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For in vitro diagnostic and laboratory professional use.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack when used in combination with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator is a chemiluminescent immunoassay intended for the qualitative detection of IgG antibodies to SARS-CoV-2 in human serum and plasma (K2-EDTA and K3-EDTA) samples collected on or after 15 days post-symptom onset using the VITROS ECi/ECiO/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated Systems. The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test is intended for use as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection.

VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator

For use in the calibration of the VITROS ECi/ECiQ/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated Systems for the in vitro qualitative detection of IgG antibodies to SARS-CoV-2 in human serum and plasma.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test is a qualitative chemiluminescent immunoassay performed on the VITROS Systems (VITROS ECi/ECiO Immunodiagnostic System, VITROS 3600 Immunodiagnostic System, VITROS 5600 Integrated System and VITROS XT 7600 Integrated System) providing fully automated random-access testing.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test is performed using the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack in combination with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator and the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Controls on the VITROS Systems.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack is supplied as ready to use and contains:

• 100 wells coated with 100ng/well of recombinant SARS-CoV-2 spike antigen derived from human cells.
• 18.0 mL assay reagent (buffer with bovine protein stabilizers and antimicrobial agent)
• 20.4 mL conjugate reagent [anti-human IgG (murine monoclonal) conjugated to horseradish peroxidase, 5ng/mL] in buffer with bovine protein stabilizers and antimicrobial agent.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator contains:

• 2 vials of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 1gG Calibrator 0 (anti-SARS-CoV-2 IgG in anti-SARS-CoV-2 IgG negative human serum with antimicrobial agent, 1 mL)
• Lot calibration card
• Protocol card
• 8 calibrator bar code labels

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Controls contain:

• 3 sets of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Controls 1 and 2 (defibrinated human plasma with anti-microbial agent, 2 mL). Control 1 is non-reactive and Control 2 is reactive

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test is designed for use on the VITROS Systems. The VITROS Systems use the following ancillary reagents (general purpose reagents):

• VITROS Immunodiagnostic Products Signal Reagent
• VITROS Immunodiagnostic Products Universal Wash Reagent

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

Device: VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack, VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator (Chemiluminescent Immunoassay)

Purpose: Qualitative detection of IgG antibodies to SARS-CoV-2 in human serum and plasma, intended for use as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection.

1. Table of Acceptance Criteria and Reported Device Performance

The document describes the performance of the device rather than explicitly stating pre-defined acceptance criteria in a dedicated table. However, we can infer the implicit acceptance criteria from the observed results and the FDA's decision to grant the De Novo request.

2. Sample Size and Data Provenance

• Test Set (Clinical Agreement Study):

  • Total Samples: 642 unique retrospective clinical samples.
  • Population 1 (SARS-CoV-2 Positive): 338 samples from individuals with a prior SARS-CoV-2 positive RT-PCR test result. Collected within the United States between April 2020 and March 2021.
  • Population 2 (Presumed SARS-CoV-2 Negative): 304 samples collected prior to December 2019 (pre-COVID-19 widespread outbreak) within the United States. 30% from blood donor centers.
  • Retrospective: All clinical samples were retrospective.

• Other Analytical Studies:

  • Assay Cut-Off: A collection of pre-COVID-19 negative samples and samples from RT-PCR positive individuals. (Specific count for cut-off determination not explicitly stated beyond "pre-COVID-19 samples" and "samples from individuals with a prior SARS-CoV-2 RT-PCR positive result").
  • Cross-Reactivity: Number of samples tested per category varied (e.g., 10 for Influenza A, 15 for HCV, 21 for OC43, etc.). Total ~300 instances of known interfering substances tested (summing 'Number of Samples Tested' from Table 6).
  • Interference: Tested using 3 reactive (low positive) and 3 non-reactive (negative) samples for each interferent.
  • Specimen Stability: Freshly drawn whole blood from individual donors (number not specified).
  • Analytical Sensitivity (CRM): Serial dilutions of WHO First International Standard for Anti-SARS-CoV-2 Immunoglobulin (human) code 20/136.

3. Number of Experts and Qualifications for Ground Truth

The document does not mention the use of experts or their qualifications for establishing ground truth. Instead, the ground truth for the clinical study was established based on:

• Population 1 (Positive): Prior SARS-CoV-2 positive RT-PCR test results (FDA-determined appropriate comparator).
• Population 2 (Negative): Samples collected prior to the widespread COVID-19 outbreak (pre-December 2019).

For analytical studies, ground truth was based on:

• Precision/Reproducibility: Defined panel members (control materials, plasma pools).
• Cross-Reactivity/Interference: Samples with known levels/presence of interfering substances.
• Analytical Sensitivity: WHO Certified Reference Material.

4. Adjudication Method for the Test Set

No adjudication method is described for the test set. The device's results were directly compared to the established RT-PCR status (for positive cases) or pre-COVID-19 status (for negative cases).

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC study was performed or described. This device is an automated in vitro diagnostic (IVD) immunoassay, not an AI-assisted imaging device, so MRMC studies involving human readers are not applicable to its evaluation. Its performance is machine-read.

6. Standalone Performance

Yes, the entire evaluation is based on the standalone performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test, as it is an automated IVD platform. There is no human-in-the-loop component for reading the assay results. The performance metrics (PPA, NPA, analytical performance) are all algorithm-only results.

7. Type of Ground Truth Used

• Clinical Ground Truth:
  • For positive cases: SARS-CoV-2 RT-PCR positive test result (as determined by an FDA-appropriate comparator).
  • For negative cases: Collection prior to the widespread COVID-19 pandemic (presumed negative).
• Analytical Ground Truth:
  • Known concentrations/presence of analytes/interfering substances (e.g., WHO Certified Reference Material for analytical sensitivity, defined control materials for precision, samples with known antibody status for cross-reactivity).

8. Sample Size for the Training Set

The document does not provide information about a separate "training set" for an AI or machine learning model. This device is a chemiluminescent immunoassay, which is a traditional laboratory diagnostic test following established biochemical principles, not a machine learning algorithm that requires a distinct training phase with labeled data in the same sense as an AI for image analysis.

The "assay cut-off" was determined using a collection of negative samples (prior to COVID-19) and samples from RT-PCR positive individuals. This process could be seen as optimizing the device's threshold for qualitative results, but it's not a "training set" for an AI model.

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

As noted above, a distinct "training set" for an AI model is not mentioned for this device. The assay cut-off was optimized using a Receiver Operating Characteristic (ROC) curve analysis on a collection of negative samples (collected prior to the pandemic) and samples from individuals with a prior RT-PCR positive result. This implicitly used the RT-PCR status or pre-pandemic status as the ground truth for establishing the optimal cut-off value.

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For in vitro diagnostic and laboratory professional use.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack when used in combination with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator is a chemiluminescent immunoassay intended for the qualitative detection of total antibodies to SARS-CoV-2 in human serum and plasma (K-EDTA. K-EDTA and lithium heparin) samples collected on or after 15 days post-symptom onset using the VITROS ECi/ECiQ/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated Systems. The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test is intended for use as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection.

For use in the calibration of the VITROS ECi/ECiO/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated Systems for the in vitro qualitative detection of total antibodies to SARS-CoV-2 in human serum and plasma.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test is a qualitative chemiluminescent immunoassay performed on the VITROS Systems (VITROS ECi/ECiQ Immunodiagnostic System, VITROS 3600 Immunodiagnostic System, VITROS 5600 Integrated System and VITROS XT 7600 Integrated System) providing fully automated random-access testing.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test is performed using the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack in combination with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator and the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Controls on the VITROS Systems.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack is supplied as ready to use and contains:

• . 100 coated wells (streptavidin, bacterial; binds ≥3 ng biotin per well; biotin recombinant SARS-CoV-2 antigen 0.1 ug/mL)
• 6.0 mL assay reagent (buffer with bovine protein stabilizers and antimicrobial agent) .
• . 16.2 mL conjugate reagent (HRP-recombinant SARS-CoV-2 antigen) in buffer with bovine protein stabilizers and antimicrobial agent

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator contains:

• . 2 vials of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator (anti-SARS-CoV-2 in anti-SARS-CoV-2 negative human plasma with antimicrobial agent, 1 mL)
• . Lot calibration card
• . Protocol card
• . 8 calibrator bar code labels

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Controls contain:

• . 3 sets of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Controls 1 and 2 (defibrinated human plasma with anti-microbial agent, 2 mL). Control 1 is non-reactive and Control 2 is reactive.
  The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test is designed for use on the VITROS Systems. The VITROS Systems use the following ancillary reagents (general purpose reagents):
• . VITROS Immunodiagnostic Products Signal Reagent
• VITROS Immunodiagnostic Products Universal Wash Reagent .

The document describes the evaluation of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack and VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator, a chemiluminescent immunoassay intended for qualitative detection of total antibodies to SARS-CoV-2.

Here's an analysis of the acceptance criteria and the study proving the device meets them:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state "acceptance criteria" for the clinical performance in a single, clear table with pass/fail thresholds. However, the Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) are the key clinical performance metrics presented. The FDA's decision to grant De Novo status implies that the reported performance met their internal criteria for safety and effectiveness for its intended use.

Here's a summary of the reported clinical performance:

Note: The PPA for samples collected early (0-7 days and 8-14 days post-symptom onset) is considerably lower (e.g., 36.00% to 44.00% for 0-7 days), reflecting the time required for antibody development. The indication for use specifies "samples collected on or after 15 days post-symptom onset," making the PPA for ≥15 days the most relevant for the primary intended use.

2. Sample sized used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

• Test Set Sample Size:

  • PPA (Clinical Sensitivity Equivalent): 296 samples from individuals with prior SARS-CoV-2 positive RT-PCR results were initially acquired. However, the "Number of Subjects Tested" varies slightly per analyzer, typically around 282-286 for individual system reporting, and 237-239 for the ≥15 days post-symptom onset group which is the most relevant for the device's claims.
  • NPA (Clinical Specificity Equivalent): 513 presumed SARS-CoV-2 negative samples collected prior to the COVID-19 pandemic. The "Presumed Negative" count also varies slightly per analyzer, typically around 505-511.

• Data Provenance:

  • Country of Origin: All samples were collected within the United States.
  • Retrospective or Prospective: The samples were collected retrospectively. Population 1 (positive samples) was collected between April 2020 and April 2021. Population 2 (negative samples) was collected prior to December 2019.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This is an in vitro diagnostic device for antibody detection, not an imaging AI system. Therefore, the "ground truth" for the clinical study was established by RT-PCR test results for SARS-CoV-2 infection (for positive samples) and collection of samples prior to the COVID-19 pandemic (for negative samples). There is no mention of human experts (e.g., pathologists or radiologists) adjudicating the ground truth for this type of test.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Not applicable for this type of in vitro diagnostic test where RT-PCR is the comparator and pre-pandemic samples define the negative group. Discrepancy resolution with expert radiologists would be relevant for imaging-based AI studies, not serology tests.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

Not applicable. This is an in vitro diagnostic (IVD) device for laboratory use, not an AI-assisted diagnostic tool for human readers (e.g., radiologists interpreting images). Its performance is evaluated as a standalone laboratory test.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, the clinical performance (PPA and NPA) presented for the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test is its standalone performance as an automated laboratory assay. There is no human-in-the-loop component for the interpretation or usage of the result beyond the laboratory professional's decision to report the qualitative positive/negative result.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)

• For Positive Samples (PPA): Ground truth was established by prior SARS-CoV-2 positive RT-PCR test results. The document states, "...using a comparator that FDA determined is appropriate (RT-PCR test)."
• For Negative Samples (NPA): Ground truth was established by collection date prior to the widespread outbreak of COVID-19 (i.e., prior to December 2019), deeming them "presumed SARS-CoV-2 negative samples."

8. The sample size for the training set

This document describes the validation of a commercial in vitro diagnostic (IVD) product, not an AI/machine learning model where a distinct 'training set' of patient data in the typical AI sense would be used to train the algorithm. The "training" of this device involves the development and optimization of the chemical reagents, assay parameters, and cutoff values performed internally by the manufacturer (Ortho-Clinical Diagnostics).

The closest equivalent to a "training" activity described in the context of setting the device's operational parameters is the Assay Cut-Off determination study (page 12-13). This study used:

• "a collection of negative samples collected prior to the COVID-19 pandemic"
• "samples collected from individuals with a prior SARS-CoV-2 RT-PCR positive result."

The specific numbers of these samples for the cutoff determination are not explicitly stated, but are implied to be part of the broader pool of samples available to the manufacturer during development. The ROC curve analysis was performed on these samples to optimize sensitivity and specificity at the S/C = 1.00 cutoff.

9. How the ground truth for the training set was established

As noted in point 8, this isn't an AI model with a conventional training set. For the "samples" used in the Assay Cut-Off determination (analogous to internal optimization/training data):

• Negative Ground Truth: Established by "negative samples collected prior to the COVID-19 pandemic."
• Positive Ground Truth: Established by "samples collected from individuals with a prior SARS-CoV-2 RT-PCR positive result."

This implies a similar method to the clinical validation set for establishing true positive and true negative status, but performed during the device development phase to define the S/C cutoff.

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