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cobas SARS-CoV-2 Qualitative for use on the cobas 6800/8800 Systems is a real-time RT-PCR test intended for the qualitative detection of nucleic acids from SARS-CoV-2 in nasal and nasopharyngeal specimens collected from symptomatic individuals suspected of COVID-19 by their healthcare provider.

Results are for the detection of SARS-CoV-2 RNA. Positive results are indicative of the presence of SARS-CoV-2 RNA; clinical correlation with patient history and other diagnostic information is necessary to determine patient infection status. Positive results do not rule out bacterial infection or co-infection with other pathogens.

Negative results do not preclude SARS-CoV-2 infection and should not be used as the sole basis for patient management decisions. Results are meant to be used in conjunction with clinical observations, patient history, recent exposures and epidemiological information, and laboratory data, in accordance with the guidelines provided by the relevant public health authorities. cobas SARS-CoV-2 is intended for use by qualified clinical laboratory personnel specifically instructed and trained in the techniques of real-time PCR and on the use of the cobas 6800/8800 Systems.

cobas SARS-CoV-2 Qualitative is based on fully automated sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection. The cobas 6800/8800 Systems consist of the sample supply module, the transfer module, the processing module, and the analytic module. Automated data management is performed by the cobas 6800/8800 Systems software(s), which assigns test results for all tests. Results can be reviewed directly on the system screen and printed as a report.

Nucleic acid from patient samples and added internal control RNA (RNA IC) molecules are simultaneously extracted. Nucleic acid is released by addition of proteinase and lysis reagent to the sample. The released nucleic acid binds to the silica surface of the added magnetic glass particles. Unbound substances and impurities, such as denatured protein, cellular debris and potential PCR inhibitors, are removed with subsequent wash steps and purified nucleic acid is eluted from the magnetic glass particles with elution buffer at elevated temperature. External controls (positive and negative) are processed in the same way.

Selective amplification of target nucleic acid from the sample is achieved by the use of target-specific forward and reverse primers for ORF1 a/b non-structural region that is unique to SARS-CoV-2. Additionally, a conserved region in the structural protein envelope E-gene were chosen for pan-Sarbecovirus detection. The pan-Sarbecovirus detection sets will also detect SARS-CoV-2 virus.

Selective amplification of RNA Internal Control is achieved by the use of non-competitive sequence specific forward and reverse primers which have no homology with the coronavirus genome. A thermostable DNA polymerase enzyme is used for amplification.

The cobas SARS-CoV-2 Qualitative master mix contains detection probes which are specific for the coronavirus type SARS-CoV-2, members of the Sarbecovirus subgenus, and the RNA Internal Control nucleic acid. The coronavirus and RNA Internal Control detection probes are each labeled with unique fluorescent dyes that act as a reporter. Each probe also has a second dye which acts as a quencher. When not bound to the target sequence, the fluorescent signals of the intact probes are suppressed by the quencher dye. During the PCR amplification step, hybridization of the probes to the specific single-stranded DNA template results in cleavage of the probe by the 5' to 3' exonuclease activity of the DNA polymerase resulting in separation of the reporter and quencher dyes and the generation of a fluorescent signal. With each PCR cycle, increasing amounts of cleaved probes are generated and the cumulative signal of the reporter dye increases concomitantly. Each reporter dye is measured at defined wavelengths, which enables simultaneous detection and discrimination of the amplified coronavirus target and the RNA Internal Control. The master mix includes deoxyuridine triphosphate (dUTP), instead of deoxythimidine triphosphate (dTTP), which is incorporated into the newly synthesized DNA (amplicon). Any contaminating amplicons from previous PCR runs are destroyed by the AmpErase enzyme [uracil-N-glycosylase], which is included in the PCR mix, when heated in the first thermal cycling step. However, newly formed amplicons are not destroyed since the AmpErase enzyme is inactivated once exposed to temperatures above 55℃.

Here's a detailed breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

1. Table of Acceptance Criteria and Reported Device Performance

Note: The document does not explicitly state "acceptance criteria" for clinical performance in a pass/fail format with numerical targets. Instead, it presents the achieved performance. Therefore, the "Acceptance Criteria" column below reflects typical expectations for such devices based on the reported performance.

2. Sample Size Used for the Test Set and Data Provenance

• Clinical Performance Test Set (Clinical Specimens):

  • Total Participants enrolled: 1,154
  • Participants included in evaluation: 968
  • Reasons for exclusion: 184 specimens due to shipment issues/testing completion issues, 2 subjects for being previously enrolled.
  • Evaluable NPS results: 938 (961 participants contributed NPS, 4 failed/invalid cobas results)
  • Evaluable NS results: 934 (8 invalid/missing cobas NS results)
  • Confirmed infected status (NPS comparator): 942 participants
  • Data Provenance: Multi-center study with three external testing sites, involving prospectively collected clinical specimens (NPS and NS) from individuals with signs and symptoms of respiratory infection. Participants from 12 geographically distributed enrollment centers. The specific countries are not mentioned, but "US Food & Drug Administration" implies a US-based study or one for US market approval.

• Analytical Performance Test Sets:

  • Analytical Sensitivity (LoD): 5 concentration levels, 24 replicates per concentration, 3 independent dilution series with 3 lots of reagents.
  • Inclusivity: 9 SARS-CoV-2 strains, 4 replicates each.
  • Precision: 3 concentration levels, 90 replicates per concentration (over 15 instrument days).
  • Reproducibility: 4-member panel (positive/negative), 216 tests per concentration (at 3 testing sites, 3 reagent lots, 6 days, 2 runs/day, 3 replicates/run).
  • Analytical Specificity/Cross-reactivity: 47 microorganisms (at specified concentrations) tested in absence and presence of SARS-CoV-2 target.
  • Interference (Exogenous/Endogenous): Multiple substances at specified concentrations, tested in absence and presence of SARS-CoV-2 target.
  • Matrix Equivalency: 3 matrices (simulated, NPS, NS), 3 concentration levels (approx. 3x LoD, 1x LoD, 0.3x LoD), 25 replicates per concentration.
  • Collection Media Equivalency: 3 media types (UTM-RT, CPM, NaCl), 2 concentration levels (approx. 2x LoD, 4x LoD), at least 20 replicates for low positive, 10 for moderate positive.
  • Data Provenance: All these analytical studies appear to be laboratory-based and controlled, usually performed by the manufacturer or authorized labs. No specific country of origin is stated for these analytical studies, but they are part of the submission to the US FDA.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

The document refers to "healthcare provider" for collecting specimens and for associating patient history and diagnostic information, but does not specify the number or qualifications of experts (e.g., radiologists) used to establish the ground truth for the test set specifically for interpreting images or providing expert consensus.

Instead, for the clinical performance evaluation, the ground truth was established using a composite comparator method (described below), rather than expert consensus on a subjective measure. For laboratory-based analytical studies, ground truth is based on known concentrations of viral material.

4. Adjudication Method for the Test Set

The ground truth for the clinical test set was established using a composite comparator method:

• Method: Laboratory sites used up to three highly sensitive EUA SARS-CoV-2 molecular assays.
• Initial Comparison: The composite comparator result was defined as the concordant results from two initial comparator assays (Test A and Test B) on the NPS specimen from each subject.
• Discordance Resolution: In case of discordance between the initial two comparator assays, the sample was tested by a third assay (Test C), and the result of the third test determined the composite comparator result.
• Indeterminate Results: The composite comparator result was deemed indeterminate if valid results could not be obtained from two assays (e.g., insufficient volume for repeat testing or invalid/failed results).

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This document describes the performance of a diagnostic assay (RT-PCR test), not an AI-assisted diagnostic imaging device that involves human readers. Therefore, there is no mention of human readers or improvement with AI assistance.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, the performance study presented is a standalone (algorithm only) performance. The device is an automated RT-PCR test system (cobas SARS-CoV-2 Qualitative for use on the cobas 6800/8800 Systems). Its performance characteristics (analytical sensitivity, specificity, precision, clinical PPA/NPA) are measured directly against established standards or a composite comparator, without human interpretation of the assay results changing its output. The system software assigns test results.

7. The Type of Ground Truth Used

• Clinical Performance: Composite comparator method using up to three highly sensitive EUA SARS-CoV-2 molecular assays on NPS specimens.
• Analytical Performance:
  • Known concentrations of inactivated quantified SARS-CoV-2 virus (WHO International Standard) for LoD and reproducibility.
  • Known SARS-CoV-2 strains for inclusivity.
  • Known concentrations of various microorganisms or substances for analytical specificity and interference studies.

8. The Sample Size for the Training Set

The document describes a cobas SARS-CoV-2 Qualitative test, which is a real-time RT-PCR assay and not an AI/Machine Learning model. Therefore, the concept of a "training set" in the context of machine learning does not apply here. The document details validation studies for the assay, not the training of an algorithmic model.

9. How the Ground Truth for the Training Set Was Established

As stated above, this is an RT-PCR assay, not an AI/ML model. Therefore, there is no training set and consequently, no ground truth established for a training set. The performance is validated through various analytical and clinical studies as outlined in the document.

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