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510(k) Data Aggregation
(258 days)
Illinois 60018
Re: K243489
Trade/Device Name: Alinity m EBV
Regulation Number: 21 CFR 866.3183
Alinity m EBV | Quantitative viral nucleic acid test for transplant patient management | QLX | 21 CFR 866.3183
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.
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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
| Performance Characteristic | Acceptance Criteria with MomentaTaq Formulation (Implicitly compared to KAPA2G performance) | Reported Device Performance (MomentaTaq Formulation) |
|---|---|---|
| Limit of Detection (LoD) | Overall detection rate of ≥ 95% at 20 IU/mL (based on previous clearance of K212778). | Overall detection rate of 97.2% at 20 IU/mL. |
| Linear Range | Linear across 50 IU/mL (1.70 Log IU/mL) to 200,000,000 IU/mL (8.30 Log IU/mL). | Linear across 15 IU/mL to 250,000,000 IU/mL (1.18 Log IU/mL to 8.40 Log IU/mL). |
| Precision (Within-laboratory SD) | ≤ 0.25 Log IU/mL for 500 IU/mL to 200,000,000 IU/mL (2.70 Log IU/mL to 8.30 Log IU/mL). | Achieved for all panels in this range (0.06-0.19 Log IU/mL). |
| Precision (Within-laboratory SD) | ≤ 0.50 Log IU/mL for 20 IU/mL to |
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(266 days)
Des Plaines, Illinois 60018
Re: K241921
Trade/Device Name: Alinity m BKV Regulation Number: 21 CFR 866.3183
| Quantitative viral nucleic acid test for transplant
patient management | QMI | 21 CFR 866.3183
Alinity m BKV is an in vitro nucleic acid amplification test for the quantitation of BK virus (BKV) DNA in human EDTA plasma (K2 EDTA, K3 EDTA, and PPT) and urine stabilized using the Alinity m Urine Transport Kit on the automated Alinity m System.
In EDTA plasma (K2 EDTA, K3 EDTA, and PPT) and urine stabilized using the Alinity m Urine Transport Kit, Alinity m BKV is intended for use as an aid in the diagnosis and 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.
The results from Alinity m BKV must be interpreted in conjunction with clinical signs and other relevant laboratory findings. Alinity m BKV is not cleared as a screening test for blood or blood products or human cells, tissues, and cellular and tissue-based products.
The Alinity m BKV assay utilizes real-time polymerase chain reaction (PCR) to amplify and detect BKV genomic DNA sequences that have been extracted from human EDTA plasma or urine specimens. The steps of the Alinity m BKV assay consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. One transfer step of urine specimens into the Alinity m Urine Transport Kit by the user is required prior to placing urine specimens on the Alinity m System. Remaining steps of the Alinity m BKV assay procedure are executed automatically by the Alinity m System. Manual dilutions may be performed for low-volume plasma specimens to meet the minimum volume requirement. The Alinity m System is designed to be a randomaccess analyzer that can perform the Alinity m BKV assay in parallel with other Alinity m assays on the same instrument.
Alinity m BKV requires three separate assay specific kits as follows:
- . Alinity m BKV AMP Kit (List No. 09N85-095), consisting of 2 types of multi-well assay trays. The amplification tray (AMP TRAY 1) contains liquid, unit-dose PCR amplification/detection reagents and liquid, unit-dose Internal Control (IC) in separate wells; and the activation tray (ACT TRAY 2) contains liquid, unit-dose activation reagent. The intended storage condition for the Alinity m BKV AMP Kit is -25°C to -15°C.
- . Alinity m BKV CTRL Kit (List No. 09N85-085), 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 BKV CTRL Kit is -25°C to -15°C.
- Alinity m BKV CAL Kit (List No. 09N85-075), consisting of 2 calibrator levels, . each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m BKV CAL Kit is -25°C to -15°C.
The Alinity m BKV assay requires a transport kit for testing all urine specimens:
- Alinity m Urine Transport Kit (List No. 09N85-001) consisting of a transport tube . and transfer pipette. The transport tube contains transport buffer. The intended storage condition for the Alinity m Urine Transport Kit is 15℃ to 30℃.
BKV DNA from human plasma or urine is extracted automatically on board 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 DNA is then combined with liquid unit-dose Alinity m BKV activation reagent and liquid unit-dose Alinity m BKV 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 BKV DNA.
At the beginning of the Alinity m BKV sample preparation process, a liquid unit-dose IC on the AMP Tray is transferred 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 BKV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable amplification and detection of dual targets in the BKV genome. Amplification and detection of the two BKV targets ensures sensitive detection of the viral genome even at low levels. In addition to the BKV primers and probes, the assay utilizes an IC primer/probe set for amplification and detection of the IC target sequence, which is not related to BKV. The IC probe is labeled with a different fluorophore than the BKV probes. This allows for simultaneous detection and discrimination of both the BKV and IC amplified products within the same reaction vessel.
A BKV calibration curve is required for determination of BKV DNA concentration. Two levels of calibrators are processed through sample preparation and PCR to generate the calibration curve. The concentration of BKV 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 BKV assay also utilizes the following:
- Alinity m BKV Application Specification File (List No. 09N85-05A) .
- 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 System Solutions, (List No. 09N20):
- o Alinity m Lysis Solution (List No. 09N20-001)
- o Alinity m Diluent Solution (List No. 09N20-003)
- o 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) o
- o Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
- o Alinity m Transport Tube (List No. 09N49-011)
- o Alinity m Pierceable Cap (List No. 09N49-012)
- o Alinity m Aliquot Tube (List No. 09N49-013)
1. Acceptance Criteria and Reported Device Performance
| Acceptance Criteria | Plasma Performance | Urine Performance |
|---|---|---|
| Limit of Detection (LoD) (95% detection probability) | Claimed LoD: 50 IU/mL (1.70 Log IU/mL) | Claimed LoD: 50 IU/mL (1.70 Log IU/mL) |
| (Genotypes Ia, Ic, II, III, IV detection at ≥95%) | All genotypes detected at ≥95% at 30 IU/mL (1.48 Log IU/mL) | All genotypes detected at ≥95% at 45 IU/mL (1.65 Log IU/mL) |
| Linear Range (Quantitation Range) | 50 IU/mL (1.70 Log IU/mL) to 1,000,000,000 IU/mL (9.00 Log IU/mL) (r=1.000) | 50 IU/mL (1.70 Log IU/mL) to 1,000,000,000 IU/mL (9.00 Log IU/mL) (r=1.000) |
| (Linearity for Genotypes) | Established for Ia, Ic, II, III, IV across the quantitation range | Established for Ia, Ic, II, III, IV across the quantitation range |
| Precision (Within-laboratory SD for Log IU/mL) | ≤ 0.25 Log IU/mL for 2.70-9.00 Log IU/mL; ≤ 0.50 Log IU/mL for 1.70-0.4% w/v) and PBMCs (>1 × 10^5 cells/mL). | |
| Carryover | 0.0% (95% CI: 0.0% to 1.1%) | 0.0% (95% CI: 0.0% to 1.1%) |
| Clinical Agreement (Plasma) | High agreement with comparator across viral load ranges: 100% for TND, 100% for |
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(317 days)
CTRL Kit (List No. 09N43-085), Alinity m EBV CAL Kit (List No. 09N43-075) Regulation Number: 21 CFR 866.3183
EBV | Quantitative viral nucleic acid test
for transplant patient management | QLX | 866.3183
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.
| Performance Metric | Acceptance Criteria (Implicit from Results) | Reported Device Performance |
|---|---|---|
| Limit of Detection (LoD) for EBV Type 1 | Detect with 95% probability | 19.56 IU/mL (LoD by Probit) with 95% CI (13.09 IU/mL, 39.39 IU/mL) for least sensitive lot. Claimed LoD: 20 IU/mL. |
| LoD for EBV Type 2 | Detect 95% or greater of EBV samples | 95.7% at 20 IU/mL and 95.8% at 15 IU/mL. |
| Linearity Range | Linear across the quantitation range | 50 IU/mL to 200,000,000 IU/mL (1.70 Log IU/mL to 8.30 Log IU/mL) for both EBV types 1 & 2. Correlation coefficient r = 0.999. |
| Precision (Within-Laboratory SD) | ≤ 0.25 Log IU/mL for 2.70-8.30 Log IU/mL | ≤ 0.25 Log IU/mL. |
| ≤ 0.50 Log IU/mL for 1.30- |
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(88 days)
Pleasanton, California 94588-2722
Re: K203220
Trade/Device Name: cobas BKV Regulation Number: 21 CFR 866.3183
for transplant patient management |
| Product Codes | QLX: 21 CFR 866.3183
-------------------------------------------------------|
| Regulation Number | 21 CFR 866.3183
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
| Acceptance Criteria | Reported Device Performance (cobas® BKV in Urine) |
|---|---|
| Limit of Detection (LoD): 95% hit rate for BKV DNA. | 12.2 IU/mL (WHO International Standard, 95% confidence range: 9.2-18.3 IU/mL). Achieved ≥95% hit rate for subgroups Ia, Ic, and subtypes II, III, IV at 12.2 IU/mL. |
| Linear Range: Accuracy within ± 0.2 log10. | 7.41E+01 IU/mL to 7.41E+08 IU/mL. Maximum deviation of linear regression from better fitting non-linear regression was ≤ ± 0.2 log10 for all tested genotypes within the linear range. |
| Lower Limit of Quantitation (LLoQ): Mean deviation between observed and assigned log10 titer ≤ ± 0.3 log10 (based on upper 95% CI of worst performing lot). Total Analytical Error (TAE) ≤ 1 log10. | 200 IU/mL. Mean deviation between observed and assigned log10 titer was ≤ 0.3 log10. TAE was ≤ 0.44 for all lots and concentrations (Table 7). |
| Precision (Within-Laboratory): High precision across the concentration range. | Demonstrated high precision across a concentration range of 7.41E+02 IU/mL to 7.41E+05 IU/mL (Table 8, Table 9). Total %CV ranged from 7% (highest concentration) to 23% (lowest concentration). |
| Analytical Specificity: No interference from listed microorganisms; mean log10 titer of positive BKV samples with interfering organisms within ± 0.5 log10 of spike control. | None of the tested non-BKV pathogens (bacteria, yeast, viruses in Table 10) interfered. Mean log10 titer of positive BKV samples was within ± 0.5 log10 of the spike control. |
| Interfering Substances: No interference from listed endogenous substances and drug compounds, with mean log10 titer of positive BKV samples with interfering substances within ± 0.5 log10 of spike control. | All listed endogenous interferences and drug compounds (except talcum powder at >0.05%) did not interfere. Mean log10 titer of positive BKV samples was within ± 0.5 log10 of the spike control. |
| Cross Contamination: Zero cross-contamination rate with a low upper 95% confidence interval. | 0.0% (upper one-sided 95% CI 1.24%) with 240 replicates of negative samples. |
| Clinical Reproducibility: Acceptable reproducibility; 100% detection of 3 x LLoQ samples; 95% CI for difference between 2 measurements within ± 0.20 log10 copies/mL. | Acceptable clinical reproducibility. 100% of 3 x LLoQ samples detected. All estimated 95% CLs for the difference between 2 measurements from the same subject were within ± 0.20 log10 copies/mL. |
| Negative Percent Agreement (NPA) (Clinical): High negative percent agreement. | 100% (95% Exact CI of 94.1% to 100%) for 61 valid negative samples. |
| Clinical Concordance with LDT: High agreement at various thresholds and strong correlation. | Concordance analysis with comparator LDT showed high agreement (e.g., 93.9% at Target Not Detected threshold, 99.5% at LLoQ threshold). Deming linear regression showed a strong correlation with CI for intercept within ±0.5 log10 IU/mL. |
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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(27 days)
: cobas BKV, cobas EBV/BKV Control Kit, cobas Buffer Negative Control Kit Regulation Number: 21 CFR 866.3183
test for transplant patient management |
| Product Codes | QMI: 21 CFR 866.3183
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| Regulation Number | 21 CFR 866.3183
cobas® BKV is an in vitro nucleic acid amplification test for the quantitation of BK virus (BKV) DNA in human EDTA plasma on the cobas® 6800/8800 Systems.
cobas® BKV is intended for use as an aid in the management of BKV in transplant patients. In patients undergoing monitoring of BKV, serial DNA measurements can be used to indicate the need for potential treatment changes and to assess viral response to treatment.
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 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
The provided document is a 510(k) Summary for the cobas® BKV test for use on the cobas® 6800/8800 Systems. This document focuses on demonstrating substantial equivalence to a predicate device through non-clinical performance evaluation, rather than an AI/ML device requiring a comparative effectiveness study with human readers. Therefore, several of the requested sections (e.g., sample size for test set, number of experts, adjudication method, MRMC study, standalone performance, ground truth for test set, training set details) are not directly applicable or explicitly stated in the context of this In Vitro Diagnostic (IVD) device submission for a quantitative nucleic acid amplification test.
However, I will extract relevant information to address the applicable criteria based on the provided text.
Acceptance Criteria and Device Performance for cobas® BKV
The acceptance criteria for this diagnostic device are primarily defined by various performance characteristics required for quantitative viral nucleic acid tests. The study proves the device meets these criteria through a series of non-clinical performance evaluations.
Table of Acceptance Criteria and Reported Device Performance
| Performance Characteristic | Acceptance Criteria (Implicit from Study Design/Context) | Reported Device Performance and Study Details |
|---|---|---|
| Limit of Detection (LoD) | Determine the concentration at which 95% hit rate is achieved for the WHO International Standard and all subgroups/subtypes, across multiple lots. | - WHO International Standard (NIBSC 14/212): Determined as 21.5 IU/mL (PROBIT, 95% hit rate) with a 95% CI of 16.3 – 32.4 IU/mL in EDTA plasma, using the least sensitive lot. |
- Subgroups Ia, Ic and Subtypes II, III and IV: Verified detection at 21.5 IU/mL with a ≥ 95% hit rate for all tested genotypes (e.g., Subgroup Ia at 21.5 IU/mL: 100.0% hit rate, 63/63 positives; Subgroup Ic at 21.5 IU/mL: 100.0% hit rate, 62/62 positives). |
| Traceability | Demonstrate proportionality and correlation to the 1st WHO International Standard for BKV DNA. | - Calibration and standardization process provides quantitation values for panels and standards similar to expected values. - Maximum deviation from expected values was not more than 0.19 log10 IU/mL.
- Deming regression for BKV WHO Standard showed Y = 0.951x + 0.208 with R² = 0.973. |
| Linear Range | Demonstrate linearity of quantification within a specified range with acceptable deviation and accuracy. | - Demonstrated linear from 1.01E+01 to 1.97E+08 IU/mL. - Absolute deviation from non-linear regression ≤ ± 0.1 log10 in human EDTA plasma.
- Accuracy within ± 0.2 log10 across the linear range.
- Verified for subgroups Ia, Ic and subtypes II, III and IV: maximum deviation between linear and higher order non-linear regression ≤ ± 0.2 log10. |
| Lower Limit of Quantitation (LLoQ) | Determine the lowest titer meeting acceptance criteria for Total Analytical Error (TAE ≤ 1.0 log10 IU/mL) and difference between two measurements. | - Established as 21.5 IU/mL. - At 19.0 IU/mL (nominal concentration, lowest tested for LLoQ), all three lots combined showed TAE of 0.69 and difference between measurements (SD) of 0.73, both within 1.0 log10 IU/mL. |
| Precision – Within Laboratory | Demonstrate high precision across specified concentration ranges, instruments, operators, and days. | - High precision shown across 5.90E+01 IU/mL to 9.83E+05 IU/mL. - Total %CV ranged from 8% to 36% across the concentrations tested (e.g., 8% at 9.83E+05 IU/mL, 36% at 5.90E+01 IU/mL).
- Results represent all aspects of the test procedure. |
| Analytical Specificity | No interference or cross-reactivity with common microorganisms and endogenous/exogenous substances. | - Microorganisms: None of 17 viruses, 13 bacteria, and 3 yeast species interfered at tested concentrations (1.00E+05 to 1.00E+06 units/mL). Negative results for BKV-negative samples, positive for BKV-spiked samples. Titer within ± 0.5 log10 of control. - Interfering Substances: Elevated triglycerides, bilirubin (conjugated/unconjugated), albumin, hemoglobin, human DNA, and 17 drug compounds (including antimicrobials and immune suppressants) did not interfere. Titer within ± 0.5 log10 of control. |
| Cross-Contamination | Demonstrate a low or zero cross-contamination rate. | - 0% cross-contamination rate (0/240 negative replicates) with an upper one-sided 95% CI of 1.24%. |
| Reproducibility | Demonstrate consistent performance across different reagent lots, test sites, batches, and testing days. | - Evaluated at 3 testing sites using 3 reagent lots per site by 2 operators over 5 days. - Total Precision Standard Deviation ranged from 0.068 to 0.304 log10 IU/mL.
- Lognormal CV(%) for Total Precision ranged from 15.74% to 79.43%.
- 100% detection of 3 x LLoQ samples.
- Equivalence shown between cobas® 6800 and 8800 systems.
- Negative percent agreement (NPA) for reproducibility study: 100% (270/270 samples negative), 95% Exact CI: 98.6% to 100%. |
| Clinical Concordance | Demonstrate agreement with a well-established laboratory-developed test (LDT). | - Total of 550 valid samples (217 neat, 303 diluted clinical, 30 contrived) from 129 transplant subjects were evaluable. - Agreement with Comparator BKV LDT (IU LDT): High concordance shown across different concentration ranges.
- Negative Percent Agreement (NPA): 100% (43/43 samples negative) with 95% Exact CI of 91.8% to 100%.
- At thresholds, percent agreement was high (e.g., ≥ threshold 2.3 Log10 IU/mL: 87.7%;
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(150 days)
Regulation section
- 21 CFR 866.3183
-
- Classification
Class II
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- Product code(s):
QLX
- Product code(s):
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Nucleic Acid Test for Transplant Patient Management Class: II (special controls) Regulation: 21 CFR 866.3183
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:
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- 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.
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- 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
| Criteria | Reported Device Performance |
|---|---|
| Precision | Standard Deviation (log10 transformed titer): Ranged from 0.02 to 0.17 across various concentrations (Table 1). |
| Lognormal Percent Coefficient of Variation (%CV): Ranged from 7% to 43% for positive panel members (Table 2). | |
| Reproducibility | Total Lognormal Coefficient of Variation (% CV): Ranged from 13.7% to 46.16% among positive panel members when tested across three reagent lots, three test sites, and three instruments (Table 3). |
| Linearity (Genotype 1) | Linear Range: 35 IU/mL (LLoQ) to 1.0E+08 IU/mL (ULoQ). |
| Accuracy: Within ± 0.15 log10 IU/mL (Mean Square Error) across the linear range. | |
| Best-fitting model: 1st order for individual lots/panel types, 2nd order for combined data (minor difference to 1st order: ≤ ± 0.01 log10 IU/mL). (Table 4, Figure 1) | |
| Linearity (Genotype 2) | Accuracy: Within ± 0.12 log10 IU/mL (Mean Square Error) across the linear range, with minor differences (–0.06 log IU/mL to +0.08 log IU/mL) between 1st and 3rd order regression models. (Figure 2) |
| Traceability | Quantitation values for the cobas EBV calibration panel and RMS EBV Secondary Standard showed deviations not more than 0.15 log10 IU/mL from expected values, demonstrating traceability to the 1st WHO International Standard for EBV (NIBSC 09/260). (Figure 3) |
| Regression equations: EBV Calibration Panel: y = 1.000x - 0.002; R2 = 1.000. | |
| EBV 1st WHO Standard: y = 0.975x + 0.159; R2 = 0.983. | |
| Clinical Specimen Stability | Whole blood (EDTA-plasma tubes) stable for up to 24 hours at 2-25°C. Plasma stable for 24 hours at 2-30°C, then up to 6 days at 2-8°C, or up to 6 months at -15 to -80°C. Plasma stable for up to four freeze/thaw cycles. Mean log10 titers at different time points/conditions were within ±0.5 log10 of the reference (T0). |
| Open Kit and On-board Stability | Open test-specific reagent cassettes stable for up to 90 days at 2-8℃ (Open Kit) and up to 40 hours at 37°C (On-Board). Reusable for up to 40 runs. |
| Reagent Stability | Shelf-life stability claim of 12 months when stored at 2-8°C (supported by real-time stability data). |
| Limit of Detection (LoD) | WHO EBV Standard (Genotype 1): LoD = 18.8 IU/mL by Probit analysis (highest LoD across lots). LoD by 95% hit rate was (b) (4) for all lots. (Table 5) |
| EBV Genotype 2: LoD verified at 18.8 IU/mL with a hit rate of 95% or higher. (Table 6) | |
| Plasma vs Buffer (GSD): Comparable LoD performance in Plasma and GSD (Hit rate 98.4% at 1.5xLoD, 92.1% at 1.0xLoD). (Table 7) | |
| Lower Limit of Quantitation (LLoQ) | LLoQ: 35 IU/mL. Determined based on Total Analytical Error (TAE) and difference between two measurements. (Table 8) |
| Cross-reactivity | EBV-negative samples: Negativity rate was high (not explicitly stated as 100% but implied by lack of reported positives). |
| EBV-positive samples: Mean log10 titer of positive EBV samples with 35 potential cross-reacting microorganisms was within ±0.5 log10 of the positive spike control. (Table 9) | |
| Endogenous Interference | EBV-negative samples: All produced valid negative results. |
| EBV-positive samples: Mean log10 titer of positive EBV samples with interfering substances (NaOH2, Albumin, Bilirubin, Human DNA, Hemoglobin, Triglycerides) was within ±0.05 log10 of the spike control. (Table 10) | |
| Exogenous Interference | EBV-negative samples: 100% negativity rate. |
| EBV-positive samples: Mean log10 titer of positive EBV samples with 24 common drugs was observed to be within acceptable range (implied by table values, e.g., Max Mean Difference in log10 Titer of -0.03 for Ethanol SC). (Table 11) | |
| Cross-Contamination | 0% cross-contamination rate (upper one-sided 95% CI: 1.24%) from testing 240 replicates of EBV-negative matrix sample in checkerboard configuration with high-titer samples. |
| Concordance with Comparator EBV Test | Overall Column Percent Agreement: Ranged from 82.5% to 100% depending on analyte concentration (for valid samples on both assays, n=464). (Table 12) |
| Negative Percent Agreement (NPA): 95.4% (95% CI: 84.2%-99.4%) with comparator EBV negative samples (n=43). | |
| Agreement at clinical thresholds: High agreement, e.g., 98.0% ( |
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