This rule does not apply to devices used in the diagnosis or screening of a condition where only a single measurement is necessary for this purpose, but it would apply to diagnostic tests where multiple or serial measurements over time are intended by the manufacturer and where an incorrect result may result in a life-threatening situation for the patient or their offspring, such as when monitoring the change in concentration of a biological compound over time to aid in diagnosis.
The monitoring of non-life-threatening conditions is also covered by Rule 3j. It covers a wide range of analytes where the device acts as a significant, crucial, or the only factor in determining the best course of action for managing the patient, and where an incorrect result could put the patient's or the patient's children's life in danger due to poor treatment choices.
RULE 3k: Devices intended for the management of patients suffering from a life-threatening disease or condition
RATIONALE: Rule 3k applies to devices intended for patients diagnosed with life-threatening diseases or conditions.
The device provides information for the purpose of patient management, such as treatments/interventions, as necessary, and acts as an important, critical, or the only determinant for the right patient management decision.
The classification of these devices is mainly based on the impact of the given information on patient management and the existence of a life-threatening disease or condition. This includes equipment designed to directly identify drug-resistant pathogens linked to a condition that is life-threatening from specimens collected, such as blood, skin, or tissues, in order to make a patient management choice. However, rule 3k does not apply to devices used in conjunction with microbiological culture methods that are only intended to test the drug resistance of a pathogen that has already been detected. Examples of such devices include sensitivity discs and tablets for drug testing and Minimum Inhibitory Concentration (MIC) panels, which are not designed to treat patients with infections that are life-threatening.
RULE 3l: Devices intended for screening for congenital disorders in the embryo or foetus
RATIONALE: For devices used in routine screening of embryos and foetuses, as well as targeted screening for embryos and foetuses in families known to have inherited diseases or in areas where certain populations are more likely to inherit a disease.
Rule 3i also applies to preimplantation and genetic screening tests.
RULE 3m: Devices intended for screening for congenital disorders in new-born babies where failure to detect and treat such disorders could lead to life-threatening situations or severe disabilities
RATIONALE: Devices designed to check new-borns for a defect that is present at birth are subject to Rule 3m. This includes genetic testing with the goal of identifying congenital diseases in new-borns.
This rule applies to equipment designed to screen new-borns shortly after birth for diseases that can be treated but are not yet clinically evident. Some of the ailments that are covered by new born screening can only be identified after irreparable harm has been done.
To determine if they have a congenital disorder, new-borns who test positive are subjected to additional testing. In particular, rules 3j and 3k must be taken into account for these confirmatory and supplemental devices, as well as for congenital disorders that are clinically evident.
RULE 4
RULE 4a: Devices intended for self-testing are classified as class C, except for devices for the detection of pregnancy, for fertility testing, for determining cholesterol level, and for the detection of glucose, erythrocytes, leucocytes, and bacteria in urine, which are classified as class B.
RATIONALE: All devices intended for self-testing are classified as class C.
- devices for the detection of pregnancy, for determining fertility, for determining cholesterol level (in any specimen), and devices for the detection of glucose, erythrocytes, leucocytes, and bacteria in urine.
- those classified as class D under Annex VIII implementing rule 1.9 (for example, HIV self-tests)
RULE 4b: Devices intended for near-patient testing are classified in their own right.
RATIONALE: Devices are classified for use in close patient testing in accordance with their intended use, as determined by the manufacturer. This harmonises the classification of instruments used in near-patient testing with other instruments meant for professional use. To classify a device properly, the manufacturer must examine all the regulations.
RULE 5
Note: These devices are classified as Class A
RULE 5a: Products for general laboratory use, accessories that possess no critical characteristics, buffer solutions, washing solutions, and general culture media and histological stains, are intended by the manufacturer to be suitable for in vitro diagnostic procedures relating to a specific examination.
RATIONALE: General laboratory supplies such as pipettes, glass microscope slides, centrifuges or instrument liquid collection containers, and buffers that typically do not qualify as IVD medical devices are covered by Rule 5a.
RULE 5b: instruments intended by the manufacturer specifically to be used for in vitro diagnostic procedures
RATIONALE: Instruments designed by the manufacturer specifically for in vitro diagnostic procedures are covered by Rule 5b. Reagents and kits are classified separately from these instruments, which are classified as class A.
RULE 6
RULE 6: Devices not covered by the above-mentioned classification rules are classified as class B
RATIONALE: Devices not covered by Rules 1–5 are subject to Rule 6.
With these devices, a mistaken result is unlikely to have a significant negative effect on the patient's prognosis, result in death or severe disability, or put the patient in immediate danger.
RULE 7
RULE 7: Devices which are controls without a quantitative or qualitative assigned value are classified as class B
RATIONALE: When a control is referred to as "un-assayed" and the user, not the manufacturer, assigns the control values, Rule 7 applies. Without providing expected assay results, the manufacturer may state whether a particular analyte is present or absent in these controls.
According to implementing rule 1.6, controls with quantitative or qualitative values assigned are classified.
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