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. Detection of 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 or non-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.

Device Description

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.

AI/ML Overview

N/A

Summary

U.S. Food & Drug Administration 510(k) Clearance Letter

Page 1

U.S. Food & Drug Administration
10903 New Hampshire Avenue Doc ID# 04017.0 8 . 0 0
Silver Spring, MD 20993
www.fda.gov

November 03, 2025

Roche Molecular Systems, Inc.
Nghia Luu
Regulatory Affairs Project Manager
4300 Hacienda Drive
Pleasanton, California 94588

Re: K252484
Trade/Device Name: cobas HCV
Regulation Number: 21 CFR 866.3170
Regulation Name: Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Tests
Regulatory Class: Class II
Product Code: MZP
Dated: August 6, 2025
Received: August 7, 2025

Dear Nghia Luu:

We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

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K252484 - Nghia Luu Page 2

Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/unique-device-identification-system-udi-system.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-devices/medical-device-safety/medical-device-reporting-mdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-

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K252484 - Nghia Luu Page 3

assistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Bhawna Poonia -S

for

Uwe Scherf, M.Sc., Ph.D.
Director
Division of Microbiology Devices
OHT7: Office of In Vitro Diagnostics
Office of Product Evaluation and Quality
Center for Devices and Radiological Health

Enclosure

Page 4

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Indications for Use

Form Approved: OMB No. 0910-0120
Expiration Date: 07/31/2026
See PRA Statement below.

510(k) Number (if known)
K252484

Device Name
cobas HCV

Indications for Use (Describe)

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. Detection of 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 or non-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.

Type of Use (Select one or both, as applicable)
☒ Prescription Use (Part 21 CFR 801 Subpart D) ☐ Over-The-Counter Use (21 CFR 801 Subpart C)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services
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Paperwork Reduction Act (PRA) Staff
PRAStaff@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

Page 5

cobas® HCV for use on the cobas® 5800/6800/8800 Systems 510(k) Summary

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.

Submitter Name	Roche Molecular Systems, Inc.
Address	4300 Hacienda DrivePleasanton, CA 94588-2722
Contact	Nghia LuuPhone: (925) 366-0647FAX: (925) 225-0207Email: nghia.luu@roche.com
Date Prepared	August 6, 2025
Proprietary Name	cobas® HCV for use on the cobas® 5800/6800/8800 Systems
Common Name	cobas® HCV
Classification Name	ASSAY, HYBRIDIZATION AND/OR NUCLEIC ACID AMPLIFICATION FOR DETECTION OF HEPATITIS C RNA, HEPATITIS C VIRUS
Product Codes	MZP, 21 CFR 866.3170
Predicate Devices	cobas® HCV for use on the cobas® 5800/6800/8800 Systems (K221007)
Establishment Registration	Roche Molecular Systems, Inc. (2243471)

1. DEVICE DESCRIPTION

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1.1. Principles of the Procedure

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, < LLoQ (lower limit of quantitation), > 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).¹⁻³

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-QS in two different

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target channels.⁴'⁵ 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.

Figure 1: cobas® HCV for use on the cobas® 5800 System and cobas® 6800/8800 Systems

2. INDICATIONS FOR USE

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,

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during treatment, at the end of treatment, and at the end of follow up of treatment to determine sustained or non-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.

3. TECHNOLOGICAL CHARACTERISTICS

The primary technological characteristics and intended use of cobas® HCV are substantially equivalent to other legally marketed nucleic acid amplification test intended for the quantitative detection of hepatitis C virus. There are no changes to the assay reagents. New labeling for the assay has been included in this submission. This labeling contains revisions related to the use of the assay on the cobas® 5800/6800/8800 systems.

The technical characteristics of cobas® HCV are compared to the identified predicate device, cobas® HCV Quantitative nucleic acid test for use on the cobas® 5800/6800/8800 systems (K221007) in Table 1. The candidate device utilizes an updated analytical cycler with updated light source (Light Emitting Diode, LED) and Light Detection Digital Camera. Additionally, the cobas® 6800 system is updated to include two analytical cyclers compared to the predicate device. The system software has also been updated to version 2.0.

Table 1: Similarities and Differences between cobas® HCV and the Predicate Device

	Candidate Device: cobas® HCV	Predicate Device: cobas® HCV (K221007)
Proprietary Name	cobas® HCV Quantitative nucleic acid test for use on the cobas® 5800/6800/8800 systems	same
Regulation Number	21 CFR 866.3170	same
Regulation Name	ASSAY, HYBRIDIZATION AND/OR NUCLEIC ACID AMPLIFICATION FOR DETECTION OF HEPATITIS C RNA, HEPATITIS C VIRUS	same
Product Code	MZP	same

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	Candidate Device: cobas® HCV	Predicate Device: cobas® HCV (K221007)
Intended Use	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. Detection of 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 or non-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.	same
Conditions for Use	For Prescription Use	same
Sample Types	Human EDTA Plasma, Serum	same
Analyte Targets	Hepatitis C RNA genotypes 1 to 6	same
Sample Preparation Procedure	Automated	same
Amplification Technology	Real Time PCR	same

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	Candidate Device: cobas® HCV	Predicate Device: cobas® HCV (K221007)
Detection Chemistry	Dual detection probes labeled with target-specific fluorescent reporter dyes allowing simultaneous detection of HCV target and RNA-QS in two different target channels. Real time detection and discrimination of PCR products is accomplished by measuring the fluorescence of the released reporter dyes.	same
Controls Used	RNA-QS functions as an internal control.Three external controls: High Titer Positive, Low Titer Positive, Negative Control	same
Results Analysis	PCR cycle threshold analysis	same

4. NON-CLINICAL PERFORMANCE EVALUATION

4.1. System Equivalency Testing

The update of the analytic cycler with a different LED Source and light detection may potentially affect the Assay performance. To implement the commercially available cobas® HCV assay on the upgraded cobas® 6800/8800 systems, an assay migration approach was pursued following the FDA guidance for "Assay Migration Studies for In Vitro Diagnostic Devices" (April 25, 2013). Using this guidance, RMS determined that the existing clinical data provided in support of the original device approval is applicable in supporting the upgraded instrument. Therefore, only a selection of performance studies was executed to demonstrate equivalence of the two platforms by executing comparative studies on both the cobas® 6800/8800 systems 2.0 and the existing cobas® 6800/8800 (where applicable).

No changes have been made to the assay reagents.

Four non-clinical performance studies were completed with cobas® HCV to demonstrate system equivalency of cobas® 6800/8800 systems 2.0 to the current on-market cobas® 6800/8800 systems. Please note that the project name of the system modification to cobas® 6800/8800 systems 2.0 is an internal name and does not construe a device versioning nomenclature.

A summary of these studies are included in the sections 4.1.1 thru 4.1.4 below.

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4.1.1. Analytical Sensitivity (Limit of Detection)

A comparison of results from testing at and around the expected LoD for cobas® HCV was completed using cobas® 6800/8800 systems 2.0 and cobas® 6800/8800 systems 1.4. A dilution series was prepared with five (5) concentration levels by diluting Roche HCV Secondary Standard, traceable to the 2nd WHO HCV International Standard in HCV negative pooled EDTA-plasma. The panels consisted of two (2) levels concentrated below the expected LoD, one (1) level concentrated near the expected LoD and two (2) levels concentrated above the expected LoD. A total of 66 replicates per concentration level and system were distributed across three (3) reagent lots, tested with three (3) cobas® 6800/8800 systems 2.0 and one (1) cobas® 6800/8800 systems 1.4 at one (1) external site, over the course of five (5) testing days.

The resulting data were analyzed to identify the Limit of Detection based on PROBIT Analysis and to determine the ≥ 95% positive reactive rate at the lowest target input level.

The difference between the log₁₀ PROBIT concentration at 95% detection rate for the new cobas® 6800/8800 systems 2.0 and the cobas® 6800/8800 1.4 systems is within -0.2 to +0.2 log₁₀ interval.

These results meet the Acceptance Criteria and demonstrate performance equivalency between the new cobas® 6800/8800 systems 2.0 and the cobas® 6800/8800 systems 1.4 for cobas® HCV in regards to Limit of Detection (LoD).

4.1.2. Linearity / LLoQ

A study to assess the linearity and LLoQ for cobas® HCV on cobas® 6800/8800 systems 2.0 was completed. In this study, HCV aRNA, HCV clinical material and HCV negative pooled EDTA-plasma were used to produce a dilution series consisting of sixteen (16) concentration levels, tested with three (3) kit lots, on six (6) testing days, and on three (3) cobas® 6800/8800 2.0 system. The resulting data were analyzed to identify the deviation from linearity according to CLSI guideline EP6-Ed2.

Two (2) separate dilution series were prepared to create sixteen (16) concentration levels by serially diluting HCV artificial stock material and high positive clinical material in pooled HCV negative EDTA-plasma. A total of thirty-six (36) replicates per concentration level, with sample input volume of 500 μL, were distributed across three (3) cobas® 6800/8800 systems 2.0 and three (3) cobas® HCV reagent kit lots. Dilutions and testing were performed at one (1) external

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site over the course of six (6) testing days. Per day, three (3) runs, containing two (2) replicates per concentration level, were performed.

The results of the study have shown that, for all panel members with concentrations within the linear range, the absolute deviation for the linear regression was demonstrated to be equal to or less than ± 0.24 log₁₀ for cobas® 6800/8800 systems 2.0, and therefore demonstrates performance equivalency between the new cobas® 6800/8800 systems 2.0 and the current on-market cobas® 6800/8800 systems 1.4 in regard to Linearity/LLoQ for cobas® HCV. No impact on the claimed LLoQ for cobas® HCV on the new cobas® 6800/8800 systems 2.0 was observed.

4.1.3. Precision

Precision was assessed by testing a panel consisting of seven (7) concentrations where three (3) levels were diluted from an HCV positive artificial stock material (aRNA) and four (4) levels were diluted from a high positive clinical specimen in HCV negative pooled EDTA-plasma. On twelve (12) testing days, two runs were completed each day with both one (1) cobas® 6800/8800 systems 2.0 instruments and one (1) cobas® 6800/8800 systems 1.4 instrument at one (1) external site. In each of the runs, three (3) replicates of the seven (7) panel members were tested. The study was conducted by using three (3) different reagent kit lots of cobas® HCV.

Two separate dilution series were prepared with seven (7) concentration levels by diluting HCV aRNA high positive material as well as clinical material in HCV negative pooled EDTA-plasma. A total of 72 replicates per concentration level and system were distributed across three (3) cobas® HCV reagent lots, tested with one (1) cobas® 6800 system 2.0 and one (1) cobas® 8800 systems 1.4 at one (1) external site on twelve (12) testing days.

The Precision results for cobas® HCV on the cobas® 6800/8800 systems 2.0 and cobas® 6800/8800 systems 1.4 show the mean observed Log₁₀ titer per panel member and the SD of all valid replicates per panel member and demonstrate performance equivalency between the new cobas® 6800/8800 systems 2.0 and the current on-market cobas® 6800/8800 Systems 1.4 in regards to Precision for cobas® HCV.

4.1.4. Method Comparison

The purpose of this study was to demonstrate equivalency between the cobas® 6800/8800 systems 2.0 and cobas® 6800/8800 systems 1.4 for the cobas® HCV in regard to Method Comparison.

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155 archived, contrived or purchased anonymized, well-characterized clinical HCV positive specimens in EDTA plasma as well as 30 individual HCV negative single donor specimens were used to assess the performance equivalency in regard to Method Comparison.

The individual HCV positive specimens were diluted if necessary to achieve the sample size of ~ 50 well-characterized HCV positive plasma specimens between 1.5E+01 – 3.0E+03 IU/mL, ~ 50 specimens between 3.0E+03 – 5.0E+05 IU/mL and ~50 specimens between 5.0E+05 – 1.0E+08 IU/mL.

The individual HCV positive and individual HCV negative specimens were distributed across three (3) cobas® HCV kit lots and tested on three (3) cobas® 6800/8800 systems 2.0 as well as one (1) cobas® 6800/8800 systems 1.4. Testing was performed at one (1) external site over the course of five (5) working days.

The following methods of analyses were completed for this study in accordance with the CLSI EP-09c: Deming Regression Analysis, Systematic Bias Analysis, Allowable Total Difference and Negative Agreement Analysis.

Based on the results for the clinical acceptance criteria 100% of differences in viral load measurement between the cobas® 6800/8800 systems 2.0 and cobas® 6800/8800 systems 1.4 for positive samples were less than 0.5 log₁₀ in viral concentration, and 100% of negative sample results agreed between cobas® 6800/8800 Systems 2.0 and cobas® 6800/8800 systems 1.4. Performance equivalency between the new cobas® 6800/8800 systems 2.0 and the current on-market cobas® 6800/8800 systems 1.4 for cobas® HCV in regard to Method Comparison was demonstrated.

4.2. System Equivalency Testing Conclusion

All predefined clinical acceptance criteria were met for the Precision and Method Comparison studies. The LoD and Linearty/LLoQ studies met their acceptance criteria(s). Each of the four studies which covered LoD, Linearty/LLoQ, Precision, and Method Comparison supports the conclusion of substantial equivalence between cobas® HCV on the upgraded cobas® 6800/8800 systems and the current on-market cobas® 6800/8800 systems.

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5. CLINICAL PERFORMANCE EVALUATION

5.1. System Equivalency

Equivalency of the cobas® HCV on the upgraded cobas® 6800/8800 systems and the current on-market cobas® 6800/8800 systems was demonstrated via performance studies and are summarized in the previous section on non-clinical performance evaluation.

6. CONCLUSIONS

No changes have been made to the assay reagents.

Four non-clinical performance studies were completed with cobas® HCV to demonstrate system equivalency of cobas® 6800/8800 systems 2.0 to the current on-market cobas® 6800/8800 systems. A comparison of the technological characteristics and conclusions drawn from nonclinical performance studies demonstrate that the device is as safe, as effective, substantially equivalent, and performs as well as the legally marketed predicate device identified above.

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7. REFERENCES

Longo MC, Berninger MS, Hartley JL. Use of uracil DNA glycosylase to control carry-over contamination in polymerase chain reactions. Gene. 1990;93:125-8. PMID: 2227421.
Savva R, McAuley-Hecht K, Brown T, Pearl L. The structural basis of specific base-excision repair by uracil-DNA glycosylase. Nature. 1995;373:487-93. PMID: 7845459.
Mol CD, Arvai AS, Slupphaug G, et al. Crystal structure and mutational analysis of human uracil-DNA glycosylase: structural basis for specificity and catalysis. Cell. 1995;80:869-78. PMID: 7697717.
Heid CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR. Genome Res. 1996;6:986-94. PMID: 8908518.
Higuchi R, Dollinger G, Walsh PS, Griffith R. Simultaneous amplification and detection of specific DNA sequences. Biotechnology (N Y). 1992;10:413-7. PMID: 1368485.

Regulation Number and Section

§ 866.3170 Nucleic acid-based hepatitis C virus ribonucleic acid tests.

(a)
Identification. A nucleic acid-based hepatitis C virus (HCV) ribonucleic acid (RNA) test is identified as an in vitro diagnostic device intended for prescription use as an aid in the diagnosis of HCV infection in specified populations, and/or as an aid in the management of HCV-infected patients including guiding the selection of genotype-specific treatment in individuals with chronic HCV infection. The test is intended for use with human serum or plasma. The test is not intended for use as a donor screening test for the presence of HCV antibodies in blood, blood products, or tissue donors.(b)
Classification. Class II (special controls). The special controls for this device are:(1) For all nucleic acid-based HCV RNA tests, the labeling required under § 809.10(b) of this chapter must include:
(i) A prominent statement that the test is not intended for use as a donor screening test for the presence of HCV RNA from human cells, tissues, and cellular and tissue-based products.
(ii) A detailed explanation of the principles of operation and procedures for performing the assay.
(iii) A detailed explanation of the interpretation of results.
(iv) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. These limitations must include, but are not limited to, statements that indicate:
(A) The specimen types for which the device has been cleared and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.
(B) When applicable, that assay performance characteristics have not been established in populations of immunocompromised or immunosuppressed patients or, other populations where test performance may be affected.
(C) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with the individual's clinical presentation, history, and other laboratory results.
(2) For all nucleic acid-based HCV RNA tests, the design verification and validation must include:
(i) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the device methodology. Additional information appropriate to the technology must be included such as design of primers and probes, rationale for the selected gene targets, specifications for amplicon size, and degree of nucleic acid sequence conservation.
(ii) For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate (
e.g., a recognized consensus standard). In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance or approval, or when there is a transition to a new calibration standard.(iii) Documentation and characterization (
e.g., determination of the identity, supplier, purity, and stability) of all critical reagents (including nucleic acid sequences for primers and probes) and protocols for maintaining product integrity.(iv) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of detection (LoD), upper and lower limits of quantitation (ULoQ and LLoQ, respectively), linearity, precision, endogenous and exogenous interferences, cross reactivity, carryover, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States. Cross-reactivity studies must include samples from HCV RNA negative subjects with other causes of liver disease, including autoimmune hepatitis, alcoholic liver disease, chronic hepatitis B virus, primary biliary cirrhosis, and nonalcoholic steatohepatitis, when applicable. The effect of each claimed nucleic-acid isolation and purification procedure on detection must be evaluated.
(v) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.
(vi) Final release criteria to be used for manufactured test lots with appropriate evidence 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) Multisite reproducibility study that includes the testing of three independent production lots.
(viii) All stability protocols, including acceptance criteria.
(ix) Final release test results for each lot used in clinical studies.
(x) Analytical sensitivity and specificity of the test must be the same or better than that of other cleared or approved tests.
(xi) Lot-to-lot precision studies, as appropriate.
(3) For devices intended for the qualitative detection of HCV RNA, in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, the design verification and validation must include detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved qualitative HCV RNA test, or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with appropriate numbers of HCV positive and negative samples in applicable risk categories. Additional genotypes must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:
(i) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 95 percent.
(ii) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 96 percent.
(4) For devices intended for the quantitative detection of HCV RNA, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:
(i) Labeling required under § 809.10(b) of this chapter must include a prominent statement that the test is not intended as a diagnostic test to confirm the presence of active HCV infection, when applicable.
(ii) Design verification and validation must include the following:
(A) Detailed documentation of the following analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including but not limited to: LoD, ULoQ and LLoQ. LoD, LLoQ, and linearity studies must demonstrate acceptable device performance with all HCV genotypes detected by the device.
(B) Detailed documentation of clinical performance testing from either:
(
1 ) A multisite clinical study with an appropriate number of clinical samples from chronically HCV infected patients in which the results are compared to an FDA-cleared or approved quantitative HCV RNA test, or a comparator that FDA has determined is appropriate. This study must include a sufficient number of HCV positive samples containing an analyte concentration near the LLoQ to describe performance at this level. Clinical samples must cover the full range of the device output and must be consistent with the distribution of these genotypes in the U.S. population. Clinical samples may be supplemented with diluted clinical samples for those viral load concentrations that are not sufficiently covered by natural clinical specimens, or(
2 ) A clinical study with prospectively collected samples demonstrating clinical validity of the device.(C) Detailed documentation of a qualitative analysis near the lower end of the measuring range demonstrating acceptable performance when used as an aid in diagnosis.
(5) For devices intended for HCV RNA genotyping, in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, design verification and validation must include the following:
(i) Detailed documentation of an analytical performance study demonstrating the LoD for all HCV genotypes detected by the device.
(ii) Detailed documentation, including results, of a multisite clinical study that assesses genotyping accuracy (
i.e., the proportion of interpretable results that match with the reference method result) and the genotyping rate (i.e., the proportion of results that were interpretable).(6) For any nucleic acid-based HCV RNA test intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:
(i) Clinical studies must be conducted at PoC sites.
(ii) Additional labeling must include a brief summary of the instructions for use that are appropriate for use in a PoC environment.