The Medical Device Coordination Group (MDCG), an advisory body of the European Commission responsible for medical devices regulations, has published a guidance document dedicated to the performance evaluation of SARS-CoV-2 in vitro diagnostic medical devices.
Please note that this document should not be construed as the one expressing the official position of the European Commission and is not binding in its nature.
The present guidance issued by the MDCG addresses issues related to the performance evaluation of in vitro diagnostic (IVD) medical devices intended to be used for diagnosing SARS-CoV-2 or the “novel coronavirus.” The scope of the guidance covers IVDs for detection or quantification of SARS-CoV-2 nucleic acid, antigens, and also detection or quantification of antibodies against SARS-CoV-2. The document is intended to provide additional clarifications regarding the applicable regulations, including the Directive 98/79/EC and the In Vitro Diagnostic medical devices Regulation 2017/746 (IVDR), as well as recommendations to be considered by all the parties involved in operations with IVDs, including medical devices manufacturers and notified bodies duly designated to conduct conformity assessment of such devices.
The MDCG also reserves the right to amend the present guidance in order to reflect changes in circumstances, as well as scientific and technical knowledge.
First, the document provides the definitions of the most important terms and concepts used in the context of COVID-related IVDs, including the following:
- Diagnostic sensitivity stands for the ability of a device to identify the presence of a target marker associated with SARS-CoV-2;
- Diagnostic specificity means the ability of a device to recognize the absence of a target marker associated with SARS-CoV-2;
- The limit of detection (LOD) refers to the smallest amount of the target market that can be precisely detected; the LOD is part of the analytical sensitivity of the device;
- Analytical specificity means the ability of the method to determine solely the target marker;
- The robustness of an analytical procedure stands for the capacity of an analytical procedure to remain unaffected by small but deliberate variations in method parameters and provides an indication of its reliability during normal usage.
Apart from those listed above, the present MDCG guidance also provides the definitions of such terms as “true positive”, “false negative”, “false positive”, “true negative”, “nucleic acid amplification techniques (NAT)”, “rapid tests”, “cross-reactivity”, “interference”, “whole system failure rate”, “first-line assay”, “confirmatory assay”, “supplementary assay”, “virus typing essay”, and “95% positive cut-off value for NAT assays”.
According to the present guidance, evaluation of the actual performance of in vitro diagnostic medical devices intended to identify SARS-CoV-2 should be based on the comparison with similar medical devices already placed on the market. It is stated that the new device should be at least equivalent to one already available. The MDCG additionally emphasizes that the population participating in the evaluation should be equivalent to the European population as the tests covered by the scope of the guidance are intended to be used in the EU. In case of any discrepancies in the results active, an additional evaluation should be performed.
Key Aspects to be Considered
The guidance further describes the main aspects to be considered with regard to in vitro diagnostic medical devices intended to identify SARS-CoV-2. These aspects include the following:
- Sensitivity and specificity. In order to ensure the accuracy and reliability of the results of performance evaluation, samples used should reflect different stages and patterns. It is stated that in the case of SARS-CoV-2 tests, the samples used should be collected 1 day or less before the evaluation. According to the guidance, evaluation should start with negative samples and then move slightly to ones with the highest concentration of the substance to be identified. The patient population from which the samples are derived should be as wide as possible and include such categories as pregnant women or blood donors. The document further describes in detail certain additional aspects to be considered with regard to various types of SARS-CoV-2 tests.
- Interference and cross-reactivity. In order to ensure the reliability of the results, samples used for evaluation should cover a wide enough range of specific cases.
- Anticoagulants. In the case of in vitro diagnostic devices that should be used with plasma, the assessment shall also cover the effectiveness of the device with regard to anticoagulants with which the device is initially intended to be used. According to the document, the minimum amount of specimens to be used should be 50 (positive and negative equally).
- Batch testing. The testing should be conducted in a way ensuring all the batches are duly tested.
- Self-tests. In the case of in vitro diagnostic devices intended to be used by laypersons, it is also important for evaluation to be carried out by laypersons as well in order to ensure the device could be used in a safe and efficient manner by persons having no special knowledge or experience in the relevant field. This evaluation should be performed in the form of use of the device in accordance with the instructions for use provided by the medical device manufacturer and supplied with the device. The authority additionally emphasizes that the laypersons selected for the performance evaluation should be representative of the intended user groups.
Apart from the general matters described above, the document also highlights certain specific issues to be taken into consideration with regard to in vitro diagnostic devices intended to be used during the pandemic. In particular, the document contains five tables outlining specific considerations related to various types of devices, namely:
- Table 1 refers to the following first-line assays (including rapid tests) for antibodies against SARS-CoV-2 (anti-SARS-CoV-2): IgG-only, IgD combined with IgM and/or IgA, and total antibody;
- Table 2 refers to assays for detection of anti-SARS-CoV-2 IgM and/or IgA (including rapid tests);
- Table 3 refers to confirmatory or supplementary assays for anti-SARS-CoV-2;
- Table 4 refers to antigen SARS-CoV-2 tests, including rapid antigen tests;
- Table 5 refers to nucleic acid amplification techniques (NAT) assays for SARS-CoV-2 RNA.
In summary, the present guidance document issued by the MDCG addresses the most important aspects associated with the performance evaluation of in vitro diagnostic devices intended to be used in the context of the COVID-19 outbreak. The document highlights the points to be covered by such an evaluation and also the way the evaluation should be performed by the party intended to place its product on the EU market.
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