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Elecsys Anti-SARS-CoV-2 is an immunoassay intended for the in vitro qualitative detection of total antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in human serum and Li-heparin, K2-EDTA and K3-EDTA plasma collected on or after 15 days post-symptom onset. The test is intended as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e 601 immunoassay analyzer.

Elecsys Anti-SARS-CoV-2 is a qualitative, serological, double-antigen sandwich principle immunoassay to be used on the cobas e 601 analyzer with an 18-minute test time. Results are determined automatically by the software by comparing the electrochemiluminescence signal obtained from the reaction product of the sample with the signal of the cutoff value previously obtained by calibration. The Elecsys Anti‑SARS‑CoV-2 assay uses a recombinant protein representing the nucleocapsid (N) antigen for the determination of antibodies against SARS‑CoV‑2.

The reagent working solutions include: rackpack (kit placed on the analyzer)

• M Streptavidin-coated microparticles (transparent cap), 1 bottle, 12 mL: Streptavidin-coated microparticles 0.72 mg/mL; preservative.
• R1 SARS-CoV-2-Ag~biotin, (gray cap), 1 bottle, 16 mL: Biotinylated SARS‑CoV‑2‑specific recombinant antigen (E. coli)

The provided FDA 510(k) clearance letter and summary describe the acceptance criteria and the study that proves the device, Elecsys Anti-SARS-CoV-2, meets those criteria.

Here's the breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" as clear numerical targets for PPA and NPA prior to presenting the results. However, implied acceptance criteria for qualitative serology tests typically involve a high percentage of agreement. Based on the reported performance, we can infer the acceptance criteria were met by these results.

Additional Non-Clinical Acceptance Criteria (Met for all):

• Precision: Standard Deviation (SD) and Coefficient of Variance (CV) values within predetermined limits for repeatability, between-run, between-day, between-lot, and between-site precision.
• Hook Effect: No hook effect observed.
• Potential Interference (Endogenous Substances): Biotin tolerance $\le$ 1200 ng/mL; no interference within specification for Intralipid, Bilirubin, Hemoglobin, Rheumatoid Factor, IgG, IgM, IgA, human serum albumin, ANA, cholesterol, and triglycerides.
• Analytical Cutoff Sensitivity: Cutoff of 1.00 COI corresponds to 1.137 BAU/mL (demonstrated alignment with international standard).
• Analytical Specificity- Potential Cross-Reactivity: False positive rate for cross-reacting antibodies within acceptable limits (2 false positives out of 7 MERS-CoV glycoprotein samples observed, overall 1836 samples tested).
• Exogenous Interference: Results within specification for 17 common drugs and 18 special drugs (with the exception of Ritonavir, which was within specification at 1x daily dose).
• Matrix Comparison: Matrix equivalency demonstrated for serum, Li-Heparin, K2-EDTA, K3-EDTA plasma, and separation gel tubes.
• Reagent, Calibrator, and Control Stability: Met stated storage times and conditions (e.g., 28 days on-board reagent, 10 hours on-board PreciControl, 30 days refrigerator after first opening, 28 days after first opening for PreciControl, 25 days lot calibration stability, 7 days on-board calibration stability).
• Specimen Stability: Met stated storage times and conditions (e.g., 7 days at 15-25°C, 14 days at 2-8°C, 28 days at -20°C, 3 freeze-thaw cycles).
• Fresh/Frozen Study: All results within specification for fresh vs. frozen samples.

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

• Negative Percent Agreement (NPA):
  • Sample Size: 9007 pre-pandemic specimens.
  • Data Provenance: Not explicitly stated (e.g., country of origin), but implicitly "pre-pandemic" suggests samples collected before December 2019. This is retrospective data.
• Positive Percent Agreement (PPA) - Traditional Clinical Study:
  • Sample Size: 254 specimens collected $\ge$ 15 days post symptom onset (DPSO), excluding COVID-19 vaccinated individuals and immunocompromised subjects.
  • Data Provenance: Not explicitly stated (e.g., country of origin), but described as collected under "routine laboratory conditions." This is retrospective or potentially a mix of retrospective and prospective, reflecting real clinical samples.
• PPA - Real-World Data:
  • Sample Size: 285 samples from non-immunocompromised subjects who did not receive the COVID-19 vaccine, collected $\ge$ 15 DPSO.
  • Data Provenance: Collaborating institution in the United States, collected from March 2020 – March 2021. This is retrospective data.

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

For this serology test, the ground truth is established through laboratory methods, not by human expert readers in the way an imaging AI would be adjudicated.

• NPA: Ground truth was "presumed to be negative for anti-SARS-CoV-2 antibodies" based on collection before December 2019, prior to the widespread circulation of SARS-CoV-2.
• PPA (Traditional Clinical Study): Ground truth was established by a composite comparator method comprised of 3 SARS-CoV-2 serology assays (including the predicate assay). Seropositivity was determined by majority rule ($\ge$ 2 out of 3). Additionally, these individuals had a history of SARS-CoV-2 infection confirmed by a prior FDA authorized RT-PCR test.
• PPA (Real-World Data): Ground truth was established by PCR as the comparator. Data was collected from electronic medical records and laboratory information systems.

Qualifications of Experts: Not applicable in the context of serology ground truth determination as it relies on other laboratory assays.

4. Adjudication Method (e.g., 2+1, 3+1, none) for the Test Set

• NPA: No adjudication method as samples were "presumed negative" based on collection date.
• PPA (Traditional Clinical Study): A form of "majority rule" for the composite comparator method was used: $\ge$ 2 out of 3 serology assays. This is akin to a 2/3 agreement rule, but applied to the reference method rather than human readers adjudicating an AI's output. The confirmatory RT-PCR also served as a strong initial ground truth.
• PPA (Real-World Data): PCR was the direct comparator, so no explicit adjudication method beyond the result of the PCR test itself.

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

This is a clinical laboratory immunoassay (serology test), not an AI software intended for medical image interpretation or human-in-the-loop assistance. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not applicable and was not performed.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

The device itself is a standalone immunoassay system (Elecsys Anti-SARS-CoV-2 on the cobas e 601 analyzer) that provides a qualitative result (positive/negative) automatically. The entire clinical performance evaluation section describes the standalone performance of this device against established ground truths. Thus, a standalone performance evaluation was indeed done.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

• NPA: Pre-pandemic sample collection date (before December 2019), implying presumed negative status. This serves as a strong epidemiological ground truth for SARS-CoV-2 negativity.
• PPA (Traditional Clinical Study):
  • Composite Comparator Method: Majority rule ($\ge$ 2 out of 3) of other FDA-de novo and EUA-authorized Anti-SARS-CoV-2 serology assays.
  • Confirmatory RT-PCR: Individuals had a history of SARS-CoV-2 infection confirmed by a prior FDA authorized RT-PCR test.
• PPA (Real-World Data): FDA authorized RT-PCR test results from electronic medical records and laboratory information systems.

In summary, the ground truth primarily relies on a combination of other FDA-authorized laboratory tests (serology and RT-PCR) and epidemiological/temporal evidence.

8. The Sample Size for the Training Set

This document describes the validation of a serology immunoassay, not a machine learning or AI model. Therefore, there is no "training set" in the context of AI model development. The "training" for such an assay would typically involve analytical development and optimization of reagents and protocols, not a data-driven training set in the AI sense.

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

As there is no AI training set described or applicable for this type of device, this question is not relevant to the provided information. The ground truth for performance evaluation was established as described in point 7.

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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.

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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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