(27 days)
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%;
§ 866.3183 Quantitative viral nucleic acid test for transplant patient management.
(a)
Identification. A quantitative viral nucleic acid test for transplant patient management is identified as a device intended for prescription use in the detection of viral pathogens by measurement of viral DNA or RNA using specified specimen processing, amplification, and detection instrumentation. The test is intended for use as an aid in the management of transplant patients with active viral infection or at risk for developing viral infections. The test results are intended to be interpreted by qualified healthcare professionals in conjunction with other relevant clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10(b) of this chapter must include:
(i) A prominent statement that the device is not intended for use as a donor screening test for the presence of viral nucleic acid in blood or blood products.
(ii) Limitations which must be updated to reflect current clinical practice. These limitations must include, but are not limited to, statements that indicate:
(A) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with clinical signs and symptoms and other relevant laboratory results; and
(B) Negative test results do not preclude viral infection or tissue invasive viral disease and that test results must not be the sole basis for patient management decisions.
(iii) A detailed explanation of the interpretation of results and acceptance criteria must be provided and include specific warnings regarding the potential for variability in viral load measurement when samples are measured by different devices. Warnings must include the following statement, where applicable: “Due to the potential for variability in [analyte] measurements across different [analyte] assays, it is recommended that the same device be used for the quantitation of [analyte] when managing individual patients.”
(iv) A detailed explanation of the principles of operation and procedures for assay performance.
(2) Design verification and validation must include the following:
(i) Detailed documentation of the device description, including all parts that make up the device, ancillary reagents required for use with the assay but not provided, an explanation of the methodology, design of the primer/probe sequences, rationale for the selected gene target, and specifications for amplicon size, guanine-cytosine content, and degree of nucleic acid sequence conservation. The design and nature of all primary, secondary and tertiary quantitation standards used for calibration must also be described.
(ii) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions;
(iii) Documentation and characterization (
e.g., determination of the identity, supplier, purity, and stability) of all critical reagents and protocols for maintaining product integrity throughout its labeled shelf-life.(iv) Stability data for reagents provided with the device and indicated specimen types, in addition to the basis for the stability acceptance criteria at all time points chosen across the spectrum of the device's indicated life cycle, which must include a time point at the end of shelf life.
(v) All stability protocols, including acceptance criteria.
(vi) Final lot release criteria along with documentation of an appropriate justification that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.
(vii) Risk analysis and documentation demonstrating how risk control measures are implemented to address device system hazards, such as Failure Mode Effects Analysis and/or Hazard Analysis. This documentation must include a detailed description of a protocol (including all procedures and methods) for the continuous monitoring, identification, and handling of genetic mutations and/or novel viral stains (
e.g., regular review of published literature and annual in silico analysis of target sequences to detect possible primer or probe mismatches). All results of this protocol, including any findings, must be documented.(viii) Analytical performance testing that includes:
(A) Detailed documentation of the following analytical performance studies: limit of detection, upper and lower limits of quantitation, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, quality control, specimen stability studies, and additional studies as applicable to specimen type and intended use for the device;
(B) Identification of the viral strains selected for use in analytical studies, which must be representative of clinically relevant circulating strains;
(C) Inclusivity study results obtained with a variety of viral genotypes as applicable to the specific assay target and supplemented by in silico analysis;
(D) Reproducibility studies that include the testing of three independent production lots;
(E) Documentation of calibration to a reference standard that FDA has determined is appropriate for the quantification of viral DNA or RNA (
e.g., a recognized consensus standard); and(F) Documentation of traceability performed each time a new lot of the standardized reference material to which the device is traceable is released, or when the field transitions to a new standardized reference material.
(ix) Clinical performance testing that includes:
(A) Detailed documentation from either a method comparison study with a comparator that FDA has determined is appropriate, or results from a prospective clinical study demonstrating clinical validity of the device;
(B) Data from patient samples, with an acceptable number of the virus-positive samples containing an analyte concentration near the lower limit of quantitation and any clinically relevant decision points. If an acceptable number of virus-positive samples containing an analyte concentration near the lower limit of quantitation and any clinically relevant decision cannot be obtained, contrived samples may be used to supplement sample numbers when appropriate, as determined by FDA;
(C) The method comparison study must include predefined maximum acceptable differences between the test and comparator method across all primary outcome measures in the clinical study protocol; and
(D) The final release test results for each lot used in the clinical study.