(213 days)
P150015
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No
The summary describes a standard nucleic acid amplification test (NAAT) with automated sample preparation, PCR amplification, and real-time detection. There is no mention of AI or ML algorithms being used for data analysis, interpretation, or any other function of the device. The data management is described as assigning results based on predefined thresholds.
No.
The cobas® HCV is an in vitro diagnostic (IVD) test that detects and quantifies hepatitis C virus (HCV) RNA in human plasma or serum. It is intended to aid in the diagnosis and management of HCV infection, but it does not treat or directly affect the body's structure or function.
Yes
The "Intended Use / Indications for Use" section explicitly states that the device "is intended for use as an aid in the diagnosis of HCV infection."
No
The device is an in vitro diagnostic test that involves physical sample preparation, chemical reactions, and detection on specific hardware systems (cobas® 5800, 6800, and 8800 Systems). While it utilizes software for data management and analysis, it is not solely software.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The "Intended Use / Indications for Use" section explicitly states that the cobas® HCV is an "in vitro nucleic acid amplification test." It is designed to detect and quantify HCV RNA in human plasma or serum, which are biological specimens taken from the body.
- Purpose: The intended uses described (aid in diagnosis, aid in management of therapy) are typical applications for in vitro diagnostic devices.
- Device Description: The description details a laboratory-based test that involves sample preparation, nucleic acid extraction, amplification, and detection using specific reagents and instrumentation. This is consistent with the nature of an IVD.
- Performance Studies: The summary of performance studies describes evaluations of the test's analytical and clinical performance using biological samples, which is a requirement for IVD regulatory submissions.
- Predicate Device: The mention of a "Predicate Device(s)" with a K number (P150015) indicates that this device is being compared to a previously cleared IVD, further confirming its classification.
All of these elements align with the definition and characteristics of an In Vitro Diagnostic device.
N/A
Intended Use / Indications for 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.
Product codes (comma separated list FDA assigned to the subject device)
MZP, 21 CFR 866.3170
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.
Mentions image processing
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Mentions AI, DNN, or ML
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Input Imaging Modality
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Anatomical Site
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Indicated Patient Age Range
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Intended User / Care Setting
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Description of the training set, sample size, data source, and annotation protocol
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Description of the test set, sample size, data source, and annotation protocol
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Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
System Equivalency / System Comparison:
System equivalency of the cobas® 5800, cobas® 6800 and cobas® 8800 Systems was demonstrated via performance studies. The term Technical Equivalency Verification (TEV) studies is used to described these system equivalency studies. To transfer the commercially available cobas® HCV assay from the cobas® 6800/8800 System to the cobas® 5800 System, an assay migration approach has been pursued following the FDA guidance for "Assay Migration Studies for In Vitro Diagnostic Devices" (FDA-2008-N-0642). Therefore, only a selection of performance studies for cobas® HCV has been executed to prove equivalence of the two platforms. The results presented in the Instructions for Use support equivalent performance for all systems. Key results include:
- Limit of Detection (LoD) – EDTA Plasma: Confirmed Equivalent for cobas® 5800 System, 8.5 IU/mL for cobas® 6800/8800 System.
- Limit of Detection (LoD) – Serum: Confirmed Equivalent for cobas® 5800 System, 9.6 IU/mL for cobas® 6800/8800 System.
- Linearity - EDTA Plasma and Serum: Confirmed Equivalent for cobas® 5800 System, 15 IU/mL to 1.00E+08 IU/mL for cobas® 6800/8800 System.
- Reproducibility (Precision): Confirmed Equivalent for cobas® 5800 System.
- Cross-Contamination: Confirmed Equivalent for cobas® 5800 System, 0.42% cross-contamination rate for cobas® 6800/8800 System.
- cobas® HCV Open Kit stability: 90 days (40 runs) for cobas® 5800 System, 90 days (40 runs) for cobas® 6800/8800 System.
- cobas® HCV On-Board stability: 36 days for cobas® 5800 System, 40 hours for cobas® 6800/8800 System.
- cobas® HBV/HCV/HIV-1 Control Kit On-Board Stability: 36 days for cobas® 5800 System, 8 hours for cobas® 6800/8800 System.
Reproducibility (Precision) Study:
Sample size: A panel ranging from 1.50E+01 IU/mL to 1.00E+08 IU/mL, consisting of clinical specimen and plasmid RNA sample, was used to generate 7 panel members. Testing of 3 replicates was performed over 5 days.
Data source: 3 cobas® 5800 instruments at 3 different sites (1 internal and 2 external); 3 cobas® 6800/8800 instruments at 1 internal site.
Annotation protocol: 2 runs per day per instrument and by using overall three different lots of the cobas® HCV kits.
Key results: Standard Deviation and Coefficient of Variance (%) for cobas® HCV on cobas® 5800 and cobas® 6800/8800 were measured for all panel members.
Method Comparison Study:
Study type: Method comparison study.
Sample size: 150 archived or contrived, well-characterized HCV positive plasma specimens with titers ranging from 1.5E+01 to 1E+08 IU/mL. 30 HCV negative individual specimens were also used.
Data source: Specimens were tested on the cobas® 5800 System at three different sites (1 internal and 2 external) and on a cobas® 6800/8800 System at one site (internal).
Key results:
- Clinical Criteria: With all sites combined, 100% of differences in viral load measurement between the cobas® 5800 and cobas® 6800/8800 Systems for positive samples were less than ±0.5 log10 (viral concentration). With all sites combined, 100% of negative sample results agreed between cobas® 5800 and cobas® 6800/8800 Systems based on point estimate of NPA. Both clinical criteria were met.
- Statistical Criteria: Bias estimates were statistically significant but not clinically significant.
- Bias (95% CI) at 25 IU/mL: -0.028 (-0.045, -0.012)
- Bias (95% CI) at 800,000 IU/mL: 0.027 (0.022, 0.031)
- Bias (95% CI) at 6,000,000 IU/mL: 0.037 (0.031, 0.044)
- The lower bound of one sided 95% CI of the ATD zone percentage was 100% for all sites combined and 100% for each site. This criterion was met.
- NPA =100% with lower bound of 95% CI as 96.667% for all sites combined. This criterion was met.
The study met all clinical and statistical acceptance criteria, with the exception of bias estimates being statistically significant but not clinically significant.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
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Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
cobas® HCV for use on the cobas® 6800/8800 Systems (P150015)
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
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Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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.
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Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services seal on the left and the FDA acronym with the full name of the agency on the right. The seal features an abstract design with three human profiles and a caduceus-like symbol. The FDA part of the logo is in blue, with the acronym in a square and the full name, "U.S. Food & Drug Administration," written out next to it.
November 4, 2022
Roche Molecular Systems, Inc. Ashley Malich Manager Regulatory Affairs 4300 Hacienda Drive Pleasanton, California 94588-2722
Re: K221007
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: April 4, 2022 Received: April 5, 2022
Dear Ashley Malich:
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 (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 located 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.
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
1
801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-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 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 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-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/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-device-advice-comprehensive-regulatoryassistance/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).
Sincerelv.
Maria I. Garcia -S
Maria Garcia, Ph.D. Assistant Director Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K221007
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 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.
| Type of Use (Select one or both, as applicable) | |||
|---|---|---|---|
| X Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) | ||
| CONTINUE ON A SEPARATE PAGE IF NEEDED. |
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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 Drive | |
| Pleasanton, CA 94588-2722 | ||
| Contact | Ashley Malich | |
| Phone: (925) 368-0881 | ||
| FAX: (925) 225-0207 | ||
| Email: ashley.malich@roche.com | ||
| Date Prepared | March 25, 2022 | |
| 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® 6800/8800 Systems (P150015) | |
| Establishment Registration | Roche Molecular Systems, Inc. (2243471) |
1. 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.
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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, 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). 13 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
5
target channels.45 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.
Image /page/5/Figure/1 description: This image is labeled Figure 1 and shows the text "cobas® HCV for use on the cobas® 5800 System and cobas® 6800/8800 Systems". The text appears to be a title or caption for a figure in a document. The cobas systems mentioned are likely medical or laboratory equipment.
Image /page/5/Picture/2 description: The image shows two boxes of Cobas brand medical testing kits. The box on the left is labeled "cobas HCV" and has the number 192 printed on it. The box on the right is labeled "cobas HBV/HCV/HIV-1 Control Kit" and has the reference number 09040773190.
INDICATIONS FOR USE 2.
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,
6
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.
3. TECHNOLOGICAL CHARACTERISTICS
The primary technological characteristics and intended use of the RMS cobas® HCV for use on the cobas® 5800 System is substantially equivalent to other legally marketed nucleic acid amplification test intended for the quantitative detection of hepatitis C virus.
As indicated in Table 1 cobas® HCV for use on the cobas® 5800 System, is substantially equivalent to significant characteristics of the identified predicate device, cobas® HCV for use on the cobas® 6800/8800 Systems (P150015).
Comparison of the cobas® HCV for use on the cobas® 5800 System, and Table 1: Predicate device cobas® HCV for use on the cobas® 6800/8800 Systems
| | Submitted Device:
cobas® HCV for use on the cobas® 5800 System | Predicate Device:
cobas® HCV for use on the cobas®
6800/8800 System (P150015) |
|---------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------|
| 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 |
| | Submitted Device: | Predicate Device: |
| | cobas® HCV for use on the cobas® 5800 System | cobas® HCV for use on the cobas® 6800/8800 System (P150015) |
| 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.
| 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 |
| | Submitted Device:
cobas® HCV for use on the cobas® 5800 System | Predicate Device:
cobas® HCV for use on the cobas®
6800/8800 System (P150015) |
| 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 |
7
8
ASSAY PERFORMANCE 4.
4.1. System Equivalency / System Comparison
System equivalency of the cobas® 5800, cobas® 6800 and cobas® 8800 Systems was demonstrated via performance studies. The term Technical Equivalency Verification (TEV) studies is used to described these system equivalency studies.
To transfer the commercially available cobas® HCV assay from the cobas® 6800/8800 System to the cobas® 5800 System, an assay migration approach has been pursued following the FDA guidance for "Assay Migration Studies for In Vitro Diagnostic Devices" (FDA-2008-N-0642). Therefore, only a selection of performance studies for cobas® HCV has been executed to prove equivalence of the two platforms. A summary of these studies is included in Table 2 and the sections below.
The results presented in the Instructions for Use support equivalent performance for all systems.
Performance Summary of the cobas® HCV assay on the cobas® 6800/8800 Table 2: System and the cobas® 5800 System
| Performance Characteristic | cobas® 5800 System | cobas® 6800/8800 System |
|---|---|---|
| Limit of Detection (LoD) – EDTA Plasma | Confirmed Equivalent | 8.5 IU/mL |
| Limit of Detection (LoD) – Serum | Confirmed Equivalent | 9.6 IU/mL |
| Linearity - EDTA Plasma and Serum | Confirmed Equivalent | 15 IU/mL to 1.00E+08 IU/mL |
| Reproducibility (Precision)* | Confirmed Equivalent | |
| Cross-Contamination | Confirmed Equivalent | 0.42% cross-contamination rate |
9
| Performance Characteristic | cobas® 5800 System | cobas® 6800/8800 System |
|---|---|---|
| Method Comparison** | Confirmed Equivalent | |
| cobas® HCV Open Kit stability | 90 days (40 runs) | 90 days (40 runs) |
| cobas® HCV On-Board stability | 36 days | 40 hours |
| cobas® HBV/HCV/HIV-1 Control Kit On-Board | ||
| Stability | 36 days | 8 hours |
*See Section 4.2 for more information on Reproducibility.
**See Section 4.3 for more information on Method Comparison.
4.2. Reproducibility (Precision)
Reproducibility was assessed for HCV with a panel ranging from 1.50E+01 IU/mL to 1.00E+08 IU/mL. A dilution series consisting of clinical specimen and plasmid RNA sample was used to generate the Reproducibility (Precision) panel. HCV positive material was serially diluted in plasma to create a panel of 7 members that includes concentration levels at, below, and above medical decision points. The testing of 3 replicates was performed over 5 days, using 3 cobas® 5800 instruments at 3 different sites (1 internal and 2 external) and 3 cobas® 6800/8800 instruments at 1 internal site, 2 runs per day per instrument and by using overall three different lots of the cobas® HCV kits. The results for cobas® HCV on the cobas® 5800 and cobas® 6800/8800 Systems are displayed in Table 3.
Table 3: Standard Deviation and Coefficient of Variance (%) for cobas® HCV on cobas® 5800 and cobas® 6800/8800. Three Systems at three Sites combined (Absolute and Percentage)
| Standard Deviation (SD) and Percent Coefficient of Variation (CV) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Platform | Panel | ||||||||||||
| Member | Mean | Site | Day | Run | Within-Run | Total | |||||||
| observed | |||||||||||||
| log10 | |||||||||||||
| Titer | |||||||||||||
| (IU/mL) | N | SD | CV | ||||||||||
| [%] | SD | CV | |||||||||||
| [%] | SD | CV | |||||||||||
| [%] | SD | CV [%] | SD | CV | |||||||||
| [%] | |||||||||||||
| cobas | |||||||||||||
| 5800 | PM1 | 7.80 | 90 | 0.18 | 2.31 | 0.08 | 1.00 | 0.02 | 0.26 | 0.05 | 0.66 | 0.20 | 2.61 |
| PM2 | 6.65 | 90 | 0.14 | 2.17 | 0.07 | 1.03 | 0.01 | 0.12 | 0.04 | 0.67 | 0.17 | 2.50 | |
| PM3 | 5.79 | 90 | 0.15 | 2.65 | 0.06 | 1.11 | 0.00 | 0.00 | 0.06 | 1.04 | 0.18 | 3.05 | |
| PM4 | 4.07 | 90 | 0.11 | 2.65 | 0.07 | 1.77 | 0.04 | 1.07 | 0.06 | 1.54 | 0.15 | 3.70 | |
| PM5 | 2.01 | 90 | 0.15 | 7.68 | 0.00 | 0.00 | 0.04 | 1.96 | 0.16 | 8.17 | 0.23 | 11.38 | |
| PM6 | 1.50 | 89 | 0.09 | 5.70 | 0.00 | 0.00 | 0.05 | 3.65 | 0.23 | 15.14 | 0.25 | 16.59 | |
| PM7 | 1.28 | 90 | 0.16 | 12.20 | 0.09 | 6.94 | 0.00 | 0.36 | 0.27 | 21.37 | 0.33 | 25.57 |
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| Standard Deviation (SD) and Percent Coefficient of Variation (CV) | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Platform | Panel | ||||||||||||
| Member | Mean | Site | Day | Run | Within-Run | Total | |||||||
| observed | |||||||||||||
| log10 | |||||||||||||
| Titer | |||||||||||||
| (IU/mL) | N | SD | CV | ||||||||||
| [%] | SD | CV | |||||||||||
| [%] | SD | CV | |||||||||||
| [%] | SD | CV [%] | SD | CV | |||||||||
| [%] | |||||||||||||
| cobas | |||||||||||||
| 6800/ | |||||||||||||
| 8800 | PM1 | 7.99 | 90 | 0.00 | 0.00 | 0.04 | 0.50 | 0.01 | 0.07 | 0.04 | 0.49 | 0.06 | 0.71 |
| PM2 | 6.78 | 90 | 0.01 | 0.09 | 0.03 | 0.39 | 0.02 | 0.27 | 0.04 | 0.65 | 0.05 | 0.81 | |
| РМЗ | 5.93 | 89 | 0.01 | 0.24 | 0.04 | 0.59 | 0.02 | 0.35 | 0.03 | 0.58 | 0.06 | 0.93 | |
| PM4 | 4.12 | 90 | 0.00 | 0.00 | 0.02 | 0.41 | 0.00 | 0.00 | 0.06 | 1.51 | 0.06 | 1.57 | |
| bM5 | 2.14 | 90 | 0.01 | 0.64 | 0.07 | 3.26 | 0.00 | 0.00 | 0.12 | 5.66 | 0.14 | 6.56 | |
| PM6 | 1.58 | 90 | 0.00 | 0.00 | 0.05 | 3.20 | 0.00 | 0.00 | 0.24 | 15.21 | 0.25 | 15.55 | |
| PM7 | 1.26 | 88 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.25 | 19.80 | 0.25 | 19.80 |
Method Comparison 4.3.
A Method comparison study was performed using 150 archived or contrived, well-characterized HCV positive plasma specimens with titers ranging from 1.5E+01 to 1E+08 IU/mL to assess the assay performance equivalency. In addition, 30 HCV negative individual specimens were used. Each of the specimens was tested on the cobas® 5800 System at three different sites (1 internal and 2 external) and on a cobas® 6800/8800 System at one site (internal).
The Method Comparison study for cobas® HCV met all the clinical and statistical acceptance criteria with the exception of the statistical criterion for bias estimates at the 3 medical decision points. 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 of the cobas® HCV on the cobas® 6800/8800 Systems and both the upper and lower bound of the 95% Cls are close to zero. Therefore, the two systems are clinically equivalent at all medical decision points. It is important to note that for high precision molecular assays, small differences may be statistically significant but may not be clinically relevant. A summary of the results can be found in Table 4.
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| Table 4: Summary Method Comparison for HCV | ||
|---|---|---|
| Clinical Criteria | |||
|---|---|---|---|
| Acceptance Criteria | Achieved Results | Met | |
| With all sites combined, 95% of differences in viral load measurement between the cobas® 5800 and cobas® 6800/8800 Systems for positive samples should be less than ±0.5 log10 (viral concentration). | With all sites combined, 100% of differences in viral load measurement between the cobas® 5800 and cobas® 6800/8800 Systems for positive samples were less than ±0.5 log10 (viral concentration). | Yes | |
| With all sites combined, 95% of negative sample results should agree between cobas® 5800 and cobas® 6800/8800 Systems. | With all sites combined, 100% of negative sample results agreed between cobas® 5800 and cobas® 6800/8800 Systems based on point estimate of NPA. | Yes | |
| Statistical Criteria | |||
| With all sites combined, bias estimates should not be statistically significant, i.e. their confidence intervals should include zero. | Medical decision point (IU/mL) | Bias (95% CI) | |
| 25 | -0.028 (-0.045, -0.012) | No | |
| 800,000 | 0.027 (0.022, 0.031) | No | |
| 6,000,000 | 0.037 (0.031, 0.044) | No | |
| The lower bound of one sided 95% confidence intervals of the ATD zone percentages should be greater than 90%. | The lower bound of one sided 95% CI of the ATD zone percentage was 100% for all sites combined and 100% for each site. | Yes | |
| The lower bound of the two-sided 95% confidence interval of the NPA should be greater than 90% based on 90 valid test results with 30 negative samples tested at each of the 3 sites. | NPA =100% with lower bound of 95% CI as 96.667% for all sites combined. | Yes |
CONCLUSIONS 5.
The cobas® HCV for use on the cobas® 5800 System is the same as the device approved in PMA P150015. There have been no changes to the device to accommodate this claim expansion to include use on the cobas® 5800 System.
A comparison of the technological characteristics and conclusions drawn from nonclinical performance studies demonstrate that the device is substantially equivalent and performs as well as the legally marketed predicate device identified above.
12
REFERENCES 6.
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- Savva R, McAuley-Hecht K, Brown T, Pearl L. The structural basis of specific baseexcision repair by uracil-DNA glycosylase. Nature. 1995;373:487-93. PMID: 7845459.
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- 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. 4. 1996;6:986-94. PMID: 8908518.
- Higuchi R, Dollinger G, Walsh PS, Griffith R. Simultaneous amplification and detection of 5. specific DNA sequences. Biotechnology (N Y). 1992;10:413-7. PMID: 1368485.