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cobas® HCV is an in vitro nucleic acid amplification test for both the detection and quantitation of hepatitis C virus (HCV) RNA, in human EDTA plasma or serum, of HCV antibody positive or HCV-infected individuals. Specimens containing HCV genotypes 1 to 6 are validated for detection and quantitation in the assay.

cobas® HCV is intended for use as an aid in the diagnosis of HCV infection in the following populations: individuals with antibody evidence of HCV with evidence of liver disease, individuals suspected to be actively infected with HCV antibody evidence, and individuals at risk for HCV infection with antibodies to HCV RNA indicates that the virus is replicating and therefore is evidence of active infection.

cobas® HCV is intended for use as an aid in the management of HCV-infected patients undergoing anti-viral therapy. The assay can be used to measure HCV RNA levels at baseline, during treatment, at the end of treatment, and at the end of follow up of treatment to determine sustained viral response. The results must be interpreted within the context of all relevant clinical and laboratory findings.

cobas® HCV has not been approved for use as a screening test for the presence of HCV in blood or blood products. Assay performance characteristics have been established for individuals treated with certain direct-acting antiviral agents (DAA) regimens. No information is available on the assay's predictive value when other DAA combination therapies are used.

cobas® HCV is a quantitative test performed on the cobas® 5800 System, cobas® 6800 System and cobas® 8800 System. cobas® HCV enables the detection and quantitation of HCV RNA in EDTA plasma or serum of infected patients. Dual probes are used to detect and quantify, but not discriminate genotypes 1–6. The viral load is quantified against a non-HCV armored RNA quantitation standard (RNA-QS), which is introduced into each specimen during sample preparation. The RNA-QS also functions as an internal control to assess substantial failures during the sample preparation and PCR amplification processes. In addition, the test utilizes three external controls: a high titer positive, a low titer positive, and a negative control.

cobas® HCV is based on fully automated sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection. The cobas® 5800 System is designed as one integrated instrument. 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® 5800 System or cobas® 6800/8800 Systems software(s) which assigns test results for all tests as target not detected, ULoQ (upper limit of quantitation) or HCV RNA detected, a value in the linear range LLoQ ≤ x ≤ ULoQ. Results can be reviewed directly on the system screen, exported, or printed as a report.

Nucleic acid from patient samples, external controls and added armored RNA-QS molecules are simultaneously extracted by addition of proteinase and lysis reagent to the sample. The released nucleic acid binds to the silica surface of the added magnetic glass particles. Unbound substances and impurities, such as denatured protein, cellular debris and potential PCR inhibitors are removed with subsequent wash buffer steps and purified nucleic acid is eluted from the magnetic glass particles with elution buffer at elevated temperature.

Selective amplification of target nucleic acid from the patient sample is achieved by the use of target virus-specific forward and reverse primers which are selected from highly conserved regions of HCV. Selective amplification of RNA-QS is achieved by the use of sequence-specific forward and reverse primers which are selected to have no homology with the HCV genome. A thermostable DNA polymerase enzyme is used for both reverse-transcription and PCR amplification. The target and RNA-QS sequences are amplified simultaneously utilizing a universal PCR amplification profile with predefined temperature steps and number of cycles. The master mix includes deoxyuridine triphosphate (dUTP), instead of deoxythimidine triphosphate (dTTP), which is incorporated into the newly synthesized DNA (amplicon). Any contaminating amplicon from previous PCR runs are eliminated by the AmpErase enzyme, which is included in the PCR mix, during the first thermal cycling step. However, newly formed amplicon are not eliminated since the AmpErase enzyme is inactivated once exposed to temperatures above 55°C.

The cobas® HCV master mix contains dual detection probes specific for the HCV target sequences and one for the RNA-QS. The probes are labeled with target-specific fluorescent reporter dyes allowing simultaneous detection of HCV target and RNA-OS in two different target channels. When not bound to the target sequence, the fluorescent signal of the intact probe is suppressed by a quencher dye. During the PCR amplification step, hybridization of the probes to the specific single-stranded DNA template results in cleavage of the probe by the 5'-to-3' nuclease activity of the DNA polymerase resulting in separation of the reporter and quencher dyes and the generation of a fluorescent signal. With each PCR cycle, increasing amounts of cleaved probes are generated and the cumulative signal of the reporter dye increases concomitantly. Real-time detection and discrimination of PCR products is accomplished by measuring the fluorescence of the released reporter dyes for the viral targets and RNA-QS.

Here's a breakdown of the acceptance criteria and study details for the cobas® HCV device, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are primarily derived from the "Method Comparison" study, which compares the cobas® HCV on the new cobas® 5800 System to the predicate cobas® HCV on the cobas® 6800/8800 Systems.

Assessment of "No" for Statistical Criteria: The document states that "Although the bias estimates were statistically significant, the differences are not clinically significant given that the biases are well below the standard deviation observed in the Reproducibility Study... and both the upper and lower bound of the 95% Cls are close to zero." This indicates that while the strict statistical criterion was not met, the clinical relevance of the difference was deemed acceptable.

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

• Sample Size for Method Comparison (Test Set):
  • HCV positive samples: 150 archived or contrived, well-characterized HCV positive plasma specimens with titers ranging from 1.5E+01 to 1E+08 IU/mL.
  • HCV negative samples: 30 individual HCV negative specimens.
  • Total: 180 samples.
• Data Provenance:
  • The document states "archived or contrived" samples. This indicates a retrospective or laboratory-created dataset.
  • The study was conducted at "three different sites (1 internal and 2 external)" for the cobas® 5800 System, and "one site (internal)" for the cobas® 6800/8800 System. The specific country of origin is not explicitly stated, but "Roche Molecular Systems, Inc." is located in Pleasanton, California, USA, implying the study likely took place within the US or involved US-based entities.

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

The document does not specify the number or qualifications of experts used to establish the "ground truth" for the test set. It mentions "well-characterized HCV positive plasma specimens" which implies the ground truth was established prior to this study, likely through established clinical diagnostic methods or previous validations. For HCV quantitative assays, gold standards often involve highly calibrated reference methods or known concentrations of viral RNA.

4. Adjudication Method for the Test Set

Not applicable. This device is a quantitative nucleic acid amplification test, and the "ground truth" for its performance is typically based on pre-characterized samples with known concentrations or clinical status, rather than subjective expert consensus and adjudication as might be seen for imaging interpretation. The comparison is between the new system and a predicate system.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No. This study is a method comparison study for an in vitro diagnostic (IVD) device, not an MRMC study for imaging interpretation by human readers. The comparison is between two automated systems (cobas® 5800 and cobas® 6800/8800) for quantifying HCV RNA. Therefore, there is no effect size on how human readers improve with AI vs. without AI assistance.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, essentially. The cobas® HCV assay on both the cobas® 5800 System and the cobas® 6800/8800 System operates as a fully automated, standalone diagnostic device. The performance evaluation presented is algorithm-only (system-only) without a human-in-the-loop component for result generation, although human operators perform the testing. The comparison is the cobas® 5800 system performance versus the cobas® 6800/8800 system performance.

7. The Type of Ground Truth Used

The ground truth for the method comparison study was based on pre-characterized clinical specimens (archived) and contrived samples with known HCV viral loads (titers). This implies a highly controlled and quantitative ground truth, as is typical for molecular diagnostic assays.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for a "training set." This type of submission (510(k)) is for demonstrating substantial equivalence of a new device (cobas® HCV on cobas® 5800) to a legally marketed predicate device (cobas® HCV on cobas® 6800/8800). The focus is on verification and validation (performance studies) rather than training an AI model from scratch. The cobas® HCV assay itself, as a software-driven assay, would have been developed and optimized using various samples and experiments, but these are not explicitly termed a "training set" in the context of this 510(k) summary.

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

Given that this is not an AI/ML model for visual interpretation, but rather a molecular diagnostic assay, the concept of "training set ground truth" in the traditional AI sense doesn't directly apply. The "ground truth" for the development and optimization of the assay (which could be analogous to "training") would have involved:

• Known concentrations: Using highly purified and quantified viral RNA standards to establish the linear range, limit of detection, and accuracy.
• Clinical samples with confirmed status: Testing samples from patients confirmed to be HCV positive or negative by established reference methods.
• Spiked samples: Adding known amounts of virus to negative matrices to challenge the assay's performance at specific concentrations.

These steps are part of the standard assay development and validation process for IVD devices, ensuring the assay's chemical and algorithmic components function correctly against known inputs.

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