ARCHITECT ANTI-HCV ASSAY; ARCHITECT ANTI-HCV CALIBRATOR; ARCHITECT ANTI-HCV CONTROL
Device Facts
| Record ID | P050042 |
|---|---|
| Device Name | ARCHITECT ANTI-HCV ASSAY; ARCHITECT ANTI-HCV CALIBRATOR; ARCHITECT ANTI-HCV CONTROL |
| Applicant | Abbott Laboratories, Inc. |
| Product Code | MZO · Microbiology |
| Decision Date | Jun 7, 2006 |
| Decision | APRL |
| Regulation | 21 CFR 866.3169 |
| Device Class | Class 2 |
Intended Use
The ARCHITECT Anti-HCV assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative detection of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to hepatitis C virus (anti-HCV) in human adult serum and plasma (potassium EDTA, lithium heparin, and sodium heparin). Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with HCV (state of infection or associated disease not determined) in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection.
Device Story
The ARCHITECT Anti-HCV assay is a two-step chemiluminescent microparticle immunoassay (CMIA) performed on the automated ARCHITECT i System. Input samples (serum/plasma) are combined with recombinant HCV antigen-coated paramagnetic microparticles and assay diluent. After washing, an acridinium-labeled murine anti-human IgG/IgM conjugate is added. Following a second wash, pre-trigger and trigger solutions are added to initiate a chemiluminescent reaction, measured as relative light units (RLUs). The system calculates a sample-to-cutoff (S/CO) ratio; results ≥ 1.00 are reactive. Used in clinical laboratories by trained personnel to provide presumptive evidence of HCV infection. Results assist clinicians in identifying potential HCV exposure, necessitating further supplemental testing (e.g., RIBA, HCV RNA) for definitive diagnosis. Benefits include early identification of HCV infection, enabling appropriate clinical management and reducing transmission risk.
Clinical Evidence
Prospective multi-center study of 2,027 specimens (1,310 increased risk, 717 symptomatic). Positive percent agreement was 99.68% (614/616; 95% CI: 98.83-99.96%). Negative percent agreement was 97.66% (1,378/1,411; 95% CI: 96.73-98.38%). Precision studies (20-day and 5-day reproducibility) showed total %CVs ranging from 3.1% to 9.5% across various controls and panels.
Technological Characteristics
CMIA technology using recombinant HCV antigen-coated paramagnetic microparticles. Conjugate: acridinium-labeled murine anti-human IgG/IgM. Buffers: MES, TRIS. Preservatives: ProClin 300, sodium azide. Energy source: automated analyzer (ARCHITECT i System). Connectivity: standalone analyzer. Sterilization: N/A (in vitro diagnostic).
Indications for Use
Indicated for qualitative detection of IgG and IgM antibodies to hepatitis C virus in human adult serum and plasma. Used for individuals with signs/symptoms of hepatitis or those at risk for HCV infection. No known contraindications.
Regulatory Classification
Identification
A hepatitis C virus (HCV) antibody test is identified as an in vitro diagnostic device intended for use with human serum, plasma, or other matrices as a prescription device that aids in the diagnosis of HCV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection. The test is not intended for screening blood, plasma, cell, or tissue donors.
Special Controls
*Classification.* Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10(b) of this chapter must include: (i) A prominent statement that the test is not intended for the screening of blood, plasma, and cell or tissue donors. (ii) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. The limitations must include, but are not limited to, statements that indicate: (A) When appropriate, the performance characteristics of the test have not been established in populations of immunocompromised or immunosuppressed patients or, other special populations where test performance may be affected. (B) The detection of HCV antibodies indicates a present or past infection with hepatitis C virus, but does not differentiate between acute, chronic, or resolved infection. (C) The specimen types for which the device has been cleared, and that use of the test with specimen types other than those specifically cleared for this device may result in inaccurate test results. (D) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with the individual's clinical presentation, history, and other laboratory results. (E) A non-reactive test result may occur early during acute infection, prior to development of a host antibody response to infection, or when analyte levels are below the limit of detection of the test. (iii) A detailed explanation of the principles of operation and procedures for performing the test. (2) Design verification and validation must include the following: (i) A detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, and design of the antigen(s) and capture antibody(ies) sequences, rationale for the selected epitope(s), degree of amino acid sequence conservation of the target, and the design and nature of all primary, secondary, and subsequent standards used for calibration. (ii) Documentation and characterization ( *e.g.,* supplier, determination of identity, and stability) of all critical reagents (including description of the antigen(s) and capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.(iii) 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. (iv) 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. (v) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range. (vi) All stability protocols, including acceptance criteria. (vii) Final release test results for each lot used in clinical studies. (viii) Multisite reproducibility study that includes the testing of three independent production lots. (ix) Analytical performance studies and results for determining the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility) including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, specimen stability, reagent stability, and cross-genotype antibody detection sensitivity, when appropriate. (x) Analytical sensitivity of the test is the same or better than that of other cleared or approved tests. (xi) Detailed documentation of clinical performance testing from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved HCV antibody test, or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with an acceptable number of HCV positive and negative samples in applicable risk categories. Additional relevant patient groups must be validated as appropriate. The samples may be a combination of fresh and repository samples, sourced from geographically diverse areas. The study designs, including number of samples tested, must be sufficient to meet the following criteria: (A) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 95 percent. (B) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 96 percent. (3) For any HCV antibody 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.
Reference Devices
- Chiron RIBA HCV 3.0 Strip Immunoblot Assay (SIA)
- Roche COBAS AMPLICOR Hepatitis C Virus (HCV) Test v2.0
Related Devices
- P010021 — VITROS IMMUNODIAGNOSTIC PRODUCTS ANTI-HCV REAGENT PACK AND CALIBRATOR · Ortho-Clinical Diagnostics, Inc. · Aug 30, 2001
- P970027 — ABBOTT AXSYM ANTIBODY TO HCV · Abbott Laboratories · Feb 5, 2004
- P190011 — LIAISON XL MUREX HCV Ab; LIAISON XL MUREX Control HCV Ab · DiaSorin, Inc. · Oct 18, 2019
- P030056 — ADVIA CENTAUR HCV READY PACK REAGENTS, ADVIA CENTAUR HCV QUALITY CONTROL MATERIALS · Siemens Healthcare Diagnostics · Dec 22, 2004
- P090009 — ELECSYS ANTI-HCV IMMUNOASSAY & ELECSYS PRECICONTROL ANTI-HCV FOR USE ON MODULAR ANALYTICS E170 IMMUNOSSAY ANALYZER · Roche Diagnostics Corp. · Apr 29, 2010
Submission Summary (Full Text)
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# Summary of Safety and Effectiveness Data
## I. GENERAL INFORMATION:
Device Generic Name: Antibody to Hepatitis C Virus (HCV)
Device Trade Name: ARCHITECT® Anti-HCV Reagent Kit
ARCHITECT® Anti-HCV Calibrator
ARCHITECT® Anti-HCV Controls
Name and Address of Applicant: Abbott Laboratories
Abbott Diagnostics Division
100 Abbott Park Road
Abbott Park, IL 60064-3500
Date of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P050042
Date of Notice of Approval to the Applicant: June 7, 2006
## II. INDICATIONS FOR USE:
ARCHITECT® Anti-HCV Reagent Kit
The ARCHITECT Anti-HCV assay is a chemiluminescent microparticle immunoassay (CMIA) for the qualitative detection of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to hepatitis C virus (anti-HCV) in human adult serum and plasma (potassium EDTA, lithium heparin, and sodium heparin). Assay results, in conjunction with other laboratory results and clinical information, may be used to provide presumptive evidence of infection with HCV (state of infection or associated disease not determined) in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis C infection.
ARCHITECT® Anti-HCV Calibrator
The ARCHITECT Anti-HCV Calibrator is used for the calibration of the ARCHITECT i System when the system is used for the qualitative detection of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to hepatitis C virus (anti-HCV) using the ARCHITECT Anti-HCV Reagent Kit.
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ARCHITECT® Anti-HCV Controls
The ARCHITECT Anti-HCV Controls are used for monitoring the performance of the ARCHITECT i System when used for the qualitative detection of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to hepatitis C virus (anti-HCV) when using the ARCHITECT Anti-HCV Reagent Kit.
III. CONTRAINDICATIONS: None known.
IV. WARNINGS AND PRECAUTIONS: For in vitro diagnostic use only.
Warnings and precautions for ARCHITECT Anti-HCV Reagent Kit, ARCHITECT Anti-HCV Calibrator, and ARCHITECT Anti-HCV Controls are stated in the respective product labeling.
V. DEVICE DESCRIPTION:
Kit Configurations and Components
For detection of antibodies to hepatitis C virus, the ARCHITECT Anti-HCV Reagent Kit is composed of the following three components:
- ARCHITECT Anti-HCV Microparticles: 1 or 4 Bottle(s) (6.6 mL/27.0 mL) HCV antigen (recombinant E. coli, recombinant yeast) coated microparticles in MES buffer. Minimum concentration: 0.14% solids. Preservatives: antimicrobial agents.
- ARCHITECT Anti-HCV Conjugate: 1 or 4 Bottle(s) (5.9 mL/26.3 mL) murine anti-human IgG/IgM acridinium-labeled conjugate in MES buffer with protein (bovine) additive (152 μM) and surfactant. Minimum concentration: (IgG) 8 ng/mL /(IgM) 0.8 ng/mL. Preservatives: antimicrobial agents.
- ARCHITECT Anti-HCV Assay Diluent: 1 or 4 Bottle(s) (10.0 mL/50.9 mL) anti-HCV assay diluent containing TRIS buffer with protein (goat) additive (102.6 g/L) and surfactant. Preservative: ProClin® 300.
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Summary of Safety and Effectiveness Data
In addition, the following components are required for the ARCHITECT Anti-HCV Reagent Kit:
- ARCHITECT i System is an analyzer designed to perform automated immunoassay tests based on the use of CMIA detection technology.
- ARCHITECT Anti-HCV Calibrator, which consists of one calibrator level for the calibration of the instrument.
- ARCHITECT Anti-HCV Controls (or other control material), which consist of a negative control and a positive control.
- ARCHITECT i Pre-Trigger Solution contains 1.32% (w/v) hydrogen peroxide.
- ARCHITECT i Trigger Solution contains 0.35N sodium hydroxide.
- ARCHITECT i Wash Buffer contains phosphate buffered saline solution with preservative.
The ARCHITECT Anti-HCV Calibrator Kit contains:
- 1 Bottle (4 mL) ARCHITECT Anti-HCV Calibrator 1 is recalcified, heat-inactivated anti-HCV positive human plasma in recalcified anti-HCV negative human plasma. Calibrator 1 is green and contains Acid Yellow No. 23 and Acid Blue No. 9 dyes. Preservative: sodium azide.
The ARCHITECT Anti-HCV Control Kit contains:
- 2 Bottles (8 mL each) of ARCHITECT Anti-HCV Controls (1 bottle of negative control and 1 bottle of positive control).
- The negative control is recalcified human plasma. Preservative: sodium azide.
- The positive control is recalcified, heat-inactivated anti-HCV positive human plasma in recalcified anti-HCV negative human plasma. The positive control is blue and contains Acid Blue No. 9 dye. Preservative: sodium azide.
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## Assay Principle and Format
The ARCHITECT Anti-HCV assay is a two-step immunoassay for the qualitative detection of anti-HCV in human serum and plasma using CMIA technology with flexible assay protocols, referred to as Chemiflex®.
In the first step, sample, recombinant HCV antigen coated paramagnetic microparticles, and assay diluent are combined. Anti-HCV present in the sample binds to the HCV coated microparticles. After washing, anti-human IgG/IgM acridinium-labeled conjugate is added in the second step. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs). A relationship exists between the amount of anti-HCV in the sample and the RLUs detected by the ARCHITECT i optical system.
The ARCHITECT Anti-HCV Calibrator Kit is used to calibrate the ARCHITECT i System. The presence or absence of anti-HCV in the sample is determined by comparing the chemiluminescent signal in the reaction to the cutoff signal determined from an active ARCHITECT Anti-HCV calibration curve. If the chemiluminescent signal of the sample is greater than or equal to the cutoff signal, the sample is considered reactive for anti-HCV.
## Results
The ARCHITECT i System calculates the cutoff RLU from the mean chemiluminescent signal of three Anti-HCV Calibrator 1 replicates and stores the result. The cutoff RLU is determined by multiplying the Anti-HCV Calibrator 1 mean RLU by 0.074.
Cutoff RLU = Calibrator 1 Mean RLU x 0.074
The ARCHITECT i System calculates a result based on the ratio of the sample RLU to the cutoff RLU (S/CO) for each specimen and control.
S/CO = Sample RLU/Cutoff RLU ratio.
## Interpretation of Results
| Initial ARCHITECT Anti-HCV Results | | | |
| --- | --- | --- | --- |
| Initial Result (S/CO) | Instrument Flag | Interpretation | Retest Procedure |
| "≥ 1.00 | REACTIVE | Reactive | No retest required. |
| 0.80 to 0.99 | GRAYZONE | Grayzone | Retest in duplicate. |
| 0.00 to 0.79 | NONREACTIVE | Nonreactive | No retest required. |
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| ARCHITECT Anti-HCV Results | | | |
| --- | --- | --- | --- |
| Initial Result | Retest Result | Result | Interpretation |
| Reactive | No retest required. | Reactive | Presumptive evidence of antibodies to HCV; follow CDC recommendations for supplemental testing. |
| Grayzone | Both of the duplicate retests are reactive. | Reactive | Presumptive evidence of antibodies to HCV; follow CDC recommendations for supplemental testing. |
| | One or both of the duplicate retests are repeatedly in the grayzone or one retest is reactive and the other nonreactive. | Equivocal | Antibodies to HCV may or may not be present; another specimen should be obtained from the individual for further testing or follow CDC recommendations for supplemental testing. |
| | Both of the duplicate retests are nonreactive. | Nonreactive | Antibodies to HCV not detected; does not exclude the possibility of exposure to HCV. |
| Nonreactive | No retest required. | Nonreactive | Antibodies to HCV not detected; does not exclude the possibility of exposure to HCV. |
## VI. ALTERNATIVE PRACTICES AND PROCEDURES
Determining the presence of HCV in patients may be achieved by using a variety of commercially available, FDA-approved, serological tests. When these test results are used in combination with a physician’s assessment and other laboratory test results, infection with HCV can be identified.
## VII. MARKETING HISTORY
ARCHITECT Anti-HCV, List No. 1L79, has not been marketed in any other country.
## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
The ARCHITECT Anti-HCV materials are for in vitro diagnostic use, thus there is no direct adverse effect on the patient. Failure of the product to perform as intended, or errors in the use of the product, may lead to a false result. A false reactive (false positive) result using an anti-HCV assay is not considered a patient or public health concern because a reactive enzyme immunoassay (EIA) result in a clinical lab should be followed up with supplemental tests (e.g., strip immunoblot assay (SIA) and/or polymerase
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chain reaction (PCR) for detection of HCV RNA) to determine inactive or resolved infection versus active HCV replication.' Treatment of the patient with chronic HCV infection is initiated only after extensive clinical, laboratory and behavioral assessment of the patient (e.g., elevated ALT levels for six months, detectable serum HCV RNA, liver biopsy with portal fibrosis, patient compliance, and abstinence from drugs and alcohol). A false nonreactive (false negative) anti-HCV result in a diagnostic setting may lead to a patient with HCV going unidentified. Under these circumstances, there is a safety concern for both the patient and the public, since such individuals may be capable of transmitting HCV infection. However, if a patient is known to be at high risk of HCV infection, or is symptomatic, and the physician's suspicion of HCV infection is high, HCV RNA testing is often employed and is of diagnostic value, even after an initial negative anti-HCV test result.
## IX. SUMMARY OF NONCLINICAL STUDIES
Nonclinical studies were performed at Abbott Laboratories to evaluate the performance characteristics of the ARCHITECT Anti-HCV assay. The studies are described below.
### Tube Type Interference
A study was conducted to evaluate which anticoagulants (blood collection tube types) are acceptable for use with the ARCHITECT Anti-HCV assay. Sample sets of human specimens were collected in the control tube type (glass serum) and the blood collection tube types selected for evaluation. The blood collection tubes for the sample sets were supplemented with anti-HCV positive serum or plasma to prepare high negative samples (targeted to 0.80 S/CO) and low positive samples (targeted to 1.20 S/CO) and were tested.
On average, the tube types listed in Table 1 below showed less than a 10% difference when compared to the control tube type (glass serum) for high negative samples (S/CO range: 0.60 to 0.99) and low positive samples (S/CO range: 1.00 to 1.40).
### Table 1
ARCHITECT Anti-HCV
Tube Type Interference
Distribution of Differences
| Tube Type | Distribution of the differences | | |
| --- | --- | --- | --- |
| | < 10% | ≥ 10% to ≤ 20% | > 20% |
| Glass Serum Separator | 85.0%
(34/40) | 15.0%
(6/40) | - |
| Plastic Serum | 95.0%
(38/40) | 5.0%
(2/40) | - |
| Plastic Serum Separator | 90.0% | 7.5% | 2.5% |
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| | (36/40) | (3/40) | (1/40) |
| --- | --- | --- | --- |
| Plastic Lithium Heparin Plasma Separator | 72.5%
(29/40) | 22.5%
(9/40) | 5.0%
(2/40) |
| Plastic Sodium Heparin | 75.0%
(30/40) | 22.5%
(9/40) | 2.5%
(1/40) |
| Plastic Dipotassium EDTA | 72.5%
(29/40) | 20.0%
(8/40) | 7.5%
(3/40) |
The data support the use of the following blood collection tube types in the ARCHITECT Anti-HCV assay:
**Glass tubes**
- Serum
- Serum separator
**Plastic tubes**
- Serum
- Serum separator
- Dipotassium EDTA
- Lithium heparin plasma separator
- Sodium heparin
**Interferences – Bilirubin, Hemoglobin, Total Protein, and Triglycerides**
A study was conducted to evaluate the susceptibility of the ARCHITECT Anti-HCV assay to potentially interfering substances based on guidance from the Clinical Laboratory Standards Institute (CLSI) document EP7-A.
A bilirubin test sample was prepared by supplementing high negative and low positive samples with bilirubin (conjugated and unconjugated) at > 20 mg/dL (targeted to 22 mg/dL). A hemoglobin test sample was prepared by supplementing the high negative and low positive samples with hemolysate at > 500 mg/dL (targeted to 550 mg/dL). A high protein test sample (> 12 g/dL [targeted to 13.2 g/dL]) was prepared by concentrating a nonreactive, normal protein specimen and supplementing with anti-HCV positive stock to yield two test samples with different analyte levels (0.80 and 1.20 S/CO). A triglyceride test sample was prepared by supplementing the high negative and low positive samples with Liposyn® III at > 3000 mg/dL (targeted to 3300 mg/dL). Control samples were prepared for each test sample at each analyte level. The control and test samples were tested.
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At the concentrations listed below, bilirubin, hemoglobin, total protein, and triglycerides showed less than 10% interference in the ARCHITECT Anti-HCV assay for high negative samples targeted to 0.80 S/CO (S/CO range: 0.60 to 0.99) and low positive samples targeted to 1.20 S/CO (S/CO range: 1.00 to 1.40):
- Bilirubin (≤ 20 mg/dL)
- Hemoglobin (≤ 500 mg/dL)
- Total Protein (≤ 12 g/dL)
- Triglycerides (≤ 3000 mg/dL)
## Sample Stability of Serum and Plasma
A study was conducted to evaluate the sample storage temperatures and number of freeze/thaw cycles for each blood collection tube type acceptable for use with the ARCHITECT Anti-HCV assay. Sample sets of human specimens were collected in each of the blood collection tube types and supplemented with anti-HCV positive stock (targeted at 1.1 S/CO). The samples were tested at time point 0 and after being stored at 2 to 8°C for > 7 days, at room temperature (study performed at 20 to 23°C) for > 3 days, and after being subjected to three freeze/thaw cycles. Specimens that were stored at the room temperature condition and 2 to 8°C condition were tested from the blood collection tubes, as on the clot represents worst-case condition (i.e. specimen contact with the red blood cells). The specimens that were subjected to the freeze/thaw conditions were tested off the clot.
The data demonstrate that human serum (including serum collected in serum separator tubes) or plasma collected in dipotassium EDTA, lithium heparin plasma separator, or sodium heparin tubes may be used with the ARCHITECT Anti-HCV assay when:
- stored at 2 to 8°C for up to 7 days
- stored at room temperature (study performed at 20 to 23°C) for up to 3 days
- subjected to up to 3 freeze/thaw cycles.
## Sample On Board Stability
A study was conducted to evaluate samples when stored on the ARCHITECT i System (on board storage) and tested with the ARCHITECT Anti-HCV assay. High negative samples (targeted to 0.80 S/CO) and low positive samples (targeted to 1.20 S/CO) were tested using one lot of reagents, one lot of calibrator, and one
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Summary of Safety and Effectiveness Data
lot of controls on two instruments (one i2000 and one i2000SR). Time point 0 consisted of testing the two analyte levels immediately after pipetting the samples. Time point 1 consisted of testing the two analyte levels after being stored on board the instrument for longer than 3 hours.
The data support sample storage of up to 3 hours on board the ARCHITECT i System when tested with the ARCHITECT Anti-HCV assay.
## Within-Laboratory Precision
A 20-day precision study was conducted to evaluate the precision performance of the ARCHITECT Anti-HCV assay based on guidance from the Clinical and Laboratory Standards Institute (CLSI) document EP5-A2. Testing was performed using three ARCHITECT Anti-HCV reagent lots, three calibrator lots, and one control lot on two instruments (one i 2000 and one i 2000SR). The ARCHITECT Anti-HCV Negative Control and Positive Control, high negative panel (targeted to 0.80 S/CO) and low positive panel (targeted to 1.20 S/CO) were assayed in replicates of two at two separate times of day for 20 testing days.
The ARCHITECT Anti-HCV assay demonstrates the following precision in Tables 2a and 2b beginning on page 8.
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Table 2a
ARCHITECT Anti-HCV
Within-Laboratory Precision Study - Overall Precision
Individual Components
| Instrument | Sample | n | Grand Mean S/CO | Within-run | | Between-run | | Between-day | | Between-lot | | Total* | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| i 2000 | Positive Control | 240 | 3.54 | 0.088 | 2.5 | 0.039 | 1.1 | 0.053 | 1.5 | 0.071 | 2.0 | 0.110 | 3.1 |
| | High Negative | 240 | 0.77 | 0.026 | 3.4 | 0.011 | 1.4 | 0.000 | 0.0 | 0.025 | 3.3 | 0.028 | 3.7 |
| | Low Positive | 240 | 1.13 | 0.039 | 3.5 | 0.012 | 1.1 | 0.000 | 0.0 | 0.027 | 2.4 | 0.041 | 3.6 |
| | Negative Control | 240 | 0.20 | 0.013 | NA | 0.035 | NA | 0.061 | NA | 0.021 | NA | 0.071 | NA |
| i 2000SR | Positive Control | 240 | 3.52 | 0.100 | 2.8 | 0.000 | 0.0 | 0.061 | 1.7 | 0.063 | 1.8 | 0.117 | 3.3 |
| | High Negative | 240 | 0.76 | 0.029 | 3.8 | 0.000 | 0.0 | 0.016 | 2.1 | 0.034 | 4.4 | 0.033 | 4.3 |
| | Low Positive | 240 | 1.13 | 0.041 | 3.6 | 0.000 | 0.0 | 0.013 | 1.1 | 0.037 | 3.3 | 0.043 | 3.8 |
| | Negative Control | 240 | 0.17 | 0.009 | NA | 0.022 | NA | 0.019 | NA | 0.021 | NA | 0.031 | NA |
* Total variability contains within-run, between-run, and between-day variance components.
NA = not applicable
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Table 2b
ARCHITECT Anti-HCV
Within-Laboratory Precision Study - Overall Precision
Cumulative Components
| | | | | Within-Run | | Within-Day | | Within-Laboratory Precision | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Instrument | Sample | n | Grand Mean S/CO | SD | %CV | SD | %CV | SD | %CV |
| i 2000 | Positive Control | 240 | 3.54 | 0.088 | 2.5 | 0.096 | 2.7 | 0.131 | 3.7 |
| | High Negative | 240 | 0.77 | 0.026 | 3.4 | 0.028 | 3.7 | 0.038 | 4.9 |
| | Low Positive | 240 | 1.13 | 0.039 | 3.5 | 0.041 | 3.6 | 0.049 | 4.3 |
| | Negative Control | 240 | 0.20 | 0.013 | NA | 0.037 | NA | 0.075 | NA |
| i 2000SR | Positive Control | 240 | 3.52 | 0.100 | 2.8 | 0.100 | 2.8 | 0.133 | 3.8 |
| | High Negative | 240 | 0.76 | 0.029 | 3.8 | 0.029 | 3.8 | 0.047 | 6.2 |
| | Low Positive | 240 | 1.13 | 0.041 | 3.6 | 0.041 | 3.6 | 0.057 | 5.0 |
| | Negative Control | 240 | 0.17 | 0.009 | NA | 0.024 | NA | 0.037 | NA |
Within-Laboratory Precision contains within-run, between-run, between-day and between-lot variance components.
NA = not applicable
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## Analytical Specificity
A study was conducted to evaluate the ARCHITECT Anti-HCV assay for potential cross-reactivity for specimens from individuals with medical conditions unrelated to HCV infection. Specimens with various medical conditions were obtained and tested with the ARCHITECT Anti-HCV assay and the comparator anti-HCV assay. The final results for each of the specimens were compared between the two assays. Specimen results that were discordant between the two assays were sent to an external reference laboratory for supplemental testing.
For the medical conditions evaluated, the ARCHITECT Anti-HCV assay demonstrates no potential cross-reactivity for specimens from individuals with medical conditions unrelated to HCV. The data are summarized in Table 3 on page 13.
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Table 3 Reactivity of the ARCHITECT Anti-HCV Assay in Individuals with Medical Conditions Unrelated to HCV Infection
| | Comparator Anti-HCV assay | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Nonreactive | | | Equivocal | | | Reactive^{a} | | |
| | | ARCHITECT Anti-HCV | | | ARCHITECT Anti-HCV | | | ARCHITECT Anti-HCV | | |
| Category | n | NR^{b} | EQ^{b} | R^{b} | NR^{b} | EQ^{b} | R^{b} | NR^{b} | EQ^{b} | R^{b} |
| Cytomegalovirus (anti-CMV positive) | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Epstein-Barr Virus (anti-EBV positive) | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Hepatitis A Virus (anti-HAV positive) | 10 | 8 | 0 | 0 | 1^{e} | 0 | 0 | 0 | 0 | 1 |
| Hepatitis B Virus (anti-HBV positive) | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Human Immunodeficiency Virus (anti-HIV-1 positive) | 10 | 6 | 0 | 0 | 0 | 0 | 0 | 1^{d} | 0 | 3 |
| Anti-Nuclear Antibody (ANA) | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Escherichia coli (E.Coli) | 3 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Elevated IgG | 10 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Elevated IgM | 10 | 8 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
| Elevated total bilirubin | 10 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 6 |
| Elevated total protein | 8 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| Herpes Simplex Virus (HSV) IgG | 5 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Human T-cell Lymphotropic Virus (HTLV) | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Human anti-mouse antibodies (HAMA) positive | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Influenza vaccine recipients | 10 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Multiparous female | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Non-viral liver disease | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Rheumatoid factor positive | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Rubella | 10 | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Syphilis | 10 | 6 | 0 | 0 | 0 | 0 | 0 | 1^{e} | 0 | 3 |
| Systemic Lupus Erythematosus (SLE) | 4 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Toxoplasmosis IgG positive | 9 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Varicella Zoster (VZV) positive | 10 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Yeast infection | 9 | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Total | 218 | 194 | 0 | 0 | 1 | 0 | 0 | 2 | 0 | 21 |
a Each reactive anti-HCV result was verified using the comparator anti-HCV assay.
b NR = Nonreactive, EQ = Equivocal, R = Reactive
c The final result of the anti-HAV positive specimen was anti-HCV negative when tested using the Chiron RIBA® HCV 3.0 Strip Immunoblot Assay (SIA) and HCV RNA negative when tested using the Roche COBAS AMPLICOR™ Hepatitis C Virus (HCV) Test v2.0.
d The final result of the anti-HIV-1 positive specimen was anti-HCV indeterminate when tested using the Chiron RIBA HCV 3.0 SIA and HCV RNA negative when tested using the Roche COBAS AMPLICOR HCV Test v2.0.
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| | Comparator Anti-HCV assay | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | Nonreactive | | | Equivocal | | Reactive^{a} | | |
| | | ARCHITECT
Anti-HCV | | | ARCHITECT
Anti-HCV | | ARCHITECT
Anti-HCV | | |
| Category | n | NR^{b} | EQ^{b} | R^{b} | NR^{b} | EQ^{b} | R^{b} | NR^{b} | EQ^{b} |
The final result of the syphilis specimen was anti-HCV negative when tested using the Chiron RIBA HCV 3.0 SIA and HCV RNA negative when tested using the Roche COBAS AMPLICOR HCV Test v2.0.
## Seroconversion Panels
A study was conducted to evaluate the seroconversion detection of the ARCHITECT Anti-HCV assay when compared to the comparator anti-HCV assay. Nineteen anti-HCV patient seroconversion panel sets were obtained from two commercial vendors and tested using the ARCHITECT Anti-HCV assay and the comparator anti-HCV assay. For members of panels that had a reactive status in the ARCHITECT Anti-HCV assay earlier than in the comparator anti-HCV assay, supplemental testing with the Chiron RIBA HCV 3.0 SIA and the Roche COBAS AMPLICOR HCV Test v2.0 was performed on the reactive panel members.
The ARCHITECT Anti-HCV assay demonstrates acceptable seroconversion detection when compared to the comparator anti-HCV assay. The data are summarized in Table 4 on page 15.
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Table 4
ARCHITECT Anti-HCV Assay
Days to Evidence of HCV Infection
Seroconversion Panels
| | Comparator Anti-HCV assay | | | ARCHITECT Anti-HCV assay | | | Chiron RIBA HCV 3.0 SIA | | | Roche COBAS AMPLICOR HCV Test v2.0 | | Difference in Days to Anti-HCV Reactive Results Comparator - ARCHITECT^{b} |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Panel ID | NR^{c} | EQ^{a} | R^{a} | NR^{c} | EQ^{a} | R^{a} | - | IND^{a} | + | - | + | |
| PHV904 | 7 | 9 | 14 | 7 | | 9 | 9 | | | | 9 | 5 |
| PHV905 | 11 | 14 | 18 | 7 | | 11 | 11 | 14 | | | 11 | 7 |
| PHV906 | | | 0 | | | 0 | -- | -- | -- | -- | -- | 0 |
| PHV907 | 13 | | 18 | 13 | | 18 | -- | -- | -- | -- | -- | 0 |
| PHV908 | 11 | 13 | 19 | 5 | | 11 | 11 | 13 | | | 11 | 8 |
| PHV909 | 30 | | **^{c} | 0 | | 28 | | 30 | | | 28 | **^{c} |
| PHV910 | 4 | | 8 | 4 | | 8 | -- | -- | -- | -- | -- | 0 |
| PHV911 | 3 | | 14 | 3 | | 14 | -- | -- | -- | -- | -- | 0 |
| PHV912 | 4 | | 7 | 4 | | 7 | -- | -- | -- | -- | -- | 0 |
| PHV914 | 19 | | 24 | 12 | | 16 | | 19 | | | 16 | 8 |
| PHV916 | 9 | 16 | 19 | 9 | | 16 | 16 | | | | 16 | 3 |
| PHV917 | 22 | | 85 | 22 | | 85 | -- | -- | -- | -- | -- | 0 |
| PHV918 | 16 | | 24 | 16 | | 24 | -- | -- | -- | -- | -- | 0 |
| PHV920 | 7 | 13 | 16 | 7 | | 13 | 13 | | | | 13 | 3 |
| HCV 6212 | 0 | | 12 | 0 | | 12 | -- | -- | -- | -- | -- | 0 |
| HCV 6213 | 35 | | 37 | 35 | | 37 | -- | -- | -- | -- | -- | 0 |
| HCV 6214 | 23 | | 25 | 25 | | 30 | -- | -- | -- | -- | -- | -5 |
| HCV 6216 | 17 | 23 | **^{c} | 17 | | 23 | | 23 | | 23 | | **^{c} |
| HCV 6229 | 10 | 17 | 20 | 10 | | 17 | 17 | | | | 17 | 3 |
a NR = Nonreactive, EQ = Equivocal, R = Reactive, IND = Indeterminate
b The dates of the first reactive test results were compared in the comparator assay and ARCHITECT Anti-HCV assay. If the first reactive test result occurred on the same day, then the difference is 0; if ARCHITECT Anti-HCV assay had an earlier date, then the difference is positive; if ARCHITECT Anti-HCV assay had a later date, then the difference is negative.
c The panel never seroconverted from a nonreactive status to a reactive status with the comparator anti-HCV assay.
- Supplemental testing was not performed.
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## Genotype Detection
A study was conducted to evaluate the genotype detection of the ARCHITECT Anti-HCV assay for the most commonly recognized genotypes when compared to the comparator anti-HCV assay. Two lots of HCV genotype panels were obtained from Teragenix Corporation which consisted of the following genotypes, as determined by the vendor: 1a, 1b, 1c, 2, 2a, 2b, 2c, 3a, 3b, 4, 4a, 4c, 4d, 5, 5a, and 6a. The lots were tested with the ARCHITECT Anti-HCV assay and the comparator anti-HCV assay, and the final results were compared.
The ARCHITECT and comparator anti-HCV assay final results were in 100% agreement for the genotypes of HCV. Therefore, the ARCHITECT Anti-HCV assay demonstrates acceptable genotype detection for the most commonly recognized genotypes.
## Calibration Curve Storage
A study was conducted to evaluate the acceptability of an ARCHITECT Anti-HCV calibration curve stored on the ARCHITECT i System for a minimum of 30 days. Testing was performed using three ARCHITECT Anti-HCV reagent lots, three calibrator lots, and one control lot on two instruments (one i 2000 and one i 2000SR). Each reagent lot was matched with a different calibrator lot. Three calibrations were performed on each instrument for each reagent lot and the calibration curve generated was stored on each instrument for the duration of the study. The ARCHITECT Anti-HCV Negative Control and Positive Control were assayed in replicates of two, at two times per day, for a total of 20 time points across a minimum of 31 days. The last time point was performed at least 31 days after calibration.
The data support the storage of an ARCHITECT Anti-HCV calibration curve on the ARCHITECT i System for a minimum of 30 days.
## Instrument Percent Agreement
A study was conducted to confirm that the ARCHITECT Anti-HCV assay can be used on the ARCHITECT i 2000 and i 2000SR systems. Surplus serum specimens were obtained from a commercial vendor and tested on both ARCHITECT instrument systems using a minimum of two lots of reagents and one lot of calibrator and controls. One replicate of each specimen was tested with the same reagent lot on both instruments.
The negative percent agreement between the two ARCHITECT instrument systems was 99.8% (919/921) with 95% confidence interval of 99.2% to 100% and the positive percent agreement between the two ARCHITECT instrument systems was 100% (329/329) with 95% confidence interval of 98.9% to 100%. The ARCHITECT Anti-HCV assay demonstrates acceptable agreement between the ARCHITECT i 2000 and i 2000SR.
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## High Dose Hook Effect
A study was conducted to characterize the performance of the ARCHITECT Anti-HCV assay when used to test specimens containing high levels of anti-HCV that have the potential to cause a high dose hook effect. Two unique stocks of recalcified anti-HCV positive human plasma with S/CO values of >15 after a minimum of a 1:4 dilution were each serially diluted with recalcified anti-HCV negative human plasma and tested on the ARCHITECT i System.
The data demonstrate that the ARCHITECT Anti-HCV assay is not susceptible to interference from specimens with high levels of anti-HCV.
## Within-Assay Sample Carryover
A study was conducted to evaluate the susceptibility of within-assay sample carryover within the ARCHITECT Anti-HCV assay by comparing the results of a low anti-HCV (0.80 S/CO) sample when tested before (protected low sample) and after testing a high anti-HCV sample with target S/CO of >15 S/CO (unprotected low sample).
The difference between the protected low sample and the unprotected low sample mean S/CO values was 0.00 S/CO with 95% confidence interval of -0.02 to 0.02. This indicated that within-assay sample carryover was not detected. Therefore, the ARCHITECT Anti-HCV assay is not susceptible to within-assay sample carryover.
## ARCHITECT Anti-HCV Microbial Challenge Characterization
A Microbial Challenge Characterization (MCC) evaluation was performed for the ARCHITECT Anti-HCV Reagents, Calibrator, and Controls, which consisted of an Antimicrobial Effectiveness Testing (AET) evaluation and a Microbial Interference Characterization (MIC) evaluation. The MCC evaluation integrated the results from both AET and MIC, which determined that the product is adequately protected.
## Reagent, Calibrator, and Control Developmental Stability
The developmental stability is an on-going study to establish the stability (shelf-life integrity) of the ARCHITECT Anti-HCV Reagents, Calibrator, and Controls at the intended storage condition of 2 to 8°C and during on board storage (for reagents only).
In addition, the developmental stability includes the in-use and freeze/thaw conditions. The in-use condition for the reagents, calibrator, and controls simulates customer use over time. The freeze/thaw condition for the reagents, calibrator, and controls supports the transport simulation study described below.
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Summary of Safety and Effectiveness Data
Stability testing is performed on three lots of 100-test kit reagents, two lots of 500-test kit reagents, three lots of calibrators, and three lots of controls.
The developmental stability is scheduled to continue for a maximum of 15 months (with a minimum of 6 months). The data support 6 months of expiration dating for the ARCHITECT Anti-HCV Reagents and 7 months of expiration dating for the ARCHITECT Anti-HCV Calibrator and Controls.
## Reagent Transport Stability
A study was conducted to support the stability of the ARCHITECT Anti-HCV Reagents following simulated transport stress conditions. One 100-test kit lot and one 500-test kit lot of the ARCHITECT Anti-HCV Reagents were tested after being subjected to simulated transport stress.
The data support the stability of the ARCHITECT Anti-HCV Reagents following transport at ambient temperatures.
## Calibrator and Control Transport Stability
A study was conducted to support the stability of the ARCHITECT Anti-HCV Calibrator and Controls following simulated transport stress conditions. One lot each of the ARCHITECT Anti-HCV Calibrator and Controls was tested after being subjected to simulated transport stress.
The data support the stability of the ARCHITECT Anti-HCV Calibrator and Controls following transport at ambient temperatures.
## X. SUMMARY OF CLINICAL STUDIES
A multi-center study was conducted to evaluate the efficacy of the ARCHITECT Anti-HCV assay for the qualitative detection of anti-HCV in human serum and plasma as measured by precision and method comparison.
### System Reproducibility
The precision (reproducibility) of the ARCHITECT Anti-HCV assay was evaluated by testing three master lots each of ARCHITECT Anti-HCV Reagents, Calibrator, and Controls at each of three clinical sites for five days. Precision testing was performed on one ARCHITECT i 2000 System and two ARCHITECT i 2000SR Systems across the three clinical sites.
The ARCHITECT Anti-HCV Negative Control and Positive Control, and a high negative panel member (Panel 1) (targeted to 0.80 S/CO) and low positive panel member (Panel 2) (targeted to 1.20 S/CO) were assayed in replicates of four at two separate times
8
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per day for five days. The analysis method of data was based on guidance from CLSI documents EP5-A2 and EP15-A2. The overall precision data are summarized in Tables 5a and 5b beginning on page 18.
## Table 5a
### ARCHITECT Anti-HCV
System Reproducibility (5-Day Precision Study)
Individual Components
| Sample | n | Grand Mean S/CO | Within-run | | Between-run | | Between-day | | Total^{a} | | Between-lot | | Between-site | | Overall^{b} | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Positive Control | 360 | 3.68 | 0.118 | 3.2 | 0.028 | 0.8 | 0.037 | 1.0 | 0.127 | 3.5 | 0.049 | 1.3 | 0.048 | 1.3 | 0.136 | 3.7 |
| High Negative | 360 | 0.77 | 0.045 | 5.9 | 0.016 | 2.0 | 0.000 | 0.0 | 0.048 | 6.2 | 0.055 | 7.1 | 0.010 | 1.3 | 0.074 | 9.5 |
| Low Positive | 360 | 1.15 | 0.064 | 5.6 | 0.014 | 1.2 | 0.009 | 0.8 | 0.066 | 5.8 | 0.083 | 7.2 | 0.020 | 1.7 | 0.107 | 9.3 |
| Negative Control | 360 | 0.12 | 0.006 | NA | 0.000 | NA | 0.003 | 2.8 | 0.007 | NA | 0.054 | NA | 0.007 | NA | 0.055 | NA |
a Total variability contains within-run, between-run and between-day variance components.
b Overall variability contains within-run, between-run, between-day, between-lot, between-site and lot-site interaction variance components.
NA = not applicable
## Table 5b
### ARCHITECT Anti-HCV
System Reproducibility (5-Day Precision Study)
Cumulative Components
| Sample | n | Grand Mean S/CO | Within-Run | | Within-Day | | Within-Laboratory Precision (Total) | | Precision with Additional Component of Between-Site | | Precision with Additional Component of Between-Lot | | Precision with Additional Components of Sit and Lot (Overall) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| Positive Control | 360 | 3.68 | 0.118 | 3.2 | 0.122 | 3.3 | 0.127 | 3.5 | 0.136 | 3.7 | 0.136 | 3.7 | 0.136 | 3.7 |
| High Negative Panel | 360 | 0.77 | 0.045 | 5.9 | 0.048 | 6.2 | 0.048 | 6.2 | 0.049 | 6.4 | 0.073 | 9.5 | 0.074 | 9.5 |
| Low Positive Panel | 360 | 1.15 | 0.064 | 5.6 | 0.066 | 5.7 | 0.066 | 5.8 | 0.069 | 6.0 | 0.106 | 9.2 | 0.107 | 9.3 |
| Negative Control | 360 | 0.12 | 0.006 | NA | 0.006 | NA | 0.007 | NA | 0.010 | NA | 0.055 | NA | 0.055 | NA |
NA = not applicable
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## Method Comparison
### Clinical Performance
A prospective multi-center study was conducted to evaluate the ability of the ARCHITECT Anti-HCV assay to detect anti-HCV antibodies in specimens from an intended use diagnostic population.
Of the 2,027 specimens tested in the ARCHITECT Anti-HCV clinical study, 1,310 specimens were obtained from individuals at increased risk of HCV infection (increased risk population) due to lifestyle, behavior, occupation, disease state, or known exposure event; and 717 specimens were obtained from individuals with signs and symptoms of a hepatitis infection.
The 2,027 specimens were collected from specimen collection sites or were purchased from specimen vendors. The number and percent of specimens obtained from each specimen collection site/specimen vendor are listed in Table 6 below.
Table 6 Number and Percent of Specimens by Specimen Collection Sites/Specimen Vendors for Overall Specimen Population
| Collection Site/Vendor | Site/Location | Group (n) | Total (n)^{a} | Percent (%) |
| --- | --- | --- | --- | --- |
| Collection Site | | | | |
| Galveston, TX | 1 | 757 | 2027 | 37.35 |
| Dallas, TX | 2 | 126 | 2027 | 6.22 |
| Miami, FL | 3 | 94 | 2027 | 4.64 |
| St. Petersburg, FL | 4 | 81 | 2027 | 4.00 |
| Chicago, IL | 5 | 181 | 2027 | 8.93 |
| Denver, CO | 6 | 140 | 2027 | 6.91 |
| Collection Vendor | | | | |
| Vendor 1: High Point, NC | 1 | 185 | 2027 | 9.13 |
| Vendor 1: Colton, CA | 2 | 118 | 2027 | 5.82 |
| Vendor 1: Plymouth, MA | 3 | 345 | 2027 | 17.02 |
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A demographic summary of the overall specimen population by race/ethnic group is provided in Table 7 below.
Table 7 Demographic Summary of Overall Specimen Population by Race/Ethnic Group
| Race/Ethnic Group | Group (n) | Total (n)* | Percent (%) |
| --- | --- | --- | --- |
| African American | 631 | 2027 | 31.13 |
| American Indian/Alaska Native | 12 | 2027 | 0.59 |
| Asian | 30 | 2027 | 1.48 |
| Caucasian | 1035 | 2027 | 51.06 |
| Hispanic | 294 | 2027 | 14.50 |
| Other | 25 | 2027 | 1.23 |
Of the 2,027 subjects, 1,126 (55.55%) were female and 901 (44.45%) were male. The age was not reported for three subjects. Of the remaining 2,024 subjects, the mean age was 41 years (age range: 18 to 83 years).
The HCV status was determined for each specimen using the comparator anti-HCV assay and, as necessary, supplemental assays (Chiron RIBA HCV 3.0 SIA and Roche COBAS AMPLICOR HCV Test v2.0). During the clinical study, all comparator and supplemental testing was performed following manufacturers' instructions. Each specimen was also tested using the ARCHITECT Anti-HCV assay at the three clinical testing sites located in Galveston, TX; Hershey, PA; and Milwaukee, WI.
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# Results by Specimen Classification
Following testing using the comparator anti-HCV assay and the supplemental assays, as necessary, the 2,027 specimens were assigned an HCV status of HCV Infected, HCV Not Determined, or HCV Not Infected based on the HCV status algorithm provided in Table 8 below.
Table 8 HCV Status Algorithm
| Comparator Anti-HCV Final Test Results | Supplemental Test Results | | HCV Status^{23} |
| --- | --- | --- | --- |
| Nonreactive | -- | | Not infected^{a} |
| | Chiron RIBA HCV 3.0 SIA | Roche COBAS AMPLICOR HCV Test v2.0 | |
| Reactive | Positive | -- | Infected^{b} |
| Reactive | Indeterminate or Negative | Positive | Infected^{c} |
| Reactive | Indeterminate or Negative | Equivocal | Not Determined^{d} |
| Reactive | Indeterminate or Negative | Negative | Not infected^{a} |
| Equivocal | Positive | -- | Infected^{b} |
| Equivocal | Indeterminate or Negative | Positive | Infected^{c} |
| Equivocal | Indeterminate or Negative | Equivocal | Not Determined^{d} |
| Equivocal | Indeterminate or Negative | Negative | Not infected^{a} |
a A negative test result does not exclude the possibility of exposure to hepatitis C virus.
b State or associated disease Not Determined.
c Indicates active HCV infection.
d HCV status cannot be determined.
-- = not performed
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## Comparison of Results
The ARCHITECT Anti-HCV assay results were compared to HCV status for the increased risk and signs and symptoms populations. The increased risk population was ranked according to the risk of HCV infection in study subjects. The risk of HCV infection was ranked based on a clinical evaluation of the likelihood of acquiring HCV through each mode of transmission. The mode of transmission was ranked higher if the likelihood of acquiring HCV was greater. Each specimen was assigned only one risk (highest ranked risk). Of the 2,027 specimens analyzed, the status of 616 specimens was HCV Infected. The status of 1,411 specimens was HCV Not Infected. No specimens had the status HCV Not Determined. The comparison of ARCHITECT Anti-HCV results by HCV status is presented in Table 9 on page 26.
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# Table 9
Comparison of ARCHITECT Anti-HCV Results to HCV Status - Overall Increased Risk (by Risk) and Signs and Symptoms Populations
| Specimen Population | HCV Status^{a} | | | | | | | | | | | | Total |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | HCV Infected | | | | | | HCV Not Infected | | | | | | |
| | Reactive | | Equivocal | | Nonreactive | | Reactive | | Equivocal | | Nonreactive | | |
| | n | % | n | % | n | % | n | % | n | % | n | % | n |
| Individuals with increased risk of HCV infection | | | | | | | | | | | | | |
| Recipients of clotting factor concentrate prior to 1987 | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 2 | 0.10 | 3 |
| Users of injecting drugs | 97 | 4.79 | 0 | 0.00 | 0 | 0.00 | 8 | 0.39 | 0 | 0.00 | 85 | 4.19 | 190 |
| Multiple sex partners | 53 | 2.61 | 0 | 0.00 | 1 | 0.05 | 6 | 0.30 | 1 | 0.05 | 587 | 28.96 | 648 |
| Transfusion recipient prior to July 1992 or received blood from donor later to be found HCV positive | 18 | 0.89 | 0 | 0.00 | 0 | 0.00 | 2 | 0.10 | 0 | 0.00 | 22 | 1.09 | 42 |
| Perinatal exposure; mother was infected with hepatitis C | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 0 | 0.00 | 3 | 0.15 | 3 |
| Men who have sex with men | 1 | 0.05 | 0 | 0.00 | 0 | 0.00 | 2 | 0.10 | 0 | 0.00 | 11 | 0.54 | 14 |
| Needle stick or mucosal exposure on the job | 13 | 0.64 | 0 | 0.00 | 0 | 0.00 | 3 | 0.15 | 2 | 0.10 | 252 | 12.43 | 270 |
| Other^{b}: Household contact with hepatitis C infected individual and/or intranasal cocaine user | 31 | 1.53 | 0 | 0.00 | 0 | 0.00 | 2 | 0.10 | 0 | 0.00 | 107 | 5.28 | 140 |
| Individuals with signs and symptoms of hepatitis infection | 400 | 19.73 | 0 | 0.00 | 1 | 0.05 | 7 | 0.35 | 0 | 0.00 | 309 | 15.24 | 717 |
| Total | 614 | 30.29 | 0 | 0.00 | 2 | 0.10 | 30 | 1.48 | 3 | 0.15 | 1378 | 67.98 | 2027 |
a Not ranked based on CDC recommendations.
b No specimens had the status HCV Not Determined.
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# Percent Agreement
The positive percent agreement and negative percent agreement between the ARCHITECT Anti-HCV assay result and HCV status, and their corresponding 95% confidence intervals were calculated for the overall population (increased risk and signs and symptoms) and for the increased risk population. The results are summarized in Table 10 below.
Table 10 ARCHITECT Anti-HCV Results versus HCV Status Overall Population (n=2027)
| ARCHITECT Anti-HCV Result | HCV Status | |
| --- | --- | --- |
| | HCV Infected | HCV Not Infected |
| Reactive | 614 | 30 |
| Equivocal | 0 | 3 |
| Nonreactive | 2 | 1378 |
| Total | 616 | 1411 |
The positive percent agreement between the ARCHITECT Anti-HCV assay results and the HCV Infected status for the overall population (n=2,027) was 99.68% (614/616) with a 95% confidence interval of 98.83% to 99.96%. Among the specimens with HCV Infected status, there were 0.00% (0/616) equivocal results by ARCHITECT Anti-HCV assay (95% confidence interval is 0.00% to 0.60%). The negative percent agreement between the ARCHITECT Anti-HCV assay results and the HCV Not Infected status for the overall population (n=2,027) was 97.66% (1,378/1,411) with a 95% confidence interval of 96.73% to 98.38%. Among the specimens with HCV Not Infected status, there were 0.21% (3/1,411) equivocal results by ARCHITECT Anti-HCV assay (95% confidence interval is 0.04% to 0.62%).
The positive percent agreement and negative percent agreement results for the increased risk population by hepatitis risk group are presented in Table 11 on page 28.
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Table 11 ARCHITECT Anti-HCV Results versus HCV Status Percent Agreement for Increased Risk Population
| Hepatitis C Ranked Risk Group | Positive Percent Agreement % (x/n)^{a} | 95% Confidence Interval | Negative Percent Agreement % (x/n)^{b} | 95% Confidence Interval |
| --- | --- | --- | --- | --- |
| Recipients of clotting factor concentrate prior to 1987 | 100.00 (1/1) | 2.50 - 100.00 | 100.00 (2/2) | 15.81 - 100.00 |
| Users of injecting drugs | 100.00 (97/97) | 96.27 - 100.00 | 91.40 (85/93) | 83.75 - 96.21 |
| Multiple sex partners | 98.15 (53/54) | 90.11 - 99.95 | 98.82 (587/594) | 97.59 - 99.52 |
| Transfusion recipient prior to July 1992 or received blood from donor later to be found HCV positive | 100.00 (18/18) | 81.47 - 100.00 | 91.67 (22/24) | 73.00 - 98.97 |
| Perinatal exposure; mother was infected with hepatitis C | NA (0/0) | NA | 100.00 (3/3) | 29.24 - 100.00 |
| Men who have sex with men | 100.00 (1/1) | 2.50 - 100.00 | 84.62 (11/13) | 54.55 - 98.08 |
| Needle stick or mucosal exposure on the job | 100.00 (13/13) | 75.29 - 100.00 | 98.05 (252/257) | 95.52 - 99.37 |
| Other^{a}: Household contact with hepatitis C infected individual and/or intranasal cocaine user | 100.00 (31/31) | 88.78 - 100.00 | 98.17 (107/109) | 93.53 - 99.78 |
| Total | 99.53 (214/215) | 97.44 - 99.99 | 97.63 (1069/1095) | 96.54 - 98.44 |
a Not ranked based on CDC recommendations.
b x = the number of reactive (or nonreactive) ARCHITECT Anti-HCV results that were generated with the HCV status as determined by comparator or supplemental testing;
n = the total number of HCV Infected status (or HCV Not Infected status) results as determined by comparator or supplemental testing.
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## Expected Results (Increased Risk Population)
Of the 2,027 specimens analyzed in the ARCHITECT Anti-HCV clinical investigation, a total of 1,310 (64.63%) specimens were from the individuals at increased risk of HCV infection. All subjects were at risk of HCV infection due to lifestyle, behavior, occupation, or known exposure event but were asymptomatic and reported no current signs or symptoms of hepatitis.
The 1,310 increased risk specimens were collected from specimen collection sites or were purchased from specimen vendors. The number and percent of specimens obtained from each collection site/vendor are listed in Table 12 below.
### Table 12 Number and Percent of Specimens by Specimen Collection Sites/Specimen Vendors for Increased Risk Population
| Collection Site/Vendor | Site/Location | Group (n) | Total (n) | Percent (%) |
| --- | --- | --- | --- | --- |
| Collection Site | | | | |
| Galveston, TX | 1 | 707 | 1310 | 53.97 |
| Dallas, TX | 2 | 64 | 1310 | 4.89 |
| Miami, FL | 3 | 56 | 1310 | 4.27 |
| St. Petersburg, FL | 4 | 56 | 1310 | 4.27 |
| Chicago, IL | 5 | 19 | 1310 | 1.45 |
| Denver, CO | 6 | 44 | 1310 | 3.36 |
| Collection Vendor | | | | |
| High Point, NC | 1 | 185 | 1310 | 14.12 |
| Colton, CA | 2 | 76 | 1310 | 5.80 |
| Plymouth, MA | 3 | 103 | 1310 | 7.86 |
A demographic summary of the increased risk population by race/ethnic group is provided in Table 13 on page 30.
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Table 13 Demographic Summary of Increased Risk Population by Race/Ethnic Group
| Race/Ethnic Group | Group (n) | Total (n) | Percent (%) |
| --- | --- | --- | --- |
| African American | 522 | 1310 | 39.85 |
| American Indian/Alaska Native | 9 | 1310 | 0.69 |
| Asian | 10 | 1310 | 0.76 |
| Caucasian | 589 | 1310 | 44.96 |
| Hispanic | 165 | 1310 | 12.60 |
| Other | 15 | 1310 | 1.15 |
Of the 1,310 increased risk subjects, 864 (65.95%) were female and 446 (34.05%) were male. The age was not reported for three subjects. Of the remaining 1,307 subjects, the mean age was 40 years (age range: 18 to 73 years).
The ARCHITECT Anti-HCV assay was reactive in 237 (18.09%) of the individuals in the increased risk population. The number and percent of ARCHITECT Anti-HCV reactive results obtained at each collection location are presented in Table 14 below. Testing of the specimens was performed at the three clinical testing sites located in Galveston, TX; Hershey, PA; and Milwaukee, WI.
Table 14 ARCHITECT Anti-HCV Percent Reactive Results by Collection Location for Increased Risk Population
| Collection Site/Vendor | Site/Location | Reactive (n) | Total (n) | Percent Reactive (%) |
| --- | --- | --- | --- | --- |
| Collection Site | | | | |
| Galveston, TX | 1 | 132 | 707 | 18.67 |
| Dallas, TX | 2 | 15 | 64 | 23.44 |
| Miami, FL | 3 | 10 | 56 | 17.86 |
| St. Petersburg, FL | 4 | 10 | 56 | 17.86 |
| Chicago, IL | 5 | 14 | 19 | 73.68 |
| Denver, CO | 6 | 13 | 44 | 29.55 |
| Collection Vendor | | | | |
| High Point, NC | 1 | 10 | 185 | 5.41 |
| Colton, CA | 2 | 1 | 76 | 1.32 |
| Plymouth, MA | 3 | 32 | 103 | 31.07 |
| Total | | 237 | 1310 | 18.09 |
The distribution of ARCHITECT Anti-HCV reactive, equivocal and nonreactive results by age range and gender is presented in Table 15 below.
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Table 15 ARCHITECT Anti-HCV Results by Age Range and Gender for Individuals at Increased Risk of HCV Infection
| Age Group (Years) | Gender | ARCHITECT Anti-HCV Result | | | Total |
| --- | --- | --- | --- | --- | --- |
| | | Reactive n (%) | Equivocal n (%) | Nonreactive n (%) | |
| 0 to 17 | Female | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 |
| | Male | 0 (0.00) | 0 (0.00) | 0 (0.00) | 0 |
| 18 to 29 | Female | 12 (5.58%) | 1 (0.47%) | 202 (93.95%) | 215 |
| | Male | 8 (8.99%) | 0 (0.00%) | 81 (91.01%) | 89 |
| 30 to 39 | Female | 15 (7.21) | 1 (0.48) | 192 (92.31) | 208 |
| | Male | 18 (18.56) | 1 (1.03) | 78 (80.41) | 97 |
| 40 to 49 | Female | 48 (18.25) | 0 (0.00) | 215 (81.75) | 263 |
| | Male | 55 (37.16) | 0 (0.00) | 93 (62.84) | 148 |
| 50 to 59 | Female | 26 (18.98) | 0 (0.00) | 111 (81.02) | 137 |
| | Male | 47 (51.09) | 0 (0.00) | 45 (48.91) | 92 |
| 60 to 69 | Female | 1 (3.03) | 0 (0.00) | 32 (96.97) | 33 |
| | Male | 4 (25.00) | 0 (0.00) | 12 (75.00) | 16 |
| 70 to 79 | Female | 1 (16.67) | 0 (0.00) | 5 (83.33) | 6 |
| | Male | 1 (33.33) | 0 (0.00) | 2 (66.67) | 3 |
| Total | | 236 (18.06) | 3 (0.23) | 1068 (81.71) | 1307^{a} |
a Age was not reported for three subjects.
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## XI. CONCLUSIONS DRAWN FROM THE STUDIES
The data from the nonclinical studies demonstrated acceptable precision, analytical specificity, seroconversion panel detection, and genotype detection of the ARCHITECT Anti-HCV assay when used according to the instructions for use as stated in the labeling, the warnings and precautions, and the Specimen Collection and Preparation for Analysis and Limitations sections of the labeling.
The clinical studies in this application indicate that the ARCHITECT Anti-HCV assay is safe and effective when used according to the directions for use in the labeling.
## RISK BENEFIT ANALYSIS
As a diagnostic test, the ARCHITECT Anti-HCV assay involves removal of blood from an individual for testing purposes. This test presents no more of a safety hazard to an individual than is presented to an individual who is having their blood drawn for any other diagnostic evaluation. The benefits to HCV-infected individuals tested by the assay outweigh any potential adverse event or risk to the patient or user due to assay malfunction or operator error.
The potential risks encountered with this *in vitro* diagnostic test are not unusual in the clinical laboratory setting. Appropriate warnings for these risks are contained in the labeling and package inserts for the device. Standard good laboratory practices are considered sufficient to mitigate the risks to the end user.
## SAFETY
Based on the results of the preclinical and clinical laboratory studies, the ARCHITECT Anti-HCV assay, when used according to the provided directions and in conjunction with other serological and clinical information, should be safe and effective and pose minimal risk to the patient due to false test results.
## EFFECTIVENESS
The effectiveness of the ARCHITECT Anti-HCV assay has been demonstrated for use in determining if antibodies to Hepatitis C virus are present in an individual’s serum or plasma. A reasonable determination of effectiveness of the ARCHITECT Anti-HCV assay for aiding in the status of HCV infection in suspected individuals has been demonstrated.
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## XII. PANEL RECOMMENDATIONS
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Microbiology Advisory Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.
## XIII. CDRH DECISION
FDA issued an approval order on June 7, 2006.
The applicant’s manufacturing facility was inspected on 5/8/06 (N. Chicago), 5/16/06 (Abbott Park), and 5/19/06 (Puerto Rico) and found to be in compliance with the Quality Systems Regulation (21 CFR 820).
## XIV. APPROVAL SPECIFICATIONS
Directions for use: See the labeling.
Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions and Adverse Events in the labeling.
Postapproval Requirements and Restrictions: See approval order.
