Performance studies for SARS-CoV-2 IVD tests have become a hot topic since the publication of the MDCG 2021-21 and the common list of COVID-19 IVD tests. These two documents have strengthened the requirements to place SARS-CoV-2 IVD tests in the EU Market. Consequently, manufacturers are forced, in some cases, to demonstrate the analytical and clinical performance of their IVDs adequately. Hence, we have prepared a practical article to support manufacturers and pave their way to understanding SARS-CoV-2 IVD performance studies.
SARS-CoV-2 IVD tests
There are different types of SARS-CoV-2 diagnostic tests available in the market according to the analyte measured. The list of available tests is simplified to (1) detecting or quantifying SARS-CoV-2 nucleic acids, (2) antigens (specific proteins or whole virus) and (3) antibodies against the virus. Regardless of the analyte they measure, these tests are all classified as IVDs in the context of conformity assessment under either Directive 98/79/EC (IVDD) or Regulation (EU) 2017/746 (IVDR).
Due to higher accuracy and reliability, nucleic acid amplification tests (NAAT, type 1) remain the “gold standard” for COVID-19 diagnosis. On the other hand, rapid antigen tests (RATs, type 2), though being generally less accurate than NAATs, are increasingly being used to maximize testing capacities while shortening turnaround times and reducing costs.
Overall, the unprecedented demand for SARS-CoV-2 tests due to the COVID-19 pandemic has filled the market with many IVD testing options. Most of them have not undergone conformity assessment through notified bodies and have used self-certification strategies under the IVDD (EU). Consequently, this situation has derived in significant numbers of substandard tests being made available on the market.
To overcome the lack of reliability for certain IVD tests, the EU has strengthened the requirements to place SARS-CoV-2 IVD tests on the market. Therefore, a significant number of manufacturers are now asked to perform new performance studies to comply with EU guidance. Additionally, the European Commission has created a database for all CE-marked COVID-19 IVDs where available information on COVID-19 tests performance is collected. This database is manually curated and periodically updated.
First things first: Analytical and Clinical Performance Studies
Performance studies shall focus on obtaining both analytical and clinical performance data. According to the in vitro diagnostics medical device regulation (IVDR) and the guidance document for Clinical Evidence for IVD medical devices GHTF/SG5/N6:2012, analytical and clinical performance are defined as follows:
- Analytical performance means the ability of a device to correctly detect or measure a particular analyte.
Its demonstration is determined by analytical performance studies, which may include analytical sensitivity (e.g. limit of detection), analytical specificity (e.g. interference, cross-reactivity), accuracy (derived from trueness and precision) and linearity.
- Clinical performance means the ability of a device to yield results that are correlated with a particular clinical condition or a physiological or pathological process or state in accordance with the target population and intended user.
Clinical performance data can be derived from multiple sources such as clinical performance studies, literature or experience gained by routine diagnostic testing. Commonly, such data include diagnostic sensitivity, diagnostic specificity, negative and positive predictive values.
Consider visiting the following link to learn more about clinical performance studies under the IVDR 2017/746.
Performance Studies for SARS-CoV-2 IVD tests
Performance studies of SARS-CoV-2 IVDs are mainly designed to establish two parameters: sensitivity and specificity (both analytical and diagnostic), although this may vary depending on the type of test evaluated. Supporting guidance on how to evaluate these parameters is provided by the Medical Device Coordinating Group (MDCG), which released a guidance document for the performance evaluation of SARS-CoV-2 IVDs (MDCG 2021-21).
MDCG 2021-21 forms the basis for the SARS-CoV-2 IVDs common specifications that will need to be followed by IVD manufacturers. In addition, MDCG 2021-21 complements the IVDR by clarifying how to measure the analytical and clinical performance, including new terms such as robustness or system-wide failure.
Last but not least, the guidance specifies the need to carry out the SARS-CoV-2 IVDs Performance Evaluation on a population equivalent to the European population. This is particularly important to third country manufacturers of SARS-CoV-2 in vitro diagnostic medical devices.
Please visit the following link to get more information about MDCG 2021-21.
EU Common list for Rapid Antigen Tests
Among the different SARS-CoV-2 IVDs referenced in the above mention guidelines, RATs have been pointed out as complementary screening tools to PCRs (which belong to the type 2, NAAT category) to keep the spread of the virus globally under control. Some RATs, however, were placed on the market with underperforming results regarding specificity and sensitivity. Thus, in conjunction with the Member States, the Health Security Committee (HSC) set a common list of appropriate RATs to allow the mutual recognition of COVID-19 test results across the EU.
The EU COVID-19 common list includes RATs from nasopharyngeal specimens that fulfill the following conditions:
- CE-marked;
- ≥90% sensitivity and ≥97% specificity;
- Validated at least by one EU Member State.
Note that rapid antigen self-tests are not included in this list.
An important consideration is that it is possible for manufacturers to submit data and information concerning rapid antigen tests that they believe should be considered for inclusion in the HSC agreed common list. This information will then be reviewed and considered alongside the proposals put forward by the EU Member States.
How can AKRN help?
Manufacturers/sponsors may choose to appoint a medical device Clinical Research Organization (CRO) to seek regulatory approvals and set up and manage the clinical performance study.
AKRN has the clinical experience, the regulatory knowledge and the staff qualifications to conduct clinical performance studies and elaborate the performance study reports. Additionally, we are experts in preparing performance evaluation plans, reports, and all the necessary technical documentation for Notified Body conformity assessments.
Subject Matter Experts
Ruben Ruiz, M.Sc.
Clinical Affairs Manager
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Lucía García, M.Sc. Clinical Research Scientist
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