A new guidance document (MDCG 2020-21) has been published on the 3rd of August by the Medical Device Coordination Group (MDCG) pertaining to performance evaluation of SARS-CoV-2 in vitro diagnostic medical devices. This document provides extensive details on what is expected for SARS-CoV2 IVDs and is envisaged to form the basis for common specification to be adopted in coming months. Even if you are not making SARS-CoV-2 assays the testing details and sample sizes outlined in the guidance provide insight on the IVDR impact to technical documentation and Performance Evaluation Reports (PERs) and provide a glimpse into the level of evidence required.
With the movement between EU Member States being restricted during the COVID-19 pandemic, public interest has turned toward the need for more IVDs for diagnosis and detection of exposure to SARS-CoV-2, which causes COVID-19. These tests can be utilized for citizens of the EU to obtain Digital Green Certificates for safe and free movement within the EU during the COVID-19 pandemic [2,3]. These Certificates are issued based on vaccination certificates, test certificates, or certificates of recovery.
Guidance for getting medical devices, active implantable, and IVDs marketed in member states have been published for the respective directives: Medical Device Directive (MDD), Active Implantable Medical Device Directive (AIMDD), and IVDD . Although it addresses IVDD, the critical path for SARS-CoV-2 IVD manufacturers for IVDR conformity assessment is covered for the first time in the MDCG 2021-21, herein referred to as “the guidance”. The guidance provides explicit expectations for performance evaluation by expanding on the requirements in Annexes I, GSPRs, and XIII, Performance Evaluation, Performance Studies and Post-Market Performance Follow-Up, from the IVDR with context and examples for stakeholders to utilize in their submissions to Notified Bodies (NB).
In case there was any question, the guidance document highlights the increased scrutiny that the IVDR places on diagnostics and requires sample sizes more than ten times higher than an FDA EUA submission and providing specific patient populations that must be tested (e.g. 200 negative specimens from hospitalized patients that do not have SARS-CoV-2).
What is new in this guidance that makes compliance easier?
The update from MDCG provides critical elements for NB and Competent Authority (CA) appraisal of performance of SARS-CoV-2 IVDs, which will be referred to as SARS IVD(s) or devices from this point on. The guidance contains clarifications around State of the Art (SoTA) along with other terms and phrases from the IVDR as they pertain to SARS IVDs as well as considerations for performance studies, such as sample status determinations for analytical and clinical performance assessment. The guidance also establishes specific performance expectations to be demonstrated for each current device mechanism: antigen, antibody, and nucleic acid amplification techniques (NAT).
Context and Clarity of Definitions from IVDR
IVDR provides high-level definitions of some of the performance characteristics described in Annex I, 9.1(a) and 9.1(b). These elements of the Annex are intended to be the foundational topics of the Performance Evaluation Report (PER) to be included in the technical documents for conformity assessment. The guidance provides specific definitions contextualized for the various types of SARS-CoV-2 assays. For characteristics that are not defined in the IVDR, manufacturers have had to look to other sources to define these terms such as ISO  and CLSI  for definitions. New definitions presented include rapid test, whole system failure, and robustness of an analytical procedure, while cut-off is discussed for nucleic acid amplification (NAT) assays. The guidance revisits the terms that are defined in IVDR like analytical and diagnostic sensitivity and specificity, while bringing attention to new performance characteristics that have direct focus on the current pandemic and the need for SARS IVDs.
State of the Art
To meet the requirement for SoTA , the performance of SARS-CoV-2 IVDs should directly compare with devices that are currently CE marked at the time performance evaluation is required. Performance of the subject device must be at least equivalent to that of the SoTA device given the claims and targets. Performance data availability for equivalent devices especially under conformity to IVDR will be limited.
Requirements for Performance Studies for SARS-CoV-2 IVD
The guidance highlights expectations around performance interference, cross-reactivity, use with anticoagulants, and batch testing, as well as specific considerations for specific assays. The general considerations that will present unique challenges for manufactures moving forward are the requirements around test populations, specimen panels, batch verification, and risk analysis as the other requirements. The following points of discussion are new and specific to this guidance.
The MDCG Guidance provides the expectations for the study population used to qualify clinical diagnostic characteristics which should be assessed on a population equivalent to that of the EU. It will be interesting to see how manufacturers address this requirement and what kind of feedback NBs provide during review of submissions based on this direction given that prevalence of COVID-19 infection may vary from member state to member state.
Seroconversion Panels for Sensitivity and Specificity
Seroconversion panels should be included in sensitivity and specificity performance testing when possible. When it is not possible, a justification should be provided. Monitoring differential expression antibodies in COVID-19 infection is crucial to correlate seroconversion of these IgA, IgG, and IgM with clinical outcomes . This provides additional context for clinical performance characteristics of SARS assays intended to be used with serum or plasma required under IVDR and how to support claims for diagnostic sensitivity and specificity, positive/negative predictive values, and likelihood ratios, as well as expected values in normal and affected populations. The challenge presented in this expectation is the ability to detect antibodies as these proteins are temporally correlated directly to infection, and may change quickly depending on severity, comorbidities, and duration of infection . This may make these samples a challenge to obtain and analyze in clinical studies to support Annex I, 9.1(b) performance characteristics.
Risk Analysis and Whole System Failure Rate
Benefit-Risk Assessment and overall risk are included in IVDR as requirements for ongoing evaluation by the manufacturer. The expectation is for whole system failure rate to be included as part of risk analysis. Whole system failure rate is defined in the guidance as the frequency of failures when the entire process for the IVD is completed as prescribed by the manufacturer. In practice, this means determining the threshold for false-negative results yielded by known low-positive specimens, or the threshold for analytical sensitivity or limit of detection. This should be factored into the benefit-risk assessment of SARS IVDs and could potentially result in corrective actions or post-market performance follow-up studies, which could increase barrier to entry in the EU for some manufacturers .
The guidance provides the expectation of 100% batch verification to ensure every batch consistently identifies the relevant antigens, epitopes, and antibodies and is suitable for the claimed specimen types. This will have cost and logistical impacts for manufacturers through their distribution chains. It will also require additional resources as sampling plans for acceptance quality limits are often statistically based on nonconforming product by attributes and are not typically 100% [11,12].
Nasopharyngeal Swab NAT Assays are Established as Gold Standard for Respiratory Samples
The guidance specifies that NAT assays for lower respiratory tract (LRT) specimens should be compared with upper respiratory specimen tests, specifically nasopharyngeal swabs (NP), as these are the ideal samples for SARS-CoV-2 detection . Performance criteria should be compared for specificity and sensitivity between NPs and LRTs. The guidance also touches on serum and plasma equivalency as well as other body fluids. Plasma and body fluids such as saliva and urine should be equivalent to test for serum for specificity and sensitivity. This will support stakeholders in understanding how to design testing generally; however, we in industry will have to wait to see how this is interpreted by NB reviewers and CAs.
The MDCG guidance has brought industry insight into performance characteristics for SARS IVDs during the global COVID-19 pandemic. Although this cannot be accepted as the ultimate ruling on what reviewers will expect since the Common Specification is anticipated later this year, industry should consider risks to upcoming submissions and be prepared to address the delta. RQM+ has experienced professionals with a breadth of applicable experience to support IVD manufacturers navigating this unprecedented time and the ongoing shifts in the regulatory requirements for these much-needed devices.
1.) European Commission. Guidance on medical devices, active implantable medical devices and in vitro diagnostic medical devices in the COVID-19 context. https://ec.europa.eu/health/sites/default/files/md_sector/docs/md_mdcg_guidance_md_qa_covid-19_en.pdf. Last updated 03April2020. Accessed 29 August 2020.
2.) European Commission. EU Digital COVID Certificate. https://ec.europa.eu/info/live-work-travel-eu/coronavirus-response/safe-covid-19-vaccines-europeans/eu-digital-covid-certificate_en. Last updated 19 August 2021. Accessed 29 August 2021.
3.) European Centre for Disease Prevention and Control. Technical Report: The use of antibody tests for SARS-COV-2 in the context of Digital Green Certificates. https://www.ecdc.europa.eu/sites/default/files/documents/Use-of-antibody-tests-for-SARS-COV-2-in-the-context-of-Digital-Green-Certificates.pdf. Published online 10 May 2021. Accessed 29 August 2021.
4.) MDCG 2020-4, Guidance on temporary extraordinary measures related to medical device Notified Body audits during COVID-19 quarantine orders and travel restrictions. https://ec.europa.eu/health/sites/default/files/md_sector/docs/md_mdcg_2020_4_nb_audits_covid-19_en.pdf. Published online April 2020. Accessed 17 August 2021.
5.) ISO 5725-1:1994 (en) Accuracy (trueness and precision) of measurement methods and results — Part 1: General principles and definitionshttps://www.iso.org/obp/ui/#iso:std:iso:5725:-1:ed-1:v1:en. Published 1994. Accessed 20 August 2021.
6.) Clinical Laboratory Standards Institute. CLSI Harmonized Terminology Database. https://htd.clsi.org/listterms.asp?searchd. Last updated in 2021. Accessed 29 August 2021.
7.) MDCG 2021-2, Guidance on state of the art of COVID-19 rapid antibody tests.. https://ec.europa.eu/health/sites/default/files/md_sector/docs/mdcg_2021-2_en.pdf. Published online March 2021. Accessed 15 August 2021.
8.) Tay, MZ et al. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology. https://www.nature.com/articles/s41577-020-0311-8. Published 28 April 2020. Accessed 11 August 2021.
9.) Thakkar, A et al. Patterns of seroconversion for SARS-CoV-2 IgG in patients with malignant disease and association with anticancer therapy. Nature Cancer. https://www.nature.com/articles/s43018-021-00191-y. Published 22 March 2021. Accessed 27 August 2021.
10.) EU 2017/746, in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision. Official Journal of the European Union. Published 05 April 2017.
11.) ANSI/ASQ Z1.9-2003 (R2018): Sampling Procedures and Tables for Inspection by Variables for Percent Nonconforming. https://webstore.ansi.org/preview-pages/ASQ/preview_ANSI+ASQ+Z1.9+2003+(R2018).pdf. Published October 2018. Accessed 28 August 2021.
12.) TGS-8, Quality control for in vitro diagnostic medical devices for WHO prequalification. World Health Organization. https://www.who.int/diagnostics_laboratory/guidance/190410_tgs_8_quality_control_ivd_for_comments.pdf. Published 09 April 2019. Accessed 14 August 2021.
13.) Diagnostic Testing and Screening for SARS-CoV-2. European Centre for Disease Prevention and Control. https://www.ecdc.europa.eu/en/covid-19/latest-evidence/diagnostic-testing. Last updated 21 May 2021. Accessed 29 August 2021.