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K Number
DEN210040
Device Name
VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack, VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrators
Manufacturer
Ortho-Clinical Diagnostics, Inc.
Date Cleared
2023-05-05

(591 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 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.

Device Description

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 .
AI/ML Overview

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:

MetricAcceptance Criteria (Implied by De Novo Grant)Reported Device Performance (Worst Case Across Systems) [Table 15-18 for PPA; Table 19 for NPA]
Positive Percent Agreement (PPA) for ≥15 days post-symptom onsetHigh (e.g., >90%)94.09% (VITROS XT 7600 Integrated Systems) - also seen in VITROS 5600
Negative Percent Agreement (NPA)High (e.g., >98%)99.41% (VITROS ECi/ECiQ)

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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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and 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 is a stylized image of a bird, while the text is written in a combination of blue and white colors. The word "FDA" is in a blue box.

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

I Background Information:

A De Novo Number

DEN210040

B Applicant

Ortho-Clinical Diagnostics, Inc.

C Proprietary and Established Names

VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack, VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total 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 Total test is comprised of (1) the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack, (2) the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator, and (3) the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Controls.

B Measurand:

Total antibodies to SARS-CoV-2 in human serum, K2-EDTA plasma, K2-EDTA plasma and Lithium heparin plasma.

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C Type of Test: Chemiluminescent Immunoassay

III Indications for Use:

A Indication(s) for Use:

Rx ONLY

For in vitro diagnostic and laboratory professional use.

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

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.

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

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.

B Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

C Special Instrument Requirements:

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 Calibrators uses the following VITROS Systems (instruments):

  • o 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.

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IV Device/System Characteristics:

A Device Description:

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 .

B Principle of Operation

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The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test is performed using the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack and the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator on the VITROS ECi/ECiQ/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 S1 antigen coated on the well. Unbound sample is removed by washing. In the second stage horseradish peroxidase (HRP)- labeled recombinant SARS-CoV-2 spike protein SI antigen is added in the conjugate reagent. The conjugate binds specifically to any anti-SARS-CoV-2 captured on the well in the first stage. 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 TypeSystem*Incubation TimeTime to first resultTestTemperatureReactionSampleVolume
ImmunometricECi/ECiQ,3600,5600, XT 760037 minutes48 minutes37 °C80 μL

" Not all products and systems are available in all countries

Image /page/3/Figure/4 description: The image is of the text "Figure 1: Reaction Scheme". The text is black and the background is white. The text indicates that the image is of a reaction scheme and is labeled as Figure 1.

Image /page/3/Figure/5 description: This image shows a diagram of a process involving SARS-CoV-2 antigens. The process starts with a Biotinylated recombinant SARS-CoV-2 antigen, followed by Anti-SARS-CoV-2, and then HRP-labeled recombinant SARS-CoV-2 antigen. Finally, a signal reagent with an enhancer is added, resulting in luminescence.

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:

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Not applicable

3. Specimen Sampling and Handling:

Specimen Sampling:

The specimens recommended for this assay are:

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

Specimen Handling and Storage

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

4. Calibration:

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

The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Calibrator contains anti-SARS-CoV-2 antibody in human plasma. 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 Total 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 Total 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 Total Controls are provided separately from the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack and contains:

  • Control 1: Anti-SARS-CoV-2 Total non-reactive human defibrinated plasma. .

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  • . Control 2: Anti-SARS-CoV-2 Total reactive human defibrinated plasma.

Ouality 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
    • · 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 Total 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 nonconsecutive 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

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replicates x 2 runs x 20 days x 3 lots= 240 observations total). The VITROS Anti-SARS-CoV-2 Total's total precision % CV (from the "total" standard deviation) for the S/C values ranged from 3.8% - 23.2%, depending upon the sample and instrument.

VITROSPanelNumberofGrandMeanRepeatability(Within Run)Between-RunBetween-DayBetween-LotWithin-Laboratory
Systemmemberobserv(S/C)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
XT 7600PP12400.020.002N/A0.004N/A0.000N/A0.006N/A0.008N/A
XT 7600PP22403.450.0541.60.0762.20.0692.00.3249.40.34410.0
XT 7600PP32401.140.0211.80.0393.40.0272.40.17315.20.18015.8
XT 7600PP42401.060.0212.00.0393.70.0212.00.15214.30.16015.1
XT 7600PP52404.000.0691.70.0902.30.0621.60.3468.70.3709.3
XT 7600PP624011.700.1791.50.2342.00.1671.40.7546.40.8267.1
5600PP12400.020.003N/A0.003N/A0.000N/A0.005N/A0.007N/A
5600PP22403.180.0491.50.0692.20.0551.70.3129.80.32810.3
5600PP32401.060.0212.00.0413.90.0080.80.0302.80.0555.2
5600PP42400.980.0212.10.0373.80.0131.30.0323.30.0555.6
5600PP52403.700.0701.90.0842.30.0461.20.45012.20.46512.6
5600PP624011.000.2192.00.2232.00.2232.01.86216.91.89717.2
3600PP12400.020.002N/A0.002N/A0.000N/A0.002N/A0.005N/A
3600PP22402.990.0441.50.0762.50.0592.00.49916.70.51017.1
3600PP32401.000.0212.10.0313.10.0313.10.13413.40.14214.2
3600PP42400.930.0171.80.0303.20.0303.20.14715.80.15416.6
3600PP52403.500.0561.60.0872.50.0511.50.68619.60.69619.9
3600PP624010.400.1561.50.1471.40.1891.82.39723.02.41423.2
ECi/ECiQPP12400.020.001N/A0.001N/A0.000N/A0.005N/A0.005N/A
ECi/ECiQPP22402.830.0592.10.0602.10.0491.70.1505.30.1796.3
ECi/ECiQPP32400.940.0161.70.0232.40.0232.40.0000.00.0363.8
ECi/ECiQPP42400.860.0344.00.0242.80.0161.90.0263.00.0515.9
ECi/ECiQPP52403.270.0481.50.0742.30.0310.90.2507.60.2678.2
ECi/ECiQPP62409.880.1531.50.1972.00.0406.50.9789.91.19612.1

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

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 Total test was determined with EDTA plasma pool samples (TRP4, TRP5, and TRP6), quality controls (TRP1 and TRP2) and customer calibrator (TRP3)) using the VITROS ECi/ECiQ and 3600 Immunodiagnostics Systems, and the VITROS 5600 and XT 7600 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 Total test total reproducibility % CV (from the "total" standard deviation)

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for the S/C values ranged from 7.1% - 14.2%, depending upon the sample and instrument. The following results were observed per analyzer:

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

PanelMemberNumberofObsGrandMean(S/C)Repeatability(Within Run)Between RunBetween DayBetween LotaWithin-LaboratorybBetween SitecReproducibility(Overall)d
SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
TRP12700.020.007N/A+0.000N/A+0.002N/A+0.000N/A+0.007N/A+0.006N/A+0.010N/A+
TRP22703.170.1534.80.0000.00.0441.40.0000.00.1595.00.1284.00.2397.5
TRP32701.050.0666.30.0000.00.0000.00.0363.40.0757.10.0171.60.0888.4
TRP42700.970.0464.70.0191.90.0181.80.0353.60.0636.50.0000.00.0777.9
TRP52703.700.1303.50.0000.00.0531.40.1514.10.2065.60.1123.00.2637.1
TRP627011.10.393.50.000.00.181.60.807.20.908.10.484.31.109.9

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

Repeatability(Within Run)Between RunBetween DayBetween LotaWithin-LaboratorybBetween SitecReproducibility(Overall)d
PanelMemberNumberofObsGrandMean(S/C)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
TRP12700.030.027N/A+0.004N/A+0.006N/A+0.000N/A+0.028N/A+0.005N/A+0.030N/A+
TRP22703.310.1354.10.0000.00.0983.00.0000.00.1665.00.2768.30.39111.8
TRP32701.090.0867.90.0413.70.0201.90.0464.20.1079.90.0242.20.15214.0
TRP42701.020.0393.90.0141.30.0242.40.0434.20.0656.40.0454.50.0939.1
TRP52703.880.1443.70.0000.00.0972.50.0541.40.1824.70.3478.90.47212.2
TRP627011.50.332.90.000.00.181.60.675.80.776.70.998.61.4913.0

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

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

6 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 Total test evaluated on VITROS 5600 Integrated Systems

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PanelMemberNumberofObsGrandMean(S/C)Repeatability(Within Run)Between RunBetween DayBetween LotaWithin-LaboratorybBetween SitecReproducibility(Overall)d
SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
TRP12700.020.008N/A+0.001N/A+0.002N/A+0.000N/A+0.008N/A+0.003N/A+0.009N/A+
TRP22703.170.0862.70.0220.70.0000.00.0000.00.0892.80.2558.00.31810.0
TRP32701.050.0464.40.0252.40.0000.00.0191.80.0565.30.0555.20.1019.6
TRP42700.970.0323.20.0293.00.0202.10.0434.50.0646.60.0444.60.0858.8
TRP52703.650.2496.80.0812.20.0000.00.1664.60.3108.50.2657.30.49413.5
TRP627010.90.484.40.090.90.0000.00.878.00.999.10.978.91.5414.2

" 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.

· 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.

1 %CVs are not meaningful for S/C results < 0.50.

Table 5. Reproducibility of VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test evaluated on VITROS XT7600 Integrated Systems

PanelMemberNumberofObsGrandMean(S/C)Repeatability(Within Run)Between RunBetween DayBetween Lot"Within-LaboratorybBetween SitecReproducibility(Overall)d
SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)SDCV(%)
TRP12700.020.006N/A+0.001N/A+0.001N/A+0.000N/A+0.006N/A+0.005N/A+0.009N/A+
TRP22703.210.1996.20.0772.40.1193.70.0290.90.2467.70.0481.50.2899.0
TRP32701.060.0625.90.0242.20.0292.80.0383.60.0827.80.0000.00.11010.4
TRP42701.000.0363.60.0000.00.0191.90.0585.90.0717.20.0000.00.0909.0
TRP52703.780.1042.80.0000.00.0361.00.1885.00.2185.80.1052.80.2807.4
TRP627011.20.302.70.070.70.000.00.887.90.948.30.332.91.069.5

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

6 Within-Laboratory variability contains the Within 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.

1 %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 Total 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.

Table 6. Cross-reactivity study samples and results

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Sample CategoryNumber ofSamplesTestedVITROS ImmunodiagnosticProductsAnti-SARS-CoV-2 Total testResults
Non-reactiveReactive
Influenza A Antibody10100
Influenza B Antibody12120
Hepatitis C Virus (HCV) Antibody15150
Anti-Nuclear Antibody (ANA)10100
Adenovirus Antibody12120
Coxsackie B Virus Antibody10100
Echovirus Antibody10100
Poliovirus Antibody990
Respiratory Syncytial Virus (RSV) Antibody10100
Hepatitis B Virus (HBV) Antibody12120
Haemophilus influenzae Antibody12120
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
Enterovirus Antibody10100
Rhinovirus Antibody11110
Epstein-Barr Virus (EBV) Antibody11110
Epstein-Barr Virus Nuclear Antigen (EBVNA)Antibody11110
Legionella pneumophila Antibody10100
Bordetella pertussis Antibody15150
Mycoplasma pneumoniae Antibody14140
Chlamydophila pneumoniae Antibody10100
Cytomegalovirus (CMV) Antibody11110
Rheumatoid Factor (RF) Antibody11110
Severe Acute Respiratory Syndrome (SARS)coronavirus Antibody13130
Middle East Respiratory Syndrome (MERS)coronavirus Antibody14140
Rubella virus Antibody10100
Mycobacterium tuberculosis Antibody12120
Streptococcus pneumoniae Antibody10100
Streptococcus pyogenes Antibody10100
Pneumocystis jirovecii pneumonia (PJP)Antibody10100
Candida albicans Antibody14140
Pseudomonas aeruginosa Antibody13130
Staphylococcus epidermis Antibody10100
Human Anti-Mouse Antibody (HAMA)10100

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  • B. Interference: The VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total 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(4)

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 Total test

Test Concentration
SubstanceConventional UnitsSI UnitsN/A
Anti-Nuclear Antibody (ANA)>8Al
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-Mouse Antibody (HAMA)3600 ng/mL0.024 umol/L
Rheumatoid Factor (RF)35.7 - 61.7 IU/mLNIA
Total Protein9.37 g/dL93.7 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 Total test

SubstanceTest Concentration
Conventional UnitsSI Units
Acetaminophen15.6 mg/dL1.03 mmol/L
Amlodipine7.5 $\mu$ g/dL0.183 $\mu$ mol/L
Amoxicillin5.4 mg/dL148 $\mu$ mol/L
Aspirin3 mg/dL0.167 mmol/L
Atorvastatin75 $\mu$ g/dL1.34 $\mu$ mol/L
Azithromycin1.1 mg/dL14.8 $\mu$ mol/L
Biotin3510 ng/mL14.3 $\mu$ mol/L
Cefoxitin660 mg/dL15.5 mmol/L
Ceftriaxone84 mg/dL1.51 mmol/L
Dextromethorphan1.56 $\mu$ g/dL0.0575 $\mu$ mol/L
EDTA0.099 mg/dL3.39 $\mu$ mol/L
Gentamicin3.0 mg/dL62.8 $\mu$ mol/L

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Test Concentration
SubstanceConventional UnitsSI Units
Guaifenesin450 µg/dL22.7 µmol/L
Heparin330 units/dL330 units/dL
Ibuprofen21.9 mg/dL1.06 mmol/L
Intralipid2000 mg/dLN/A
Levofloxacin0.9 mg/dL24.9 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)

When Levofloxacin was tested at a concentration of 1.8 mg/dL, a positive bias (+12.03% change of the S/C value) was observed in reactive samples.

4. Assay Reportable Range:

Not applicable

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

Specimen Stability: The stability of SARS-CoV-2 antibodies in serum, K2-EDTA plasma, K 2-EDTA plasma, and Lithium heparin plasma was evaluated with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total 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 ndividual donors was collected. Of the whole blood donors (0) were unaltered and were spiked using a DI47

{12}------------------------------------------------

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 °C samples, aliquots were prepared, subjected to 5 freeze-thaw cycles (F/T) and the other subjected to (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:

(b)(4)

The results support the following specimen storage conditions for serum, K2-EDTA, K3-EDTA plasma, and Lithium heparin plasma:

Sample TypeTemperatureStabilityF/T
Serum and plasma(K2-EDTA K3-EDTA, andLithium heparin)Room Temperature(15 – 30°C)≤ 24 hoursN/A
Refrigerated(2 – 8°C)≤ 7 daysN/A
Frozen(≤-20°C)≤ 4 weeksN/A
N/AN/A5 cycles

Table 9. Summary of specimen stability

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.

6. Detection Limit:

Not applicable

7. Assay Cut-Off:

The study was performed to determine the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test S/C cutoff. The study included the testing of a collection of Big negative samples collected prior to the COVID-19 pandemic, and msamples collected from individuals with a prior SARS-CoV-2 RT-PCR positive result. All samples were tested in singlicate using one VITROS Anti-SARS-CoV-2 Total 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

{13}------------------------------------------------

resultant ROC was | proming high sensitivity and specificity of the established S/C cutoff value (Figure 2).

Image /page/13/Picture/1 description: The image is a gray rectangle with a red border. There is some text in the upper center of the image, but it is too blurry to read. The image is simple and does not contain any other objects or features.

Analytical sensitivity at the cutoff using a Certified Reference Material:

The analytical sensitivity of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test was determined using a series of serial dilutions of the WHO First International Standard for Anti-SARS-CoV-2 Immunoglobulin (human) code [ [Certified Reference Material or CRM) in negative patient matrix. Samples included in the study were prepared covering a BAU/mL to (b)(+) BAU/mL range (Table 10), Each sample was tested in triplicate for three days using one lot of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test on one VITROS analyzer (VITROS 5600).

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 represented the BAU/mL and the 1000 |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 [1632] BAU/mL using the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test.

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

Image /page/13/Figure/6 description: This image shows a table with the columns "Dilution Factor", "CRM Concentrations (BAU/mL)", "Mean", "SD", and "%CV". The table appears to be related to CRM concentrations and dilution factors. The text "(b)(4)" is present in the table, but the rest of the table is grayed out.

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B Comparison Studies:

    1. Method Comparison: Not Applicable

9. Matrix Comparison:

A matrix equivalency study was conducted to support equivalent performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test between serum, Ky-EDTA plasma, Kx-EDTA plasma, and Lithium heparin plasma. The study was conducted using 1 lot for the reagent pack, calibrator, and controls in the VITROS 5600 Integrated Systems.

(D)(F

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 Total antibodies levels representing the whole assay range (from low negative to high positive, including a | PM of samples near the cutoff). After centrifugation, the matched serum, K2-EDTA, K3-EDTA, and Lithium-heparin plasma samples were tested in duplicate

{15}------------------------------------------------

using one reagent lot on one 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)
(b)(4)

A weighted Deming regression analysis comparing K2-EDTA plasma (the comparator matrix) to K 2-EDTA plasma, to Lithium-heparin plasma, and to serum was conducted. The Deming regression analysis did not demonstrate significant deviation from the comparator matrix (Figures 4-6). Therefore, the study demonstrated equivalency between serum, K3-EDTA plasma, K3-EDTA plasma, and Lithium-heparin plasma.

Figure 4: Weighted Deming linear regression analysis between K2-EDTA plasma and K3-EDTA

Image /page/15/Picture/5 description: The image is a gray rectangle with a red border. The text "10(4)" is located at the top center of the rectangle. The background is a solid gray color.

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C Clinical Studies:

    1. Clinical Sensitivity: Not applicable
    1. Clinical Specificity: Not applicable
    1. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):

Clinical Agreement Study:

The clinical performance of VITROS Immunodiagnostic Products anti SARS- CoV-2 Total test was evaluated at three testing sites using [0] retrospective clinical samples acquired from two populations. Population Consisted of for samples collected from individuals previously infected with SARS-CoV-2 with a prior SARS CoV-2 positive test result using a comparator

DR'T

{17}------------------------------------------------

that FDA determined is appropriate (RT PCR test). Population 2 consisted of 513 samples collected prior to December 2019 (before the widespread outbreak of COVID-19).

Of the 296 samples in population 1, 31 samples were collected 0-7 days from COVID-19 symptom onset, 26 samples collected between 8 - 14 days from symptom onset, and 239 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 number samplestested)Days post-symptom onsetPercent Samples(per time bin)
0-7 days (n = 31)0 - 477.42%
0-7 days (n = 31)5 - 722.58%
8-14 days (n = 26)8 - 1142.31%
8-14 days (n = 26)12 - 1457.69%
≥ 15 days (n = 239)15 - 2111.30%
22 - 3022.18%
31 - 6044.77%
61 - 908.79%
91 - 25312.97%

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 1 samples by matrix and days post-symptom onset.

MatrixDays post-symptom onsetTotal
≤7 days8-10 days≥15 days
EDTA plasma(b)(4)70
Lithium heparin plasma82
Serum144
Total396

Table 14. Distribution of Population 2 samples by matrix.

MatrixSamples tested
EDTA plasma46
Lithium heparin plasma333
Serum134

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Total513
------------

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

Positive Percent Agreement (PPA)

A total of 296 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 April 2021. Samples were tested with the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test in each analyzer (except the samples that were not tested on one or more analyzers due to limited volume). Of the 296 samples included in the study, 70 were EDTA plasma samples, 82 were Lithium-Heparin plasma sample and 144 were serum samples.

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

Days fromSymptom OnsetNumber ofSubjects Tested(with prior RT-PCR Positive)VITROS Immunodiagnostic ProductsAnti-SARS-CoV-2 Total Test Results
ReactivePPA95% CI(Wilson score)
0-7 days25936.00%20.24% -55.48%
8-14 days191684.21%62.44% - 94.48%
≥15 days23822494.12%90.37% -96.46%
Total282------

Table 15. In the VITROS ECi/ECiQ Immunodiagnostic Systems

Table 16. In the VITROS 3600 Immunodiagnostic Systems

Days fromSymptom OnsetNumber ofSubjects Tested(with prior RT-PCR Positive)VITROS Immunodiagnostic ProductsAnti-SARS-CoV-2 Total Test Results
ReactivePPA95% CI(Wilson score)
0-7 days251144.00%26.66% - 62.93%
8-14 days221777.27%56.56% - 89.88%
≥15 days23922594.14%90.41% - 96.48%
Total286------

Table 17. In the VITROS 5600 Integrated Systems

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Days fromSymptom OnsetNumber ofSubjects Tested(with prior RT-PCR Positive)VITROS Immunodiagnostic ProductsAnti-SARS-CoV-2 Total Test Results
ReactivePPA95% CI(Wilson score)
0-7 days271037.04%21.53% - 55.77%
8-14 days191578.95%56.67% - 91.49%
≥15 days23922594.14%90.41% - 96.48%
Total285------

Table 18. In the VITROS XT 7600 Integrated Systems

Days fromSymptom OnsetNumber ofSubjects Tested(with prior RT-PCR Positive)ReactivePPA95% CI(Wilson score)
0-7 days251040.00%23.40% - 59.26%
8-14 days221777.27%56.56% - 89.88%
≥15 days23722394.09%90.33% - 96.45%
Total284------

Negative Percent Agreement (NPA)

Five hundred and thirteen (513) presumed SARS-CoV-2 negative samples collected prior to the COVID-19 pandemic within the United States were tested. Of the 513 samples, 46 were EDTA plasma samples, 333 were Lithium heparin plasma samples and 134 were serum samples . All samples were tested using VITROS ECi/ECiQ/3600 Immunodiagnostic Systems and the VITROS 5600/ XT 7600 Integrated Systems analyzer (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 Total test and 95% Confidence Interval for each VITROS analyzer is summarized in the table below:

Table 19. NPA performance of the VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total test and 95% confidence interval in all VITROS analyzers

AnalyzerPresumeNegative(Collected Pre-COVID)VITROS Immunodiagnostic ProductsAnti-SARS-CoV-2 Total Test Results
Non-ReactiveNPA95% CI(Wilson score)
VITROS ECI/ECiQ50550299.41%98.27% - 99.80%
VITROS 360051150999.61%98.58%-99.89%
VITROS 560050950899.80%98.90%-99.97%
VITROS T-760050550399.61%98.57% - 99.89%

D Clinical Cut-Off:

{20}------------------------------------------------

Not applicable

  • E Expected Values/Reference Range: Not applicable

F Other Supportive Performance Characteristics Data:

Calibration Cycle 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 Total 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 wand up to Day on the VITROS ECi/ECiQ, 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:

15/143

The percent difference to baseline should be 1014

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

VII Proposed Labeling:

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

Identified Risks and Mitigations: VIII

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

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).
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 Total 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

{22}------------------------------------------------

most definitively determine clinical truth of the presence 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.

B Summary of the Assessment of Risk:

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 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 mav 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.

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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 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 and interpretation 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.

X Conclusion:

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