The IVDD requires from the manufacturers to design and manufacture devices in such a way that they are suitable for the intended purpose, taking into account generally acknowledged state of the art. The manufacturer should therefore justify why the device is suitable for the intended purpose claimed, in light of the state of the art (MDCG, 2021).
The newly published MDCG Guidance aims at helping manufacturer 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 regards 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 and 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 consider 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 actually can be considered in conformity with the requirements of the Directive (MDCG, 2021).
More specifically, the MDCG recalls the IVDD requirements ‘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 aspect of intended user, target population, result interpretation, etc. Furthermore, devices’ technical documentation shall include adequate performance evaluation data demonstrating 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, the MDCG has taken into account over 100 COVID-19 antibody tests’ IFUs and different sources were assessed to establish 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 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 timing between sampling and potential onset of symptoms.
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 (MDCG, 2021).
- 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 (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 the diagnostic sensitivity and diagnostic specificity, 95% confidence intervals are recommended.
Finally, the MDCG cautions that above may be seen as the minimum expected from devices being placed on the market at the time of publication of the Guidance. It may be revised or replaced by other documents as scientific knowledge and technology evolves, and state of the art improves in time.
—- IVDR & state of the art —-
Even if the above guidance was prepared taking into account the IVDD requirements, we prepared an overview of the term ”state of the art”, which is mentioned in the IVDR 20 times. Manufacturers should be attentive of:
(13) The requirement to reduce risks as far as possible should be fulfilled taking into account the generally acknowledged state of the art in the field of medicine.
Performance evaluation and clinical evidence
Article 56: The clinical evidence shall be such as to scientifically demonstrate, by reference to the state of the art in medicine, that the intended clinical benefit(s) will be achieved and that the device is safe.
(m) in the case of clinical performance studies, the analytical performance has been demonstrated, taking into consideration the state of the art;
(n) in the case of interventional clinical performance studies, the analytical performance and scientific validity has been demonstrated, taking into consideration the state of the art. Where, for companion diagnostics, the scientific validity is not established, the scientific rationale for the use of the biomarker shall be provided;
(o) the technical safety of the device with regard to its use has been proven, taking into consideration the state of the art as well as provisions in the field of occupational safety and accident prevention;
Article 67: This includes, in case of performance studies, the evaluation of the analytical performance, and in case of interventional clinical performance studies, the evaluation of the analytical performance, clinical performance and scientific validity, taking into consideration the state of the art;
The European Union reference laboratories
Article 100(2) (d) to provide scientific advice regarding the state of the art in relation to specific devices, or a category or group of devices;
Article 100(5) (j) reassessing the state of the art on the basis of comparative test results or by further studies, as requested by a Member State or by the Commission.
1. …They shall be safe and effective and shall not compromise the clinical condition or the safety of patients, or the safety and health of users or, where applicable, other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art.
4. Risk control measures adopted by manufacturers for the design and manufacture of the devices shall conform to safety principles, taking account of the generally acknowledged state of the art.
9.1. Devices shall be designed and manufactured in such a way that they are suitable for the purposes referred to in point (2) of Article 2, as specified by the manufacturer, and suitable with regard to the performance they are intended to achieve, taking account of the generally acknowledged state of the art.
16.2. For devices that incorporate software or for software that are devices in themselves, the software shall be developed and manufactured in accordance with the state of the art taking into account the principles of development life cycle, risk management, including information security, verification and validation.
Chapter I, 2.1.: a description of the procedures in place to keep up to date the performance evaluation plan, taking into account the state of the art.
1.1. Performance evaluation plan
— a description of the state of the art, including an identification of existing relevant standards, CS, guidance or best practices documents
— an indication and specification of parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the intended purpose or purposes and for the analytical and clinical performance of the device;
1.3. Clinical evidence and performance evaluation report
The clinical evidence shall scientifically demonstrate that the intended clinical benefit or benefits and safety will be achieved according to the state of the art in medicine.
The performance evaluation report shall in particular include:
— the clinical evidence as the acceptable performances against the state of the art in medicine;
2.3.2. Clinical performance study plan
(g) overall synopsis of the clinical performance study, its design type, such as observational, interventional, together with the objectives and hypotheses of the study, reference to the current state of the art in diagnosis and/or medicine;
(h) a description of the expected risks and benefits of the device and of the clinical performance study in the context of the state of the art in clinical practice, and with the exception of studies using left-over samples, the medical procedures involved and patient management;
5.2. The PMPF plan shall include at least:
(f) an evaluation of the performance data relating to equivalent or similar devices, and the current state of the art;
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