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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® 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

• 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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