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Alinity m EBV is an in vitro polymerase chain reaction (PCR) assay for the quantitation of Epstein-Barr Virus (EBV) DNA in human EDTA plasma on the automated Alinity m System.

Alinity m EBV is intended for use as an aid in the management of EBV in transplant patients. In patients undergoing monitoring of EBV, serial DNA measurements can be used to indicate the need for potential treatment changes and to assess viral response to treatment.

The results from Alinity m EBV must be interpreted within the context of all relevant clinical and laboratory findings.

Alinity m EBV is not cleared for use as a screening test for donors of blood, blood products, or human cells, tissues, and cellular and tissue-based products (HCT/Ps) for EBV.

Alinity m EBV is an in vitro polymerase chain reaction (PCR) assay for the quantitation of EBV DNA in human plasma.

This device is similar to the predicate device originally cleared (K212778) with the exception that the subject device may use MomentaTaq DNA Polymerase as an alternative to KAPA2G DNA Polymerase in the reagent formulation of the assay. This formulation difference does not introduce any changes to sample processing, assay procedure, or data reduction.

Additional studies were initiated to support the formulation of the assay with MomentaTaq DNA Polymerase. Supplemental data from these studies were used with data previously obtained from the analytical and clinical testing studies submitted in K212778.

The steps of the Alinity m EBV consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. All stages of the Alinity m EBV procedure are executed automatically by the Alinity m System. No intermediate processing or transfer steps are performed by the user. The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m EBV assay in parallel with other Alinity m assays on the same instrument.

Alinity m EBV requires three separate assay specific kits as follows:

• Alinity m EBV AMP Kit (List No. 09N43-095), consisting of 2 types of multi-well assay trays. The amplification trays (AMP TRAY 1) contain lyophilized, unit-dose PCR amplification/detection reagents and lyophilized, unit-dose IC in separate wells, and the activation trays (ACT TRAY 2) contain liquid unit-dose activation reagent. The intended storage condition for the Alinity m EBV AMP Kit is 2°C to 8°C.

• Alinity m EBV CTRL Kit (List No. 09N43-085), consisting of negative controls, low positive controls, and high positive controls, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m EBV CTRL Kit is –25°C to –15°C.

• Alinity m EBV CAL Kit (List No. 09N43-075), consisting of 2 calibrator levels, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m EBV CAL Kit is –25°C to –15°C.

EBV DNA from human plasma is extracted automatically on-board in the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash, and elution. The resulting purified nucleic acids are then combined with liquid unit-dose Alinity m EBV activation reagent and lyophilized unit-dose Alinity m EBV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification, and real-time fluorescence detection of EBV targets.

At the beginning of the Alinity m EBV sample preparation process, a lyophilized unit-dose IC on the AMP Tray is rehydrated by the Alinity m System and delivered into each sample preparation reaction. The IC is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators, and controls to demonstrate proper sample processing and validity.

The Alinity m EBV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable polymerization and detection.

An EBV calibration curve is required for determination of EBV DNA concentration. Two levels of calibrators are processed through sample preparation and PCR to generate the calibration curve. The concentration of EBV DNA in specimens and controls is then calculated from the stored calibration curve.

Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remains satisfactory. During each control event, a negative control, a low-positive control, and a high-positive control are processed through sample preparation and PCR procedures that are identical to those used for specimens.

The Alinity m EBV assay also utilizes the following:

• Alinity m EBV Application Specification File, (List No. 09N43-05B)
• Alinity m System and System Software (List No. 08N53-002)
• Alinity m Sample Prep Kit 2 (List No. 09N12-001)
• Alinity m Specimen Dilution Kit I (List No. 09N50-001)
• Alinity m System Solutions, (List No. 09N20):
  • Alinity m Lysis Solution (List No. 09N20-001)
  • Alinity m Diluent Solution (List No. 09N20-003)
  • Alinity m Vapor Barrier Solution, (List No. 09N20-004)
• Alinity m Tubes and Caps (List No. 09N49):
  • Alinity m LRV Tube (List No. 09N49-001)
  • Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
  • Alinity m Transport Tube (List No. 09N49-011)
  • Alinity m Pierceable Cap (List No. 09N49-012)
  • Alinity m Aliquot Tube (List No. 09N49-013)

This document, K243489, is a 510(k) clearance letter for the Alinity m EBV assay, specifically focusing on the use of MomentaTaq DNA Polymerase as an alternative to KAPA2G DNA Polymerase. The primary goal of the studies described is to demonstrate that the device formulated with MomentaTaq DNA Polymerase performs equivalently to the previously cleared device formulated with KAPA2G DNA Polymerase (K212778).

Here's an analysis of the acceptance criteria and study information provided:

1. Table of Acceptance Criteria and Reported Device Performance

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Alinity m EBV is an in vitro polymerase chain reaction (PCR) assay for the quantitation of Epstein-Barr Virus (EBV) DNA in human EDTA plasma on the automated Alinity m System.

Alinity m EBV is intended for use as an aid in the management of EBV in transplant patients undergoing monitoring of EBV, serial DNA measurements can be used to indicate the need for potential treatment changes and to assess viral response to treatment.

The results from Alinity m EBV must be interpreted within the context of all relevant clinical and laboratory findings. Alinity m EBV is not cleared for use as a screening test for donors of blood products, or human cells, tissues, and cellular and tissue-based products (HCT/Ps) for EBV.

Alinity m EBV is an in vitro polymerase chain reaction (PCR) assay for the quantitation of EBV DNA in human plasma.

The steps of the Alinity m EBV assay consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. All stages of the Alinity m EBV procedure are executed automatically by the Alinity m System. No intermediate processing or transfer steps are performed by the user. The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m EBV assay in parallel with other Alinity m assays on the same instrument.

Alinity m EBV requires three separate assay specific kits as follows:

• . Alinity m EBV AMP Kit (List No. 09N43-095) consisting of multi-well amplification trays (AMP Trays) containing lyophilized, unit-dose PCR amplification/detection reagents and multi-well activation trays (ACT Trays) containing liquid, unit-dose activation reagents (MgCl2, TMAC, KCl, and ProClin). The intended storage condition for the Alinity m EBV AMP Kit is 2°C to 8°C.
• Alinity m EBV CTRL Kit (List No. 09N43-085) consisting of a negative control, a low positive control, and a high positive control, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m EBV CTRL Kit is —15°C to —25°C.
• . Alinity m EBV CAL Kit (List No. 09N43-075) consisting of two levels of calibrators (CAL A and CAL B), each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m EBV CAL Kit is -15°C to -25°C.

EBV DNA from specimens is extracted automatically on-board in the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash and elution. The resulting purified nucleic acids are then combined with the liquid unit-dose Alinity m EBV activation reagent and lyophilized unit-dose Alinity m EBV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification and real-time fluorescence detection of EBV targets.

An EBV calibration curve is required for the quantitation of EBV targets. Two levels of calibrators are processed through sample preparation and real-time PCR to generate the calibration curve. The concentration of EBV DNA in specimens and controls is then calculated from the stored calibration curve.

Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remain satisfactory. During each control event, a negative control, a low-positive control, and a high-positive control are processed through sample preparation and real-time PCR procedures that are identical to those used for specimens.

At the beginning of the Alinity m EBV sample preparation process, a lyophilized unit -dose of Internal Control on the AMP Tray is rehydrated by the Alinity m System and delivered into each sample preparation reaction. The Internal Control is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators and controls to demonstrate proper sample processing and assay validity.

The Alinity m EBV amplification and detection reagents include primers and probes that amplify and detect dual targets in the EBV genome. Amplification and detection of the two EBV targets ensures sensitive detection of the viral genome even at low levels.

The Alinity m EBV assay also utilizes the following accessories:

• . Alinity m EBV Application Specification File, List No. 09N43-05A
• . Alinity m System and System Software, List No. 08N53-002
• . Alinity m Sample Prep Kit 2, List No. 09N12-001
• . Alinity m Specimen Dilution Kit I, List No. 09N50-001
• . Alinity m Tubes and Caps, List No. 09N49:
  • . Alinity m LRV Tube, List No. 09N49-001
  • Alinity m Transport Tubes Pierceable Capped, List No. 09N49-010 ●
  • Alinity m Transport Tube, List No. 09N49-011 .
  • . Alinity m Pierceable Cap, List No. 09N49-012
  • . Alinity m Aliquot Tube, List No. 09N49-013
• . Alinity m System Solutions, List No. 09N20:
  • . Alinity m Lysis Solution, List No. 09N20-001
  • Alinity m Diluent Solution, List No. 09N20-003 .
  • . Alinity m Vapor Barrier Solution, List No. 09N20-004

Here's a summary of the acceptance criteria and study details for the Alinity m EBV AMP Kit, extracted from the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document describes performance characteristics but doesn't explicitly state "acceptance criteria" for each in a table. Instead, it presents the validated performance values. I've constructed a table based on the key performance metrics and their demonstrated values.

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cobas® BKV is an in vitro nucleic acid amplification test for the quantitation of BKV) DNA in human EDTA plasma and urine stabilized in cobas® PCR media on the cobas® 6800/8800 Systems.

In EDTA plasma, cobas® BKV is intended for use as an aid in the management of BKV in transplant patients. In patients undergoing monitoring of BKV in EDTA plasma, serial DNA measurements can be used to indicate the need for potential treatment changes and to assess viral response to treatment.

In urine stabilized in cobas® PCR Media, cobas® BKV is intended for use as an aid in the management of BKV in transplant patients.

The results from cobas® BKV are intended to be read and analyzed by a qualified licensed healthcare professional in conjunction with clinical signs and symptoms and relevant laboratory findings. Test results must not be the sole basis for patient management decisions .

cobas® BKV is not intended for use as a screening test for blood products or human cells, tissues, and cellular and tissue-based products (HCT/Ps).

cobas® BKV (Figure 1) is based on fully automated sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection. The cobas® 6800/8800 Systems consist of the sample supply module, the transfer module, the processing module, and the analytic module. Automated data management is performed by the cobas® 6800/8800 software which assigns test results for all tests as either target not detected, BKV DNA detected ULoQ (upper limit of quantitation), or a value in the linear range LLoQ

This document describes the acceptance criteria and supporting studies for the cobas® BKV device for the quantitation of BK virus (BKV) DNA in human urine. The information is extracted from a 510(k) summary.

1. Table of Acceptance Criteria and Reported Device Performance

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

The studies focused on analytical performance (Limit of Detection, Linearity, Precision, Specificity, Interference, Cross-contamination) and clinical performance (Reproducibility, Clinical Concordance).

• Limit of Detection (LoD):
  • WHO International Standard: 63 replicates per concentration level (total 7 levels, x3 lots = 1323 replicates).
  • Subgroups/Subtypes Verification: 63 replicates per concentration level for each genotype (total 5 genotypes, 3 levels each, x3 lots = 2835 replicates).
• Linear Range:
  • Main linearity: 36 replicates per panel member (10 panel members, x3 lots = 1080 replicates).
  • Genotype linearity: 12 replicates per level for each genotype (8 panel members each, 5 genotypes, x3 lots = 1440 replicates).
• Lower Limit of Quantitation (LLoQ): Data from the Linearity study at 100, 200, and 300 IU/mL concentrations.
• Precision (Within-Laboratory): 72 replicates for each of 5 dilution levels (x3 lots = 1080 replicates).
• Analytical Specificity: 3 replicates for each of the microorganisms listed in Table 10, both in BKV-negative and BKV-positive urine (number of microorganisms not explicitly totalled, but substantial).
• Interfering Substances: Replicates for each substance in presence and absence of BKV DNA (number of replicates not explicitly stated, but implies multiple for each substance in Table 11).
• Cross Contamination: 240 replicates of BKV-negative matrix samples, 225 replicates of high titer BKV DNA urine samples.
• Clinical Reproducibility: 270 tests per concentration (5 concentrations, total 1350 tests, not including controls).
• Clinical Performance / Concordance: 308 neat urine samples from 84 transplant subjects (for concordance analysis). 61 negative samples for NPA. 153 BKV positive urine samples from 55 transplant subjects (for correlation analysis).

Data Provenance: The document implies that the non-clinical studies were conducted internally or at authorized labs. The clinical performance evaluation was conducted at 3 testing sites, suggesting multi-site prospective data collection. The data samples were human EDTA plasma and urine. The origin of the samples (country) is not explicitly stated in the provided text. The clinical study used a retrospective cohort of samples from transplant patients.

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

The ground truth for the analytical studies was established based on known concentrations of BKV international standards or armored DNA. For clinical performance, the comparator was a "well-established laboratory developed nucleic acid test (LDT)".

The document does not mention the use of experts to establish ground truth for the test sets in the typical sense of human readers for image-based diagnostics. The "ground truth" for this diagnostic device study is based on the highly controlled properties of the spiked samples (known concentrations, genotypes) for analytical performance, and the results from a comparator LDT for clinical concordance.

4. Adjudication Method for the Test Set

Not applicable in the context of this in vitro diagnostic device, as the "ground truth" is based on quantitative measurements and known concentrations, not subjective expert assessment requiring adjudication.

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 device is an in vitro nucleic acid amplification test (NAAT) for quantitative measurement of BKV DNA. It is not an AI-assisted diagnostic device requiring human reader input or interpretation in the way an imaging diagnostic device would. Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance is not relevant to this submission.

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

Yes, the studies described are for the standalone performance of the cobas® BKV system, which is an automated molecular diagnostic assay. The system performs "fully automated sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection." The results are "assigned... by the cobas® 6800/8800 software." While "results are intended to be read and analyzed by a qualified licensed healthcare professional in conjunction with clinical signs and symptoms and relevant laboratory findings," the primary performance metrics are based on the direct output of the automated system.

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

• Analytical Studies: The ground truth for analytical studies (LoD, Linearity, Precision, Specificity, Interference) was established using known concentrations of BKV DNA, including the WHO International Standard (NIBSC 14/212), BKV armored DNA, and clinical specimens diluted to specific concentrations. Samples were spiked into BKV-negative urine.
• Clinical Studies: For clinical concordance, the ground truth was based on the results from a "well-established laboratory developed nucleic acid test (LDT) (comparator BKV LDT)" on actual clinical urine samples. DNA sequencing was also used in some cases to confirm BKV presence in discordant results.

8. The Sample Size for the Training Set

The document describes performance evaluation studies (validation and verification) rather than a machine learning model development process that typically involves distinct training and test sets.
Therefore, a separate "training set" sample size for a machine learning algorithm is not applicable in the context of this in vitro diagnostic device, which is based on established molecular biological techniques (PCR).

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

As this is not an AI/ML-based device with a "training set," this question is not applicable. The ground truth for the evaluation of the device was established through known concentrations of viral standards and comparison to a comparator LDT, as described in point 7.

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cobas EBV is an in vitro nucleic acid amplification test for the quantitation of Epstein-Barr virus (EBV) DNA in human EDTA plasma on the cobas 6800/8800 Systems.

cobas EBV is intended for use as an aid in the management of EBV in transplant patients. In patients undergoing monitoring of EBV, serial DNA measurements can be used to indicate the need for potential treatment changes and to assess response to treatment.

The results from cobas EBV are intended to be read and analyzed by a qualified licensed healthcare professional in conjunction with clinical signs and symptoms and relevant laboratory findings. Negative test results do not preclude EBV infection or EBV disease. Test results must not be the sole basis for patient management decisions.

cobas EBV is not intended for use as a screening test for donors of blood or blood products or human cells, tissues, and cellular and tissue-based products (HCT/Ps).

cobas EBV is a quantitative test performed on the cobas 6800 System and cobas 8800 System. cobas EBV enables the detection of EBV DNA in plasma specimens. The cobas EBV assay is a dual target assay, with both targets using the same dye. The DNA Internal Control, used to monitor the entire sample preparation and PCR amplification process, is introduced into each specimen during sample processing. cobas EBV enables the detection and quantitation of EBV DNA in EDTA plasma from solid organ transplant patients (SOT) and from hematopoietic stem cell transplant (HSCT) patients. The test is intended for use as an aid in the management of SOT patients and HSCT patients.

The cobas EBV consists of:

• Proteinase Solution ●
• DNA Quantitation Standard (DNA QS) ●
• Elution Buffer ●
• Master Mix Reagent 1
• . EBV Master Mix Reagent 2

The EBV viral load is quantified against a non-EBV DNA quantitation standard (DNA-OS), which is introduced into each specimen during sample preparation. The DNA-QS also functions as an internal control for sample preparation and the PCR amplification process.

In addition, the test utilizes the following separately packed and sold control materials:

• 1. cobas EBV Positive Control Kit:
  • . EBV Low Positive Control (EBV L(+)C)
  • EBV High Positive Control (EBV H(+)C) ●

The positive control contains phage packaged EBV DNA in normal human plasma and serves as a control for the cobas EBV test.

• 2. cobas Negative Control Kit:
  • cobas Buffer Negative Control (BUF (-) C) ●

Testing with the cobas EBV test requires the following materials that are not provided:

• cobas OMNI Reagents: Including the following reagents used for specimen ● processing, PCR and detection:
• cobas EBV Assay Specific Analysis Package (ASAP) software .

The cobas EBV test uses sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection, all steps are fully automated by the cobas 6800/8800 platform.

Here's an analysis of the acceptance criteria and the studies that prove the device meets these criteria, based on the provided text:

Acceptance Criteria and Device Performance

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