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K Number
DEN210038
Device Name
VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack, VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator
Manufacturer
Ortho-Clinical Diagnostics, Inc.
Date Cleared
2023-05-05

(592 days)

Product Code
QVP
Regulation Number
866.3983
Type
Direct
Panel
Microbiology
Reference & Predicate Devices
K962919,K083173,K081543,K182063
Predicate For
N/A
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
Intended Use

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.

Device Description

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
AI/ML Overview

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.

Performance MetricImplied Acceptance Criteria (via observed performance & FDA acceptance)Reported Device Performance (Summary)
Clinical Performance (PPA)High PPA for samples collected ≥15 days post-symptom onset, sufficient to aid in identifying prior infection.VITROS ECi/ECiQ: 93.86% (95% CI: 90.50%-96.10%) for ≥15 days post-symptom onset (N=293). VITROS 3600/5600: 93.52% (95% CI: 90.10%-95.81%) for ≥15 days post-symptom onset (N=293). VITROS XT 7600: 93.49% (95% CI: 90.10%-95.80%) for ≥15 days post-symptom onset (N=292). Lower PPA for earlier time bins (0-7 days: ~41-45%; 8-14 days: ~52%).
Clinical Performance (NPA)High NPA for presumed negative samples, demonstrating low false positive rate.VITROS ECi/ECiQ/3600/5600: 99.01% (95% CI: 97.14%-99.66%) (N=304). VITROS XT 7600: 99.01% (95% CI: 97.13%-99.66%) (N=303).
Precision/ReproducibilityAcceptable within-laboratory and between-laboratory variability for a diagnostic immunoassay.Within-Laboratory: Total precision %CV for S/C values ranged from 3.4% - 32.2% depending on sample and instrument. Reproducibility (Between-Laboratory): Total reproducibility %CV for S/C values ranged from 6.1% - 22.8% depending on sample and instrument. (%CVs are not meaningful for S/C results < 0.50).
Analytical Specificity (Cross-Reactivity)No significant cross-reactivity with common interfering substances/conditions.No cross-reactivity observed with any of the 40+ evaluated cross-reactants (e.g., various virus antibodies, bacteria antibodies, autoantibodies).
Analytical Specificity (Interference)Minimal interference from common endogenous and exogenous substances.All tested substances shown to not interfere (<10% bias for low reactive samples and bias <0.22 S/C for non-reactive samples), with one exception: amlodipine showed a negative bias (-11.1% change of S/C) in reactive samples at a specific concentration.
Specimen StabilityDemonstrated stability under specified storage conditions.Supported for serum & plasma (K2-EDTA, K3-EDTA) at Room Temp (15-30°C) for ≤24 hours, Refrigerated (2-8°C) for ≤7 days, Frozen (≤-20°C) for ≤4 weeks, and up to 5 freeze-thaw cycles (for frozen).
Calibration StabilityMaintained performance over specified calibration interval.Supports a calibration interval stability of 28 days.
Matrix EquivalencyEquivalent performance across serum, K2-EDTA plasma, and K3-EDTA plasma.Weighted Deming regression analysis showed no significant deviation, demonstrating equivalency between K2-EDTA plasma, K3-EDTA plasma, and serum.

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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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food & Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the text "FDA U.S. FOOD & DRUG ADMINISTRATION" on the right. The symbol features a stylized image of an eagle, while the text is written in blue, with "FDA" in a larger, bolder font than the rest of the text.

EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack, VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator DECISION SUMMARY

Background Information: I

A De Novo Number

DEN210038

B Applicant

Ortho-Clinical Diagnostics, Inc.

C Proprietary and Established Names

VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack, VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator

D Regulatory Information

ProductCode(s)ClassificationRegulationSectionPanel
QVPClass II21 CFR 866.3983 - SARS-CoV-2 serology testMI - Microbiology

II Submission/Device Overview:

A Purpose for Submission:

De Novo request for evaluation of automatic class II designation for the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test comprised of (1) the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack, (2) the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator, and (3) the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Controls.

B Measurand:

IgG antibodies to SARS-CoV-2 in human serum, K2-EDTA plasma, and K3-EDTA plasma.

C Type of Test:

Chemiluminescent Immunoassay.

III Indications for Use:

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A Indication(s) for Use: Rx ONLY

For in vitro diagnostic and laboratory professional use.

VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack

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.

B Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

C Special Instrument Requirements:

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 Calibrators uses the following VITROS Systems (instruments):

  • VITROS ECi/ECiQ Immunodiagnostic Systems .
  • VITROS 3600 Immunodiagnostic Systems .
  • . VITROS 5600 Integrated Systems
  • . VITROS XT 7600 Integrated Systems

These VITROS systems were cleared previously as part of premarket notifications: K962919, K083173, K081543, and K182063 respectively,

IV Device/System Characteristics:

A Device Description:

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

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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 .

B Principle of Operation

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test is performed using the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack and the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator on the VITROS ECi/ECiO/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated Systems. An immunometric technique is used; this involves a two- stage reaction. In the first stage antibodies to SARS-CoV-2 present in the sample bind with SARS-CoV-2 spike protein coated on the well. Unbound sample is removed by washing. In the second stage horseradish peroxidase (HRP)-labeled murine monoclonal anti-human IgG antibodies are

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added in the conjugate reagent. The conjugate binds specifically to the antibody portion of the antigen-antibody complex. If complexes are not present, the unbound conjugate is removed by the subsequent wash step.

The bound HRP conjugate is measured by a luminescent reaction. A reagent containing luminogenic substrates (a luminol derivative and a peracid salt) and an electron transfer agent is added to the wells. The HRP in the bound conjugate catalyzes the oxidation of the luminol derivative, producing light. The electron transfer agent (a substituted acetanilide) increases the level of light produced and prolongs its emission. The light signals are read by the system.

Test TypeSystemIncubation TimeTime to first resultTest TemperatureReaction SampleVolume
ImmunometricECi/ECiQ. 3600.5600. XT 760037 minutes48 minutes37 ℃20 ul
  • Not all products and systems are available in all countries.

Figure 1: Reaction Scheme

Image /page/3/Figure/5 description: The image shows a diagram of a process involving several components. It starts with a recombinant SARS-CoV-2 antigen, followed by Anti-SARS-CoV-2, and then HRP-labeled anti-human IgG murine monoclonal. The process culminates in luminescence, which is achieved using a signal reagent with an enhancer.

C Instrument Description Information

1. Instrument Name:

VITROS Systems (instruments):

  • . VITROS ECi/ECiQ Immunodiagnostic System
  • . VITROS 3600 Immunodiagnostic System
  • VITROS 5600 Integrated System .
  • VITROS XT 7600 Integrated System. .
    1. Specimen Identification:

Not applicable

    1. Specimen Sampling and Handling:

Specimen Sampling:

The specimens recommended for this assay are:

  • . Serum
  • K2-EDTA Plasma
  • K3-EDTA Plasma

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Specimen Handling and Storage:

  • . Specimens may be stored for up to 24 hours at room temperature (15-30℃) or 7 days at 2 - 8ºC.
  • Specimens may be stored frozen at < 20°C for <4 weeks. .
  • Specimens may be subjected to up to one freeze-thaw cvcles. .

4. Calibration:

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator is provided together with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator contains anti-SARS-CoV-2 IgG in human serum. In addition, the calibrator contains the lot calibration card, protocol card and 8 calibrator bar code labels.

Calibration is lot-specific: reagent packs and calibrators are linked by lot number. Reagent packs from the same lot may use the same calibration. The calibrator is supplied frozen. The analyzer automatically processes the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Calibrator in duplicate. Results are calculated as a normalized signal, relative to a cutoff value. During the calibration process a lot-specific parameter is used to determine a valid stored cutoff value for the VITROS Immunodiagnostic and VITROS Integrated Systems.

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test should be calibrated:

  • . When the reagent pack and calibrator lot changes
  • . Every 28 days
  • After specified service procedures have been performed .
  • If quality control results are consistently outside of the acceptable range. .

5. Quality Control:

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Controls are provided separately from the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack, and contains:

  • · Control I: Anti-SARS-CoV-2 IgG non-reactive human serum or defibrinated plasma.
  • . Control 2: Anti-SARS-CoV-2 IgG reactive human serum or defibrinated plasma.

Quality Control Procedure

  • To verify system performance, analyze control materials: .
    • O After calibration
    • o If the system is turned off for more than 2 hours
    • · After reloading reagent packs that have been removed from the MicroWell Supply and stored for later use
    • According to local regulations or at least once each day that the test is performed

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  • · After specified service procedures are performed
  • . If controls results fall outside the acceptance range, investigate the cause before deciding whether to report patient results.

V Standards/Guidance Documents Referenced:

CLSI EP05-A3 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition

CLSI EP07 Interference testing in Clinical Chemistry

  • CLSI EP09 Measurement Procedure Comparison and Bias Estimation Using Patient Samples. Third Edition (2016).
  • CLSI EP35 Assessment of Equivalence or Suitability of Specimen Type for Medical Laboratory measurement Procedure

CLSI EP37 Supplemental Tables for Interference Testing in Clinical Chemistry

Performance Characteristics: VI

A Analytical Performance:

1. Precision/Reproducibility:

A. Within-Laboratory Precision: The within laboratory precision of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test was evaluated with EDTA plasma pools samples (PP4, PP5, and PP6), negative and positive quality control materials (PP1, PP2), and the calibrator (PP3) on the VITROS ECi/ECiQ and 3600 Immunodiagnostics Systems and the VITROS 5600 and XT7600 Integrated Systems following the CLSI document EP05-A3. A total of 3 lots of reagent packs, calibrators and controls were included in the study. For each reagent lot, operators ran two replicates of each precision panel sample on two occasions per day for twenty non-consecutive days.

The data presented are a representation of test performance and are provided as a guideline. Variables such as sample handling and storage, reagent handling and storage, laboratory environment, and system maintenance can affect reproducibility of test results.

Each precision panel was tested in duplicate, in two runs per day, on 20 non-consecutive days, on each instrument for a total of 80 observations per sample and lot. The study included three reagent lots and was evaluated within a single calibration cycle (2 replicates x 2 runs x 20 days x 3 lots= 240 observations total). The VITROS Anti-SARS-CoV-2 IgG's total precision %CV (from the "total" standard deviation) for the S/C values ranged from 3.4% -32.2%, depending upon the sample and instrument.

VITROSSystemPanelmemberNumberofObserv.GrandMean(S/C)Repeatability(Within Run)Between-RunBetween-DayBetween-LotWithin-Laboratory
ECi/ECiQPP12400.000.000N/A0.000N/A0.000N/A0.001N/A0.001N/A
ECi/ECiQPP22400.920.0182.00.0242.60.0343.70.0303.30.0545.9

Table 1. Within-Laboratory Precision Study Data Summary (for all 4 VITROS analyzers).

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PP32400.250.007N/A0.011N/A0.011N/A0.013N/A0.022N/A
PP42400.940.0272.90.0323.40.0333.50.0919.70.10611.3
PP52403.250.0862.60.0621.90.0842.60.1695.20.2166.6
PP62407.620.0630.80.0761.00.1121.50.2082.70.2573.4
PP12400.000.000N/A0.000N/A0.001N/A0.002N/A0.002N/A
PP22401.180.0242.00.0252.10.0211.80.24020.30.24320.6
PP32400.320.007N/A0.008N/A0.006N/A0.078N/A0.079N/A
3600PP42401.180.0282.40.0342.90.0332.80.37631.90.38032.2
PP52403.940.0832.10.0922.30.0721.81.06427.01.07327.2
PP62408.560.0991.20.0991.20.1051.21.61018.81.61918.9
PP12400.000.000N/A0.000N/A0.000N/A0.001N/A0.001N/A
PP22401.030.0201.90.0272.60.0272.60.0585.60.0727.0
PP32400.280.006N/A0.010N/A0.007N/A0.025N/A0.028N/A
5600PP42401.020.0262.50.0363.50.0262.50.14013.70.14914.6
PP52403.430.0732.10.0742.20.0952.80.2888.40.3219.4
PP62407.510.0971.30.1051.40.1191.60.2763.70.3334.4
PP12400.000.000N/A0.000N/A0.000N/A0.001N/A0.001N/A
PP22401.210.0433.60.0423.50.0161.30.15312.60.16513.6
PP32400.320.009N/A0.009N/A0.010N/A0.052N/A0.055N/A
XT 7600PP42401.190.0342.90.0423.50.0373.10.23920.10.24820.8
PP52403.940.0782.00.0932.40.0882.20.60415.30.62215.8
PP62408.460.1131.30.1171.40.0981.20.89610.60.91610.8

N/A: Not Applicable, %CV is not meaningful for S/C results <0.5.

B. Reproducibility (Between-Laboratory Precision): The reproducibility of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test was determined with EDTA plasma pools samples (GRP4, GRP5, and GRP6), quality controls (GRP1 and GRP2) and customer calibrator (GRP3) using the VITROS ECi/ECiQ and 3600 Immunodiagnostics Systems, and the VITROS 5600 and XT7600 Integrated Systems. Samples were measured in triplicate using 3 reagent lots, in 2 runs per day over 5 days at 3 sites, according to CLSI EP05-A3. Variance components were calculated. The VITROS Anti-SARS-CoV-2 IgG test total reproducibility %CV (from the "total" standard deviation) for the S/C values ranged from 6.1% - 22.8%, depending upon the sample and instrument. The following results were observed per analyzer:

Table 2. Reproducibility of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test evaluated on VITROS ECi/ECiO Immunodiagnostic Systems

PanelMemberrNumberofObserv.GrandMean(S/C)Repeatability(Within Run)Between RunBetween DayBetween LotaWithin-LaboratorybBetween-SitecReproducibility(Overall)d
SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
GRP12700.010.002N/A+0.000N/A+0.000N/A+0.003N/A+0.003N/A+0.003N/A+0.006N/A+
GRP22700.980.0585.90.0000.00.0212.20.0000.00.0626.30.0181.80.0959.6
GRP32700.280.016N/A+0.007N/A+0.010N/A+0.021N/A+0.029N/A+0.000N/A+0.034N/A+
GRP42701.080.0595.50.0111.00.0353.20.20619.20.21720.20.0000.00.22521.0
GRP52703.590.1644.60.0401.10.0712.00.47913.30.51314.30.0240.70.54515.2
GRP62707.840.2202.80.0000.00.0911.20.4255.40.4876.20.3114.00.6658.5

11 Between lot: Variability of the test performance from lot to lot.

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b Within-Laboratory variability contains the Within Run, Between Run, Between Day and Between Lot variance components.

Between site: Variability of the test performance from site to site.

d Reproducibility: Variability of the test incorporating factors of site, lot, run and day.

  • % CVs are not meaningful for S/C results < 0.50.
PanelMemberNumber of Observ.Grand Mean (S/C)Repeatability (Within Run)Between RunBetween DayBetween LotaWithin-LaboratorybBetween-SitecReproducibility (Overall)d
SDCV (%)SDCV (%)SDCV (%)SDCV (%)SDCV (%)SDCV (%)SDCV (%)
GRP12700.000.001N/A+0.000N/A+0.001N/A+0.001N/A+0.002N/A+0.001N/A+0.002N/A+
GRP22701.050.0464.40.0000.00.0292.80.0514.90.0747.10.0101.00.0898.5
GRP32700.290.012N/A+0.003N/A+0.012N/A+0.026N/A+0.032N/A+0.008N/A+0.038N/A+
GRP42701.080.0434.00.0121.10.0171.50.23021.40.23521.90.0333.10.24522.8
GRP52703.570.1083.00.0401.10.0491.40.57516.10.58816.50.0822.30.61517.3
GRP62707.530.1321.80.0310.40.0550.70.4455.90.4686.20.0000.00.5096.8

Table 3. Reproducibility of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test evaluated on VITROS 3600 Immunodiagnostic Systems

a Between lot: Variability of the test performance from lot to lot.

b Within-Laboratory variability contains the Within Run, Between Run, Between Day and Between Lot variance components.

Between site: Variability of the test performance from site to site.

d Reproducibility: Variability of the test incorporating factors of site. lot, run and day.

  • %CVs are not meaningful for S/C results < 0.50

Table 4. Reproducibility of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test evaluated on VITROS 5600 Integrated Systems

PanelMemberNumberofObserv.GrandMean(S/C)Repeatability(Within Run)Between RunBetween DayBetween LotaWithin-LaboratorybBetween-SitecReproducibility(Overall)d
SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
GRP12700.000.000N/A+0.000N/A+0.001N/A+0.001N/A+0.001N/A+0.002N/A+0.002N/A+
GRP22701.050.0858.10.0000.00.0000.00.0454.30.0979.20.0000.00.11911.3
GRP32700.290.015N/A+0.002N/A+0.004N/A+0.020N/A+0.025N/A+0.002N/A+0.031N/A+
GRP42701.080.0504.60.0090.80.0272.50.20418.90.21219.70.0000.00.22120.5
GRP52703.580.1032.90.0170.50.0992.80.48313.50.50414.10.0000.00.53815.1
GRP62707.550.1371.80.0060.10.1612.10.2513.30.3284.30.0000.00.4846.4

al Between lot: Variability of the test performance from lot to lot.

b Within-Laboratory variability contains the Within Run, Between Run, Between Day and Between Lot variance components.

· Between site: Variability of the test performance from site to site.

d Reproducibility: Variability of the test incorporating factors of site, lot, run and day.

  • % CVs are not meaningful for S/C results < 0.50.
Table 5. Reproducibility of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG
test evaluated on VITROS XT 7600 Integrated Systems
PanelMemberNumber of Observ.Grand Mean (S/C)Repeatability (Within Run)Between RunBetween DayBetween LotaWithin-LaboratorybBetween-SitecReproducibility (Overall)d
mberObserv.Mean (S/C)SDCV (%)SDCV (%)SDCV (%)SDCV (%)SDCV (%)SDCV (%)SDCV (%)
GRP12700.000.001N/A+0.000N/A+0.001N/A+0.001N/A+0.001N/A+0.001N/A+0.002N/A+
GRP22701.060.0353.40.0000.00.0100.90.0393.70.0535.10.0090.90.0615.7
GRP32700.290.012N/A+0.000N/A+0.007N/A+0.023N/A+0.027N/A+0.003N/A+0.029N/A+
GRP42701.090.0373.40.0000.00.0131.20.22020.20.22420.60.0131.10.22921.1
GRP52703.590.0972.70.0000.00.0000.00.51014.20.51914.50.0180.50.53715.0
GRP62707.540.1181.60.0000.00.0320.40.3805.00.3995.30.0000.00.4576.1

a Between lot: Variability of the test performance from lot to lot

b Within-Laboratory variability contains the Within Run, Between Run, Between Lot variance components.

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Between site: Variability of the test performance from site to site.

d Reproducibility: Variability of the test incorporating factors of site, lot, run and day.

  • % CVs are not meaningful for S/C results < 0.50.
    1. Linearity:
      Not applicable
    1. Analytical Specificity:
    • A. Cross-Reactivity: Cross-reactivity of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test was evaluated by testing serum samples with antibodies to other microorganisms or underlying conditions which could cause false positive results. Cross-reactivity was evaluated in the VITROS 5600 Integrated system, with samples tested in singlicate. No cross-reactivity was observed with any of the cross-reactants evaluated. The results for cross-reactivity are presented in Table 6 below.
Sample CategoryNumber ofSamples TestedVITROS ImmunodiagnosticProductsAnti-SARS-CoV-2 IgG testResults
Non-reactiveReactive
Influenza A Antibody10100
Influenza B Antibody12120
Hepatitis C Virus (HCV) Antibody15150
Hepatitis B Virus (HBV) Antibody12120
Haemophilus influenzae Antibody12120
Anti-Nuclear Antibody (ANA)10100
Rheumatoid Factor11110
Human Anti-Mouse Antibody (HAMA)10100
Adenovirus Antibody12120
Coxsackie B Virus Antibody10100
Echovirus Antibody10100
Poliovirus Antibody990
Respiratory Syncytial Virus (RSV)Antibody10100
Anti-SARS-coronavirus13130
Anti-MERS-coronavirus14140
Human coronavirus HKU1 Antibody11110
Human coronavirus NL63 Antibody10100
Human coronavirus OC43 Antibody21210
Human coronavirus 229E Antibody24240
Human Immunodeficiency Virus (HIV)Antibody17170
Human Parainfluenza Virus (HPIV)Antibody550
Human Metapneumovirus (HMPV)Antibody10100

Table 6. Cross-reactivity study samples and results

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Sample CategoryNumber ofSamples TestedVITROS ImmunodiagnosticProductsAnti-SARS-CoV-2 IgG testResults
Non-reactiveReactive
Enterovirus Antibody10100
Rhinovirus Antibody11110
Epstein-Barr Virus (EBV) Antibody11110
Epstein-Barr Virus Nuclear Antigen(EBVNA) Antibody11110
Rubella Virus Antibody10100
Legionella pneumophila Antibody10100
Bordetella pertussis Antibody15150
Mycoplasma pneumoniae Antibody14140
Chlamydophila pneumoniae Antibody10100
Streptococcus pneumoniae Antibody10100
Streptococcus pyogenes Antibody10100
Candida albincans Antibody14140
Pneumocystis jirovecii Antibody10100
Pseudomonas aeruginosa Antibody14140
Staphylococcus epidermidis10100
Cytomegalovirus (CMV) Antibody11110
  • B. Interference: The VITROS Immunodiagnostic Products Anti SARS-CoV-2 IgG test was evaluated for interference consistent with CLSI document EP07. Commonly encountered substances were tested on one lot of reagent using the VITROS 5600 Integrated System in 3 reactive (low positive) and 3 non-reactive (negative) samples.
    (0) +

To evaluate interference, the percent bias was calculated as:

All substances evaluated have been shown to not interfere (<10% bias for low reactive samples and bias <0.22 S/C for non-reactive samples) with the test performance at the concentration listed in the table below.

Table 7. Endogenous interferants evaluated with VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test

Test Concentration
SubstanceConventionalSI UnitsN/A
Anti-Nuclear Antibody> 8 AI
Bilirubin, conjugated40 mg/dL475 umol/L
Bilirubin, unconjugated40 mg/dL684 umol/L
Cholesterol400 mg/dL10.3 mmol/L
Hemoglobin1000 mg/dL10 g/L
Human anti-Mouse3600 ng/mL0.024 umol/L
Ig (total)6 g/dL60 g/L

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Test Concentration
SubstanceConventionalSI Units
Rheumatoid Factor35.7-61.7 IU/mLN/A
Total Protein15 g/dL150 g/L
Triglycerides1500 mg/dL16.94 mmol/L

N/A: Not Applicable (alternative units are not provided)

Table 8. Exogenous interferants evaluated with VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test

SubstanceTest Concentration
ConventionalSI Units
Abacavir1.27 mg/dL44.4 µmol/L
Acetaminophen15.6 mg/dL1.03 mmol/L
Amoxicillin1.35 mg/dL37 µmol/L
Aspirin3 mg/dL0.167 mmol/L
Atorvastatin75 µg/dL1.34 µmol/L
Azithromycin1.1 mg/dL14.8 µmol/L
Biotin3510 ng/mL14.3 µmol/L
Cefoxitin660 mg/dL15.5 mmol/L
Ceftriaxone84 mg/dL1.51 mmol/L
Dextromethorphan1.56 µg/dL0.0575 µmol/L
EDTA0.099 mg/dL3.39 µmol/L
Gentamicin3.0 mg/dL62.8 µmol/L
Guaifenesin450 µg/dL22.7 µmol/L
Heparin330 units/dL330 units/dL
Ibuprofen21.9 mg/dL1.06 mmol/L
Intralipid2000 mg/dLN/A
Levofloxacin3.6 mg/dL99.7 µmol/L
Levothyroxine429 µg/dL0.552 µmol/L
Lisinopril24.6 µg/dL0.607 µmol/L
Lopinavir57.17 µg/mL90.89 µmol/L
Loratadine8.7 µg/dL0.271 µmol/L
Losartan1155 ng/mL2.505 µmol/L
Meropenem33.9 mg/dL884 µmol/L
Metformin1.2 mg/dL92.9 µmol/L
Metoprolol150 µg/dL5.61 µmol/L
Naproxen36.0 mg/dL1.56 mmol/L
Omeprazole840 µg/dL24.3 µmol/L
Oseltamivir39.9 µg/dL1.28 µmol/L
Peramivir183600 ng/mL559 µmol/L
Prednisone10 µg/dL0.276 µmol/L
Ritonavir10.98 mg/dL126.42 mmol/L
Theophylline6.0 mg/dL333 µmol/L
Vancomycin12.0 mg/dL82.8 µmol/L
Zanamivir1089 ng/mL3.28 µmol/L

N/A = Not Applicable (alternative units are not provided)

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When amlodipine was tested at a concentration of 1.88 ug/dL, a negative bias (-11.1% change of the S/C value) was observed in reactive samples.

    1. Assay Reportable Range:
      Not applicable
    1. Traceability. Stability. Expected Values (Controls, Calibrators, or Methods):
      Specimen Stability: The stability of SARS-CoV-2 antibodies in serum. K2-EDTA plasma. and K -- EDTA plasma was evaluated with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test after various storage conditions with and without freeze-thawing cycles in the VITROS 5600 Integrated Systems. The storage conditions evaluated were room temperature, 2 - 8°C, and <- 20°C with 5 freeze-thaw cycles.

Freshly drawn whole blood from individual donors was collected. Of the whole blood donors, (1) were unaltered and were spiked using a 15/41

The whole blood was distributed among the collection tubes used in the study. Each spiked sample was unique.

After centrifugation, each sample from each collection tube was tested in duplicate using one reagent lot on one VITROS 5600 Integrated System, denoted as the fresh timepoint. Aliquots of each sample were prepared and stored at room temperature, 2-8°C. and <- 20°C. For the < 20℃ samples were prepared. 1 subjected to 5 freeze-thaw cycles (F/T) and the other subjected to (0) F/F/T cycles.

For each sample type and storage temperature the percent difference to baseline was calculated as follows where baseline is considered as the fresh sample before storing at any temperature condition:

(D (4)

The results support the following specimen storage conditions for serum, K-- EDTA and K --EDTA plasma:

Sample TypeTemperatureStabilityF/T
Serum and plasma(K2-EDTA and K3-EDTA)Room Temperature(15-30°C)≤ 24 hoursN/A
Refrigerated(2-8°C)≤ 7 daysN/A
Frozen(≤-20°C)≤ 4 weeksN/A

Table 9. Summary of specimen stability

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N/AN/A1 cycle
A THE CHART COLLECT CHE CASE CONSTITUTION CONSULTION

N/A= Not Applicable

Based upon this study design and the results thereof, the specimen stability data support, storage of all matrices at: 15-30 ℃ for 24 hours, 2-8℃ for up to 7 days, and ≤-20℃ or below for up to five freeze-thaw cycle

    1. Detection Limit:
      Not applicable
    1. Assay Cut-Off:
      The study was performed to determine the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test S/C cutoff. The study included the testing of a collection of [0] megative samples collected prior to the COVID-19 pandemic, and samples collected from individuals with a prior SARS-CoV-2 RT-PCR positive result. Additionally, promogative samples collected prior to the pandemic were tested with reagent lots. All samples were tested in singlicate using one VITROS Anti-SARS-CoV-2 IgG reagent pack and calibrator lot. A Receiver Operating Characteristic (ROC) curve analyses was performed to optimize for those cutoff values that maximize both sensitivity specificity. At the cutoff S/C = 1.00 the resultant ROC was [b] confirming high sensitivity and specificity of the established S/C cutoff value (Figure 2).

Image /page/12/Figure/7 description: The image shows a figure labeled as "Figure 2:". There is also the text "(D)(4)" in the upper right corner of the figure. The image appears to be a gray rectangle with a red border. The text "Analytical sensitivity at the cutoff using a Certified Reference Material" is at the bottom of the image.

Analytical sensitivity at the cutoff using a Certified Reference Material

The analytical sensitivity of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test was determined using a series of serial dilutions of the WHO First International Standard for Anti-SARS-CoV-2 Immunoglobulin (human) code 20/136 (Certified Reference

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Material or CRM) in negative patient sodium citrate plasma. Samples included in the study were prepared covering a will BAU/mL to | BAU/mL range (Table 10). Each sample was tested in duplicate using of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test on two VITROS analyzers (VITROS ECi/ECiQ and VITROS 3600 Immunodiagnostic Systems). In addition, an internal reference calibrator was also included in the assay.

Ortho-Clinical Diagnostics collected both ALU and S/C for each of the CRM samples tested. Ortho-Clinical Diagnostics analyzed the data using the least-squares regression analysis, where the [14] represented the BAU/mL and the [10] the S/C values for each sample. Using the regression equation, Ortho-Clinical Diagnostics calculated the BAU/mL at the cutoff (S/C = 1.00). The data analysis shows that a S/C of 1.00 corresponds to 100 |BAU/mL using the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test.

Table 10: CRM serial dilutions S/C results and calculation of BAU/mL at the cutoff

CRMconcentrations(BAU/mL)VITROS ECi/ECiQ(S/C)VITROS 3600(S/C)VITROS SystemAverage S/C
(0)(4)

Figure 3: Analytical sensitivity regression analysis.

Image /page/13/Picture/5 description: The image is a gray rectangle with a thin red border. In the top center of the rectangle is the text "(b)(4)". The rectangle takes up most of the image. The image is simple and contains no other objects.

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B Comparison Studies:

    1. Method Comparison:
      Not Applicable
    1. Matrix Comparison:
      A matrix equivalency study was conducted to support equivalent performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 1gG test between serum. K3-EDTA plasma, and K3-EDTA plasma. The study was conducted using 1 lot for the reagent pack, calibrator and controls in the VITROS 5600 Integrated Systems.

For this study unique paired clinical samples were evaluated (spiked samples prepared using a high titer convalescent plasma pool and non-spiked samples) with SARS-CoV-2 IgG antibodies levels representing the whole assay range (from low negative to high positive, including a 1046 of samples near the cutoff). After centrifugation, the matched serum, Ko-EDTA, and K3-EDTA samples were tested in duplicate using one reagent lot on 100 VITROS 5600 Integrated System. Sample distribution is summarized in Table 11 below.

Table 11. Sample distribution: negative, near the cutoff and positive

GroupS/C ResultNumber ofspecimens (% total)
Negative(b)(4)
Near cutoff
Moderate Positive
High Positive
Total(b)(4)

A weighted Deming regression analysis comparing K2-EDTA plasma (the comparator matrix) to K2-EDTA plasma and to serum was conducted. The Deming regression analysis did not demonstrate significant deviation from the comparator matrix (Figure 4 - 5). Therefore, the study demonstrated equivalency between serum. K->EDTA plasma, and K-EDTA plasma.

Figure 4: Weighted Deming linear regression analysis between K2-EDTA plasma and serum

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C Clinical Studies:

    1. Clinical Sensitivity:
      Not applicable

11. Clinical Specificity:

Not applicable

12. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):

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Clinical Agreement Study:

The clinical performance of VITROS Immunodiagnostic Products anti SARS- CoV-2 IgG test was evaluated at three testing sites using 642 unique retrospective clinical samples acquired from two populations. Population 1 consisted of 338 samples collected from individuals previously infected with SARS-CoV-2 with a prior SARS-CoV-2 positive test result using a comparator that FDA determined is appropriate (RT PCR test). Population 2 consisted of 304 samples collected prior to December 2019 (before the widespread outbreak of COVID-19). Of the 304 samples, 30% of the tested samples were collected from blood donor centers.

Of the 338 samples in Population 1, 24 samples were collected 0 - 7 days from COVID-19 symptom onset, 21 samples collected between 8 - 14 days from symptom onset, and 293 samples were collected >15 days from COVID-19 symptom onset. Table 12 below shows the sample distribution and the respective percentages from the total of samples tested per "Days post-symptoms onset" time bin.

Time bin(n= total numbersamples tested)Days post-symptomonsetPercent Samples(per time bin)
0-7 days (n = 24)0 - 470.83%
5 - 729.17%
8-14 days (n = 21)8 - 1147.62%
12 - 1452.38%
≥ 15 days (n = 293)15 - 2110.58%
22 - 3010.92%
31 - 6040.61%
61 - 9026.62%
91 - 19511.26%

Table 12. Sample distribution within each "Days post symptoms onset" time bin.

Tables 13 and 14 below represents sample distribution per matrix tested for each study population (Population 1 and Population 2).

Table 13. Distribution of Population I samples by matrix and days post-symptom onset.
MatrixDays post-symptom onset
≤7 days8 - 10 days≥15 daysTotal
EDTA plasma(b)(4)169
Serum169
Total338

Table 14. Distribution of Population 2 samples by matrix.

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EDTA plasma138
Serum166
Total304

Ortho conducted the clinical agreement study at 3 testing sites: one internal site and 2 external sites.

Positive Percent Agreement (PPA)

A total of 338 samples collected from individual patients confirmed to have a prior SARS-CoV-2 positive result by RT-PCR were tested. Blood samples were collected within the United States between April 2020 and March 2021. Samples were tested with the VITROS Immunodiagnostic Products Anti SARS-CoV-2 IgG test in each analyzer (except with the VITROS XT7600 Integrated System where one sample was not tested due to limited volume). Of the 338 samples included in the study, 169 were EDTA plasma samples and 169 were serum samples.

The performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test and 95% Confidence Interval for each VITROS analyzer is summarized in the tables below.

PPA performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test and 95% Confidence Interval by system:

Days fromSymptomOnsetNumber ofSubjects Tested(with prior RT-PCR Positive)ReactivePPA95% CI(Wilson score)
0-7 days241145.83%27.89%-64.93%
8-14 days211152.38%32.37% - 71.66%
≥15 days29327593.86%90.50%-96.10%
Total338------

Table 15. In the VITROS ECi/ECiO Immunodiagnostic Systems.

Table 16. In the VITROS 3600 Immunodiagnostic Systems and the VITROS 5600 Integrated Systems

VITROS Immunodiagnostic ProductsAnti-SARS-CoV-2 IgG test Results
Days fromSymptom OnsetNumber ofSubjects Tested(with prior RT-PCR Positive)ReactivePPA95% CI(Wilson score)
0-7 days241041.67%24.47% - 61.17%
8-14 days211152.38%32.37% - 71.66%
≥15 days29327493.52%90.10% - 95.81%
Total338------

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Days fromSymptomOnsetNumber ofSubjects Tested(with prior RT-PCR Positive)ReactivePPA95% CI(Wilson score)
0-7 days241041.67%24.47% - 61.17%
8-14 days211152.38%32.37% - 71.66%
≥15 days29227393.49%90.10% - 95.80%
Total337------

Table 17. In the VITROS XT 7600 Integrated Systems

Negative Percent Agreement (NPA)

Three hundred and four (304) presumed SARS-CoV-2 negative samples collected prior to the COVID-19 pandemic within the United States were tested. Of the 304 samples, 138 were EDTA plasma samples and 166 serum samples. All samples were tested using VITROS ECi/ECiQ/3600 Immunodiagnostic Systems and the VITROS 5600/XT 7600 Integrated Systems "(except the samples that were not tested on one or more analyzers due to limited volume). The performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test and 95% Confidence Interval for each VITROS analyzer is summarized in the table below:

Table 18: NPA performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test and 95% confidence interval in all VITROS analyzers

VITROS Immunodiagnostic ProductsAnti-SARS-CoV-2 IgG test Results
AnalyzerPresumed Negative(Collected Pre-COVID)Non-ReactiveNPA95% CI(Wilson score)
VITROS ECi/ECiQ/VITROS3600/VITROS 560030430199.01%97.14%-99.66%
VITROS XT 760030330099.01%97.13% -99.66%

D Clinical Cut-Off:

Not applicable

E Expected Values/Reference Range:

Not applicable

F Other Supportive Performance Characteristics Data:

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Calibration Cvcle Stability

The purpose of this study was to establish the calibration interval, or how frequently the assay should be calibrated. The calibration interval was established by testing samples on the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test using a single calibration over time.

In the study, Ortho-Clinical Diagnostics included a panel of 6 precision pool samples. Each panel member was prepared as follows:

  • Precision Pool 1 (PP1): Control level 1 (Non-Reactive) .
  • . Precision Pool 2 (PP2): Control level 2 (Reactive)
  • Precision Pool 3 (PP3): Calibrator .
  • Precision Pool 4 (PP4): High negative EDTA plasma sample .
  • . Precision Pool 5 (PP5): Low Positive EDTA plasma sample
  • Precision Pool 6 (PP6): High Positive EDTA plasma sample .

After a single initial calibration on Day samples were tested on Day and up to Day on the VITROS ECi/ECiO, VITROS 3600, VITROS 5600, and VITROS XT7600.

For each positive sample (PP2, PP4, PP5, and PP6) linear regression analysis was conducted. In addition, percent difference from baseline was calculated as follows:

(b)(4)
--------

Percent difference to baseline should be (b)(4).The percent difference to baseline should be

The study results support a calibration interval stability of 28 days for the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG test.

VII Proposed Labeling:

The labeling supports the decision to grant the De Novo request for this device.

VIII Identified Risks and Mitigations:

Risks to HealthMitigation Measures
Risk of false test resultsCertain labeling information includinglimitations, device descriptions, explanationsof procedures and performance informationidentified in special controls (1), (3), and (5).Use of certain specimen collection devicesidentified in special control (2).Certain design verification and validationincluding documentation of devicedescriptions, certain analytical studies andclinical studies, and risk analysis strategiesidentified in special control (4).Testing of characterized samples and labelinginformation identified in special control (6).

10903 New Hampshire Avenue Silver Spring, MD 20993-0002 www.fda.gov DEN210038 -

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Risks to HealthMitigation Measures
Failure to correctly interpret the test resultsCertain labeling information includinglimitations, device descriptions, explanationsof procedures and performance informationidentified in special controls (1), (3), and (5).Use of certain specimen collection devicesidentified in special control (2).Certain design verification and validationincluding documentation of devicedescriptions, certain analytical studies andclinical studies, and risk analysis strategiesidentified in special control (4).Testing of characterized samples and labelinginformation identified in special control (6).
Failure to correctly operate the deviceCertain labeling information includinglimitations, device descriptions, explanationsof procedures and performance informationidentified in special controls (1), (3), and (5).Use of certain specimen collection devicesidentified in special control (2).

IX Benefit/Risk Assessment:

A Summary of the Assessment of Benefit:

The benefit of the assay is the ability to detect Anti-SARS-CoV-2 IgG antibodies as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection. The device could also provide a tool for tracking possible patient exposure.

True positive test results provide additional support for the diagnosis of recent or past SARS-CoV-2 infection. Results could be used in conjunction with clinical and epidemiological information, as well as other laboratory results to guide patient management. The test results may improve infection control measures and may aid in tracking and reducing transmission of infection. There is currently no SARS-CoV-2 antibody test that has undergone full FDA premarket review to most definitively determine clinical truth of the presence or absence of detectable antibodies for the method comparison study, however this uncertainty could be acceptable, particularly because the sponsor used a comparator that FDA determined is appropriate (SARS-CoV-2 RT-PCR devices), which represents the most reasonable alternative to establish clinical truth in the clinical study. This is an acceptable source of uncertainty regarding the benefits of the test.

Summary of the Assessment of Risk: B

The risks associated with the device, when used as intended, are those related to the risk of false test results, which have essentially the same impacts as the risks related to failure to correctly

{21}------------------------------------------------

interpret the test results and failure to correctly operate the device as all would cause the user to rely on incorrect information.

A false negative result could be interpreted as indicating that a person did not recently have COVID-19, which may lead a person to take fewer necessary precautions against spreading the virus to others if they are still shedding the virus from a recent infection. This may increase the risk of transmission. In the context of the current public health emergency, incorrect serological test results used to guide infection control activities could lead to misallocation of resources used for surveillance and prevention. The positive percent agreement performance point estimate of the device observed in the clinical study indicates that false negative results are not likely to occur when the device is used in the intended use population.

A false positive SARS-CoV-2 antibody result could be interpreted as a diagnosis of recent COVID-19, and a clinician may assume a patient may still be shedding the virus, which may result in unnecessary additional testing, quarantine, or self-isolation to prevent the spread of the virus to others. False positive serology test results can lead to an incorrect assessment that the tested person had an immune response to SARS-CoV-2, which may lead the person to take fewer necessary precautions against virus exposure. This may increase the individual's risk of infection and may lead the person to not seek testing if later infected, likely increasing the spread of the disease. In the context of the current public health emergency, incorrect serological test results used to guide infection control activities could lead to misallocation of resources used for surveillance and prevention.

A positive result could be wrongly interpreted as a diagnosis of acute COVID-19 to explain an individual's symptoms and delay correct diagnosis and initiation of appropriate treatment for the actual cause of patient illness. A positive test result could be wrongly interpreted as indicating that the tested person has immunity to SARS-CoV-2, which may lead the person to take fewer precautions against virus exposure. This may increase the individual's risk of infection and may lead the person to not seek testing if later infected, likely increasing the spread of the disease. A negative result may be misinterpreted as ruling out SARS-CoV-2 infection, with a concomitant delay in the correct diagnosis and treatment.

C Patient Perspectives:

This submission did not include specific information on patient perspectives for this device.

D Summary of the Assessment of Benefit-Risk:

The risks associated with the device (risk of false test results, failure to correctly interpret the results, and failure to correctly operate the device) are mitigated by labeling information, which will assist the operator in correctly performing the test and will assist healthcare providers in understanding the intended use of the test and evaluating the predictive value of a result based on the analytical and clinical performance of the test. In addition, those risks are mitigated by the use of certain validated specimen collection devices. Further, the risk of false test results and failure to correctly interpret the results are mitigated by certain design verification and validation, including analytical and clinical studies and risk analysis strategies to reduce the likelihood of such errors. Finally, the risk of false test results due to a disease or disorder that Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 www.fda.gov DEN210038 -

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presents a public health emergency, or a public health emergency that otherwise exists are addressed by special controls requiring certain testing of characterized samples and labeling information in those situations. The special controls help to ensure that errors will be uncommon and will facilitate accurate assay implementation of results. In addition, the device's performance observed in the clinical study suggests that errors will be uncommon and that the assay will provide benefits to patients as an aid in identifying individuals with an adaptive immune response to SARS-CoV-2, indicating recent or prior infection. While general controls alone are insufficient to mitigate the risks associated with the device, the benefits outweigh the risks given the special controls.

Conclusion: X

The De Novo request is granted, and the device is classified under the following regulation and subject to the special controls identified in the letter granting the De Novo request:

Product Code(s):QVP
Device Type:SARS-CoV-2 serology test
Class:Class II
Regulation:21 CFR 866.3983

N/A