The Medical Device Coordination Group has released a Guidance on state of the art of COVID-19 rapid antibody tests.
The Coronavirus pandemic is still going strong and thus the demand for rapid antibody tests is high, especially since they have become more accessible to the broad public being sold in local drugstores and supermarkets.
Making sure that the devices’ performances are adequate is not a simple task, the directive 98/79/EC on in vitro diagnostic medical devices establishes that devices must be designed and manufactured in such a way that they are suitable for the intended purpose specified by the manufacturer, taking into account the generally acknowledged state of the art.
The MDCG guidance intends to establish particular elements on the current state of the art for COVID-19 rapid antibody tests. Specifying that in this particular context, the state of the art may be seen as the minimum expected from devices being placed on the market at the time of publication of this document.
It is crucial that the manufacturer clearly specifies the device’s intended purpose, considering what levels of performance are needed and what aspects of the state of the art are relevant. Keeping in mind to continuously update/revise the device’s performance data and/or adjust the intended purpose with new available data.
The Legal requirements of Directive 98/79/EC on device performance:
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.
For COVID-19 devices it is always necessary to define the intended purpose, the intended purpose must be specified in the instructions for use and/or on the label.
Including aspects such as:
• the intended user,
• the target population,
• window between infection and antibody detection,
• result interpretation (including limitations of interpretation),
• assay design (target antigen(s), antibody types)9,
• limitations of the assay,
• whether the assay is intended, for example, to detect the antibody response in individual patients’ recovery, to assess if the patient has been previously infected, to assess response to vaccination,
• the exclusion of antibody test use as first line test for diagnosis.
It is also required that the instructions for use describe the performance of the device with regard to the non-exhaustive parameters listed above and that the technical documentation contains adequate performance evaluation data showing the performances claimed by the manufacturer. The data should originate from studies conducted in an environment targeted by the assay (e.g. clinical settings) or result from relevant references. The information on the establishment of performance should be complete to allow an assessment of its quality.
For biological analytes such as virus specific antibodies there is no reference procedure of higher order. Therefore, the performance evaluation should be done 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.
The State of the art:
102 instructions for use of COVID-19 rapid antibody tests placed on the European market before September 2020 were examined. Performance criteria/considerations for devices used for the detection of antibodies against SARS-CoV-2 published by different sources, including the WHO, were also reviewed. The outcome of this analysis was used as a basis for the following findings:
1) Performance evaluation modalities
The performance should be ideally evaluated for each claimed clinical specimen type unless equivalence between the relevant biological matrices has been demonstrated.
• Interference studies: Standard interference studies should be performed and should take into account the typical potential sources of interference in the sample matrix in question. Please refer to 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’ for more information.12
• 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). Please refer to 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’ for more information.
Note: Antibodies for other respiratory infection agents are considered as potentially pertinent cross reacting agents to be systematically tested in addition to other more usual cross reactants. As part of post market surveillance, it remains the responsibility of the manufacturer to continuously monitor the performance of their devices, including for new potentially cross-reacting agents and update their relevant documentation, where necessary.
• 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 timing between sampling and potential onset of symptoms.
Considering that diagnostic sensitivity depends highly on the time interval between the contact with the virus and sample taking, diagnostic sensitivity studies should use samples at various stage 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 the time interval between contact with the virus and sample taking.
Depending on the intended purpose of the device, it may be difficult to get access to well-defined panels reflecting the full diversity of potential antibody responses, representing e.g. different time points after infection, different follow-up courses of infection, asymptomatic / symptomatic infection, etc. Therefore, an option may be to use the device in parallel with an established device13 to investigate a representative set of samples, without preselection or exclusion of specimens, from a high incidence situation such as from a local or regional outbreak or from hospitals.
• Diagnostic specificity evaluation:
The negative panel should include at least 200 samples.
The negative panel 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 the target 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 considered.
2) Diagnostic performance of the device
Diagnostic sensitivities mentioned in the studied IFUs were heterogeneously determined, making it difficult to conclude on a minimum value reflecting the state of the art for this performance. It should nevertheless be noted that performance criteria/considerations published by different sources, including the WHO, for devices used for the detection of antibodies against SARS-CoV-2 generally require at least 90% diagnostic sensitivity for each antibody type (IgM, IgG or total Ig).
In the case of diagnostic performance established by comparison with a device used as reference, the diagnostic sensitivity should be at least equivalent to reference device(s), see Section “Legal requirements of Directive 98/79/EC on device performance”.
Diagnostic specificity should be at least 98%.
Confidence intervals should be provided for the estimates of both the diagnostic sensitivity and diagnostic specificity, 95 % confidence intervals are recommended.
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