The IVDD requires from manufacturers to design and manufacture devices in such a way that they are suitable for the intended purpose, taking into account the generally acknowledged state of the art. The manufacturer should therefore justify why the device is suitable for the claimed intended purpose, in light of the state of the art (MDCG, 2021).
The newly published MDCG Guidance aims at helping manufacturers to fulfill this requirement. Firstly, it defines state of the art, which for the purpose of this guidance, is the developed stage of current technical capability and/or accepted clinical practice with regard to products, processes and patient management, based on the relevant consolidated findings of science, technology and experience. The state of the art embodies what is currently and generally accepted as good practice in technology and medicine. The state of the art does not necessarily imply the most technologically advanced solution (MDCG, 2021).
Secondly, it reaffirms the obligation of the manufacturer to clearly specify the device’s intended purpose, considering what levels of performance are needed and what aspects of the state of the art are relevant in light of that particular intended purpose. In addition, the manufacturer is expected to continuously take into account the state of the art, as relevant new information becomes available and, where necessary, update the device’s performance data, adjust the intended purpose, or, if this cannot be done, carefully reassess whether the device can actually be considered in conformity with the requirements of the Directive (MDCG, 2021).
More specifically, the MDCG (2021) recalls the IVDD requirement that “devices must achieve the relevant performance, in particular in terms of analytical sensitivity, diagnostic sensitivity, analytical specificity, diagnostic specificity, accuracy, repeatability, reproducibility, including control of known relevant interference, and limits of detection, stated by the manufacturer”.
Specifically, for COVID-19 devices, it is always necessary to define the intended purpose and performance of the device in IFUs/labels that should cover indications on intended user, target population, result interpretation, etc. Furthermore, the devices’ technical documentation shall include adequate performance evaluation data showing the performances claimed by the manufacturer, while data should originate from studies conducted in an environment targeted by the assay or result from relevant references. Where there is no reference procedure of higher order, which is the case for virus specific antibodies, the performance evaluation shall be conducted in direct comparison to diagnostic device(s) measuring the same analyte, which are estimated as reflecting the “state of the art’’ at the time of the performance study (reference devices). Samples with discrepant test results obtained for the device under evaluation and reference (comparator) device should undergo further investigation (e.g. further assays, patient history) to clarify the probable “true” status, as far as possible (MDCG, 2021).
In developing this Guidance, over 100 COVID-19 antibody tests’ IFUs and different sources were assessed to establish the below findings on the current state of the art.
The MCDG first notes that the performance should be ideally evaluated for each claimed clinical specimen type, and presents [IMMOMD1] modalities below:
- Interference studies
Standard interference studies are to be performed and typical potential sources of interference in the sample matrix are to be considered.
- Cross reactivity studies
Samples from patients with infection history of related viruses, e.g. SARS-CoV-1, MERS-CoV, human common cold coronaviruses, or other respiratory infections (including influenza).
The MDCG invites to consult pages 25-26 of the following document ‘Current performance of COVID-19 test methods and devices and proposed performance criteria – Working document of Commission services’.
- Diagnostic sensitivity evaluation
The positive sample panel should include at least 200 samples from individuals with a confirmed diagnosis of a SARS-CoV-2 infection, with details on the timing between sampling and potential onset of symptoms.
Diagnostic sensitivity studies should use samples at various stages and severity of disease and from putative infections. Samples could be longitudinal, drawn at different times from the same individuals. The positive sample panel should include early and later samples, homogenously distributed in terms of time interval between the contact with the virus and sample taking (MDCG, 2021).
- Diagnostic specificity evaluation
The negative panel should include at least 200 samples. It should consist of samples derived either from patients tested for antibodies for SARS-CoV-2 and confirmed as negative, or samples collected prior to November 2019.
The negative samples should broadly represent the different factors present in thetarget population, according to the intended purpose of the device. Age, gender, demographics and additional factors, such as previous disease history (e.g. non-SARS-CoV-2 respiratory tract infections) or long-term medication of the patient should be taken into consideration (MDCG, 2021).
Diagnostic performance of the device
- At least 90% diagnostic sensitivity for each antibody type (IgM, IgG or total Ig);
- Diagnostic specificity should be at least 98%;
- Confidence intervals should be provided for the estimates of both diagnostic sensitivity and diagnostic specificity, 95% confidence intervals are recommended.
Finally, the MDCG cautions that the above indications may be seen as the minimum expected from devices being placed on the market at the time of publication of the Guidance. They may be revised or replaced by other documents, as scientific knowledge and technology evolves, and the state of the art improves in time.
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- MDCG. (2021). MDCG 2021-2 Guidance on state of the art of COVID-19 rapid antibody tests. Retrieved on 15.03.2021 from https://ec.europa.eu/health/sites/health/files/md_sector/docs/mdcg_2021-2_en.pdf (europa.eu)