Predicate Devices

Not Found

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The description mentions "embedded calculation algorithms" for interpreting results from fluorescent signals, which is standard for RT-PCR analysis and does not indicate the use of AI or ML. There is no mention of AI, ML, or related terms like neural networks or deep learning.

Therapeutic

No.
The device is an in vitro diagnostic (IVD) test used to detect the presence of hepatitis C virus (HCV) RNA. It provides diagnostic information but does not actively treat or prevent a disease.

Diagnostic

Yes

The device qualitatively detects hepatitis C virus (HCV) RNA in human fingerstick K2-EDTA whole blood to diagnose active HCV infection in individuals at risk or with signs and symptoms of infection.

SaMD (Software as a Medical Device)

No

The device description clearly outlines hardware components including the GeneXpert IV instrument, GeneXpert Hub, single-use disposable GeneXpert cartridge, syringe drive, ultrasonic horn, and I-CORE thermocycler, in addition to the software.

IVD (In Vitro Diagnostic)

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 Xpert HCV test is an "automated in vitro reverse transcription polymerase chain reaction (RT-PCR) test for the qualitative detection of hepatitis C virus (HCV) RNA in human fingerstick K2-EDTA whole blood". The phrase "in vitro" is a key indicator of an IVD.
Device Description: The description details a system that analyzes a biological sample (human fingerstick whole blood) outside of the body to detect a specific analyte (HCV RNA). This is the core function of an IVD.
Sample Type: The test is performed on human fingerstick K2-EDTA whole blood, which is a biological specimen.
Purpose: The purpose is to detect the presence of HCV RNA, which is used to diagnose active HCV infection. This is a diagnostic purpose.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

The Xpert HCV test, performed on the GeneXpert Xpress System, is an automated in vitro reverse transcription polymerase chain reaction (RT-PCR) test for the qualitative detection of hepatitis C virus (HCV) RNA in human fingerstick K2-EDTA whole blood from adult individuals at risk and/or with signs and symptoms of HCV infection with or without antibody evidence of HCV infection. Detection of HCV RNA indicates that the virus is replicating and therefore is evidence of active infection. Detection of HCV RNA does not discriminate between acute and chronic states of infection.

The Xpert HCV test is not intended for monitoring patients undergoing treatment or for use in screening blood, plasma, or tissue donors.

Product codes (comma separated list FDA assigned to the subject device)

SBP

Device Description

The Xpert HCV test, is an automated qualitative in vitro reverse transcription polymerase chain reaction (RT-PCR) test. The Xpert HCV test is performed on the GeneXpert Xpress System. With this system an operator can run the test by performing four steps: 1) mix the specimen. 2) transfer the liquid sample to the cartridge with a transfer pipette, 3) run the test on the instrument, and 4) read the results.

The GeneXpert Xpress System (Hub configuration) consists of a GeneXpert IV instrument that conducts the sample preparation, nucleic acid amplification and real-time fluorescent signal detection for the test, and a GeneXpert Hub with preloaded GeneXpert Xpress software for running the tests and viewing the results. The GeneXpert Hub accessory integrates the computer, touchscreen monitor and barcode scanner. Each of the GeneXpert modules in the GeneXpert IV instrument can perform separate sample preparation and testing. The module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE (Intelligent Cooling/Heating Optical Reaction) thermocycler for performing real-time PCR and RT-PCR and detection.

The Xpert HCV test requires the use of a single-use disposable GeneXpert cartridge that contains all necessary reagents for the detection of HCV RNA. Because the cartridges are self-contained, the risk of cross-contamination between samples is minimized. The Xpert HCV test includes reagents for the detection of HCV RNA in clinical specimens as well as a sample processing control (SPC) and internal control high (IC-H) used to control for adequate processing of the target and to monitor the presence of inhibitor(s) in the RT and PCR reactions. The Probe Check Control (PCC) verifies reagent rehydration. PCR tube filling in the cartridge, probe integrity, and dye stability. The Sample Volume Adequacy (SVA) control ensures the sample was correctly added to the cartridge and verifies that the correct volume of sample has been added to the sample chamber.

The Xpert HCV test is designed for use with human K2-fingerstick EDTA whole blood. The BD Microtainer for capillary whole blood collection was validated for use with the Xpert HCV test. After collecting human fingerstick EDTA whole blood in the BD Microtainer, a 100μl aliquot of the specimen is transferred to the sample chamber of the Xpert HCV cartridge using the transfer pipette supplied in the Xpert HCV kit.

The sample results are interpreted by the GeneXpert Xpress System from measured fluorescent signals and embedded calculation algorithms and are shown in the View Results window. It also reports if the test has encountered an instrument error or produces no result and needs to be repeated.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Fingerstick K2-EDTA whole blood

Indicated Patient Age Range

Adult individuals greater than or equal to 22 years of age.

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

A prospective all-comers blinded clinical study was conducted at 15 CLIA waived sites from geographically diverse locations in the US with 32 untrained operators. Participants included individuals >= 22 years of age who were at risk and/or with signs and symptoms for HCV infection. A total of 1,012 fingerstick whole blood (FS) specimens were obtained from eligible participants for testing with the Xpert HCV test. In addition, serum specimens were tested on an FDA approved HCV RNA test and an FDA approved HCV antibody test to establish the patient infected status (PIS). Patient management continued at the site per the standard practice, independent of investigational test results.

Of the 1,012 eligible samples, 30 samples were excluded due to the following reasons: 1) protocol deviations (n=15); 2) unresolved ND results for Xpert HCV test (n=11); and 3) non-evaluable comparator test results (n=4). A total of 982 FS samples tested were included in the Xpert HCV test performance calculations.

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Prospective all-comers blinded clinical study.
Sample Size: 1,012 fingerstick whole blood specimens were obtained, with 982 evaluable specimens used for performance calculations.
The Xpert HCV test demonstrated positive percent agreement (PPA) and negative percent agreement (NPA) of 93.44% and 99.77%, respectively when compared to the PIS.
Initial non-determinate rate was 6.0% (61/1,012) and overall non-determinate rate was 1.2% (12/1,012).

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Positive Percent Agreement (PPA): 93.44%
Negative Percent Agreement (NPA): 99.77%

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.

Not Found

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.

Not Found

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

Regulation Number and Section

N/A

Summary

0

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 logo on the left and the FDA logo on the right. The FDA logo includes the letters "FDA" in a blue square, followed by the words "U.S. FOOD & DRUG ADMINISTRATION" in blue text.

EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR Xpert HCV; GeneXpert Xpress System DECISION SUMMARY

I Background Information:

A De Novo Number

DEN240016

B Applicant

Cepheid

C Proprietary and Established Names

Xpert HCV; GeneXpert Xpress System

D Regulatory Information

| Product
Code(s) | Classification | Regulation
Section | Panel |
|--------------------|----------------|-------------------------------------------------------------------------------------------------------------|-------------------|
| SBP | Class II | 21 CFR 866.3171 - Simple
point-of-care nucleic acid-
based hepatitis C virus
ribonucleic acid test | MI - Microbiology |

II Submission/Device Overview:

A Purpose for Submission:

De Novo request for evaluation of automatic class III designation for Xpert HCV test and GeneXpert Xpress System.

B Measurand:

Hepatitis C Virus RNA in human fingerstick whole blood.

C Type of Test:

Automated qualitative reverse transcription polymerase chain reaction (RT-PCR).

III Indications for Use:

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002

1

A Intended Use(s):

The Xpert HCV test, performed on the GeneXpert Xpress System, is an automated in vitro reverse transcription polymerase chain reaction (RT-PCR) test for the qualitative detection of hepatitis C virus (HCV) RNA in human fingerstick K2-EDTA whole blood from adult individuals at risk and/or with signs and symptoms of HCV infection with or without antibody evidence of HCV infection. Detection of HCV RNA indicates that the virus is replicating and therefore is evidence of active infection. Detection of HCV RNA does not discriminate between acute and chronic states of infection.

The Xpert HCV test is not intended for monitoring patients undergoing treatment or for use in screening blood, plasma, or tissue donors.

B Indication(s) for Use:

See Intended Use above.

C Special Conditions for Use Statement(s):

Rx - For Prescription Use Only

D Special Instrument Requirements:

GeneXpert Xpress System

IV Device/System Characteristics:

A Device Description:

The Xpert HCV test, is an automated qualitative in vitro reverse transcription polymerase chain reaction (RT-PCR) test. The Xpert HCV test is performed on the GeneXpert Xpress System. With this system an operator can run the test by performing four steps: 1) mix the specimen. 2) transfer the liquid sample to the cartridge with a transfer pipette, 3) run the test on the instrument, and 4) read the results.

The GeneXpert Xpress System (Hub configuration) consists of a GeneXpert IV instrument that conducts the sample preparation, nucleic acid amplification and real-time fluorescent signal detection for the test, and a GeneXpert Hub with preloaded GeneXpert Xpress software for running the tests and viewing the results. The GeneXpert Hub accessory integrates the computer, touchscreen monitor and barcode scanner. Each of the GeneXpert modules in the GeneXpert IV instrument can perform separate sample preparation and testing. The module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE (Intelligent Cooling/Heating Optical Reaction) thermocycler for performing real-time PCR and RT-PCR and detection.

The Xpert HCV test requires the use of a single-use disposable GeneXpert cartridge that contains all necessary reagents for the detection of HCV RNA. Because the cartridges are self-contained, the risk of cross-contamination between samples is minimized. The Xpert HCV test includes reagents for the detection of HCV RNA in clinical specimens as well as a sample processing

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control (SPC) and internal control high (IC-H) used to control for adequate processing of the target and to monitor the presence of inhibitor(s) in the RT and PCR reactions. The Probe Check Control (PCC) verifies reagent rehydration. PCR tube filling in the cartridge, probe integrity, and dye stability. The Sample Volume Adequacy (SVA) control ensures the sample was correctly added to the cartridge and verifies that the correct volume of sample has been added to the sample chamber.

The Xpert HCV test is designed for use with human K2-fingerstick EDTA whole blood. The BD Microtainer for capillary whole blood collection was validated for use with the Xpert HCV test. After collecting human fingerstick EDTA whole blood in the BD Microtainer, a 100μl aliquot of the specimen is transferred to the sample chamber of the Xpert HCV cartridge using the transfer pipette supplied in the Xpert HCV kit.

The sample results are interpreted by the GeneXpert Xpress System from measured fluorescent signals and embedded calculation algorithms and are shown in the View Results window. It also reports if the test has encountered an instrument error or produces no result and needs to be repeated.

Materials Provided in the Xpert HCV Test:

The Xpert HCV test Kit contains sufficient cartridges to process 10 patients or quality control samples. Each kit contains the following:

Xpert HCV cartridges with integrated reaction tubes	10 per kit
• Bead 1, Bead 2 and Bead 3 (freeze-dried)	1 of each per cartridge
• Lysis Reagent (Guanidinium Thiocyanate)	1.0 mL per cartridge
• Rinse Reagent	0.5 mL per cartridge
• Binding Reagent	1.5 mL per cartridge
• Elution Reagent	1.5 mL per cartridge
Disposable 100 µL Transfer Pipettes	20 per kit
Instructions for Use
(For use with the GeneXpert Xpress System)	1 per kit
Quick Reference Instructions
(For use with the GeneXpert Xpress System)	1 per kit
CD
• Assay Definition File (ADF)	1 per kit

Instructions to import ADF into GenXpert Xpress System

Material required but not provided with the kit:

GeneXpert Xpress System (catalog number: GXIV-2-CLIA or GXIV-4-CLIA): ● GeneXpert Hub with integrated computer running proprietary GeneXpert Xpress software version 6.4a or higher, touchscreen monitor and barcode scanner, external CD drive, Getting Started Guide, and GeneXpert Xpress System User's Guide.
High-flow lancet or equivalent (2 mm minimum depth, capable of yielding at least 250 ● uL of capillary whole blood). Please note that sample collection might be difficult in individuals with callused fingers, and a deeper lancet might be needed.
. EDTA-containing capillary collection tubes for small volumes (K2 EDTA microtainer BD part number: 365974).

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NAT troll Hepatitis C Virus Positive and Negative controls ●
Alcohol wipes ●
Gauze pad ●
Bandage ●
Warm pack

B Principle of Operation

The Xpert HCV test, performed on the GeneXpert Xpress System, is an automated qualitative in vitro reverse transcription polymerase chain reaction (RT-PCR) test for the detection of hepatitis C Virus (HCV) RNA in human K2-EDTA fingerstick whole blood. The Xpert HCV test singleuse disposable cartridge includes reagents for the detection of HCV RNA in clinical specimens as well as a sample processing control (SPC), internal control high (IC-H), the Probe Check Control (PCC), and the Sample Volume Adequacy (SVA). After collecting human K2-EDTA fingerstick whole blood in the BD Microtainer, a 100ul aliquot of the specimen is transferred to the sample chamber of the Xpert HCV cartridge using the transfer pipette supplied in the Xpert HCV kit. The cartridge is loaded onto the GeneXpert Xpress System platform. The instrument then performs automated sample processing followed by amplification, detection, and reporting of results. The Xpert HCV test uses three channels to detect target organism and two internal controls (SPC and IC-H). The results are interpreted automatically by the GeneXpert Xpress System from measured fluorescent signals and embedded calculation algorithms. The GeneXpert Xpress System displays results in the View Results window. It also reports if the test has encountered an instrument error or produces no result and needs to be repeated. Test results are obtained in approximately 56 minutes.

Result	Interpretation
HCV DETECTED	HCV RNA is detected
HCV NOT DETECTED	HCV RNA is not detected.
NO RESULT - REPEAT
TEST	If the result is NO RESULT - REPEAT TEST, then retest
with a new cartridge using a new transfer pipette.*
INSTRUMENT ERROR	Result is an instrument error. Touch CLEAR ERROR and
follow the on-screen instructions. When the Home screen
appears, repeat the test using a new cartridge and a new
transfer pipette.*

Table 1. Xpert HCV test Results and interpretation.

*Do not perform more than one retest of the sample

C Instrument Description Information

1. Instrument Name:

The Xpert HCV test is performed on the Gene Xpert Xpress System (Hub Configuration) with GeneXpert Xpress Software Version 6.4a or higher.

The GeneXpert Xpress System (Hub configuration) consists of a GeneXpert IV instrument with the capability of running 2 or 4 modules and a single-unit accessory called the GeneXpert Hub that integrates the computer, touchscreen monitor and barcode scanner. The

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GeneXpert Xpress System contains preloaded GeneXpert Xpress software for running the tests and viewing the results (executes the sample preparation, nucleic acid amplification, and real-time fluorescent signal detection for the test). Simple instructions (GeneXpert Xpress Getting Started Guide) are provided for attaching the Hub and the GeneXpert System. The system is capable of bi-directional connectivity (upload and download) with the Laboratory Information System (LIS).

The GeneXpert module is the basic functional operation unit common to all GeneXpert Systems including the GeneXpert Xpress System. Each GeneXpert module is identical and operates independently. Each module consists of a syringe pump drive for dispensing fluids, an ultrasonic horn for lysing cells or spores, a valve drive to rotate the cartridge valve body for sample movement across the different cartridge chambers, and a proprietary microprocessor controlled I-CORE (Intelligent Cooling/Heating Optical Reaction) thermocycler for performing real-time PCR amplification and fluorescence signal detection.

1. Specimen Identification:
  To perform a test, the user touches the 'NEW TEST' icon on the Home Screen. Either patient information must be entered if configured by an administrator or the Sample ID screen appears.
If the Patient Information screen appears, the operator manually enters the patient ID or scans the patient ID barcode for the patient's specimen.
If the Sample ID screen appears, the operator scans the sample ID barcode or manually enter the Sample ID for the patient specimen.

The user is then instructed to scan the cartridge barcode and confirm that the appropriate cartridge for the Xpert Xpress HCV test has been selected. The test cartridge is prepared and loaded into an available instrument module that has a flashing green light which initiates the test.

1. Specimen Sampling and Handling:
  The Xpert HCV test is designed for use with human K2- EDTA fingerstick whole blood. The BD Microtainer for capillary whole blood collection was validated for use with the Xpert HCV test. The fingerstick whole blood collection should follow the package insert provided in the BD Microtainer kit. In addition, the fingerstick whole blood collection instructions are also provided in the Xpert HCV package insert, and a fingerstick whole blood collection instruction video can be accessed by scanning the QR code provided in the Xpert HCV package insert and Quick Reference Instructions (QRI). This video must be viewed before collecting the first patient sample. The video should be viewed again if sample collection issues are experienced.
1. Calibration:
  Cepheid performs all necessary optical and thermal calibrations of the GeneXpert Xpress instrument at the time of manufacture, prior to customer installation; therefore, calibration of the instrument is not required during initial system startup. Cepheid recommends that the system be checked for proper calibration on an annual basis from the point of initial use. A

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GeneXpert operator or Cepheid Field Service Engineer with Administrator user permissions can perform calibration checks during annual maintenance.

5. Quality Control:

Internal controls:

Each test includes a Sample Volume Adequacy (SVA) control, sample processing control (SPC), an internal control high (IC-H), and a Probe Check Control (PCC).

· Sample Volume Adequacy (SVA) Ensures the sample was correctly added to the cartridge. The SVA verifies that the correct volume of sample has been added in the sample chamber. The SVA passes if it meets the validated acceptance criteria. If the SVA does not pass, NO RESULT-REPEAT TESTING will be displayed. The SVA error can be caused by cartridge-related error associated with insufficient sample volume. The system will prevent the test from being processed.
· Sample Processing Control (SPC) and Internal Control High (IC-H) The SPC and IC-H are two RNA controls unrelated to HCV that are included in each cartridge and go through the whole test process. They ensure that the sample was correctly processed and detect specimen-associated inhibition of the RT-PCR. The SPC and IC-H should PASS in a negative sample and be N/A in a positive sample. The SPC and IC-H pass if they meet the validated acceptance criteria. For SPC, the valid Ct range is 31.0 to 37.0. For IC-H, the valid Ct range is 20.0 to 26.0.
· Probe Check Control (PCC) Before the start of the PCR, the GeneXpert Xpress System measures the fluorescence signal from the probes to monitor bead rehydration, reaction tube filling, probe integrity and dye stability. The PCC passes if it meets the validated acceptance criteria.

External Controls:

Additionally, external positive and negative quality controls are available but not provided with the kit:

NAT troll Hepatitis C Virus Positive Control (ZeptoMetrix Corporation, NATHCV-● 6C-IVD).
NAT troll Hepatitis C Virus Negative Control (ZeptoMetrix Corporation, NATHCVNEG-6C-IVD).

V Standards/Guidance Documents Referenced:

Standards

CLSI EP05-A3. Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-Third Edition. CLSI document EP05-A3. Wayne, PA: Clinical and Laboratory Standards Institute; 2014.

CLSI EP07-3rd Ed. Interference Testing in Clinical Chemistry, 3rd Edition. CLSI guideline EP07. Wayne, PA. Clinical and Laboratory Standards Institute; 2018.

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CLSI EP09c- 3rd Ed. Measurement Procedure Comparison and Bias Estimation Using Patient Samples, 3rd Ed. CLSI guideline EP09c. Wayne, PA. Clinical and Laboratory Standards Institute: 2018.

CLSI EP12-A2. User Protocol for Evaluation of Qualitative Test Performance, Approved Guidance - Second edition. CLSI document EP12-A2. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.

CLAI EP 17-A2. Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures, Approved Guideline - 2nd Edition. CLSI document EP17-A2. Clinical and Laboratory Standards Institute; 2012.

CLSI EP25-A. Evaluation of Stability of In Vitro Medical Laboratory Test Reagents; Approved Guideline. CLSI document EP25-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2009.

CLSI MM03 3rd Ed. Molecular Diagnostic Methods for Infectious Diseases, 3rd Edition. CLSI document MM03. Clinical and Laboratory Standards Institute; 2015.

CLSI MM13 2nd Ed. Collection, Transport, Preparation, and Storage of Specimens for Molecular Methods, 2nd Edition. CLSI guideline MM13. Clinical and Laboratory Standards Institute; 2020.

ISO 14971:2019-12. Medical Devices - Application of Risk Management to Medical Devices. Third Edition.

ISO 13485:2016. Medical devices - Quality management systems - Requirements for regulatory purposes.

ANSI AAMI IEC 62304:2006/A1:2016: Medical device software - Software life cycle processes.

IEC 60601-1-2. Edition 4.1 2020-09. Medical electrical equipment - Part 1-2: General requirements for basic safety and essential performance - Collateral Standard: Electromagnetic disturbances - Requirements and tests.

IEC 61326-1, Edition 3.0 2020-10. Electrical equipment for measurement, control and laboratory use - EMC requirements - Part 1: General requirements.

IEC 61326-2-6, Edition 3.0 2020-10. Electrical equipment for measurement, control and laboratory use - EMC requirements - Part 2-6: Particular requirements - In vitro diagnostic (IVD) medical equipment.

Guidance documents

Acceptance Review for De Novo Classification Requests: Guidance for Industry and Food and Drug Administration Staff, issued October 5, 2021.

De Novo Classification Process (Evaluation of Automatic Class III Designation): Guidance for Industry and Food and Drug Administration Staff, issued October 5, 2021.

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Consideration of Uncertainty in Making Benefit-Risk Determinations in Medical Device Premarket Approvals, De Novo Classifications, and Humanitarian Device Exemptions: Guidance for Industry and Food and Drug Administration Staff, issued August 30, 2019.

Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications: Guidance for Industry and Food and Drug Administration Staff, issued August 30, 2019.

eCopy Program for Medical Device Submissions: Guidance for Industry and Food and Drug Administration Staff, issued April 27, 2020.

Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices: Guidance for Industry and Food and Drug Administration Staff, issued September 14, 2018.

Off-The-Shelf Software Use in Medical Devices: Guidance for Industry and Food and Drug Administration Staff, issued August 11, 2023.

Content of Premarket Submissions for Device Software Functions: Guidance for Industry and Food and Drug Administration Staff, issued June 14, 2023.

General Principles of Software Validation: Guidance for Industry and FDA Staff, issued January 11,2002.

Cybersecurity in Medical Devices: Quality System Considerations and Content of Premarket Submissions: Guidance for Industry and Food and Drug Administration Staff, issued on September 27, 2023.

Cybersecurity for Networked Medical Devices Containing Off-the-Shelf (OTS) Software: Guidance for Industry, issued January 14, 2005.

Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable: Guidance for Sponsors, Institutional Review Boards, and Food and Drug Administration Staff, issued April 25, 2006.

Electromagnetic Compatibility (EMC) of Medical Devices: Guidance for Industry and Food and Drug Administration Staff, issued June 6, 2022.

Performance Characteristics: VI

A Analytical Performance:

1. Precision/Reproducibility:

Precision Study: The lot-to-lot variability of the Xpert HCV test was established through a single site, blinded, and randomized precision study using three lots of the Xpert HCV cartridges. The study tested three clinical HCV strains from Genotype (GT) 1a, GT2b, and

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GT3a and external controls (one positive and one negative). Three analyte levels were tested for each genotype: negative, ~1.5x LoD, and ~3.0x LoD. The study was conducted with two trained operators, during 5 independent days of testing, with two runs per day (1 run per operator per day), and two replicates per sample per run, using one GeneXpert Xpress System (four module system) with the Hub configuration (GeneXpert Xpress software version 6.4a or higher). The total number of replicates per sample tested was 60. Table 2 summarizes the percent correct for each panel level and 95% CI using the Wilson score method.

Panel Member	% Agreementa	95% CI
Negative	100% (60/60)	94.0% - 100%
GT1a 1.5 x LoD	100% (60/60)	94.0% - 100%
GT1a 3.0 x LoD	100% (60/60)	94.0% - 100%
GT2b 1.5 x LoD	95.0% (57/60)	86.3% - 98.3%
GT2b 3.0 x LoD	100% (60/60)	94.0% - 100%
GT3a 1.5 x LoD	100% (59/59)b	93.9% - 100%
GT3a 3.0 x LoD	100% (60/60)	94.0% - 100%

Table 2. Summary of Precision Percent Agreement Results for the Xpert HCV test.

4Number of Replicates with Expected Results / Number of Valid Replicates. All replicates provided valid results.

bone (1) samples yielded non-determinate results on initial and retesting.

The precision of the Xpert HCV test was also evaluated in terms of the fluorescence signal expressed in Ct values for each target detected. The mean, standard deviation (SD) and coefficient of variation (CV) are provided for each covariate: within-run (repeatability), between-run, between-days, between-lots, and total precision for each panel member are presented in Table 3.

Table 3. Summary of Ct Variance Components Observed in the Precision Study.

| Target and Level | Analyte of
Ct Values | Na | Mean Ct | Repeatability
(Within run) | | Between Runs | | Between Days | | Between Lots | | Total Variance
(Within-Laboratory) | |
|------------------|-------------------------|----|---------|-------------------------------|--------|--------------|--------|--------------|--------|--------------|--------|---------------------------------------|--------|
| | | | | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) |
| Negative | SPC | 60 | 35.09 | 0.43 | 1.23 | 0.00 | 0.00 | 0.22 | 0.64 | 0.35 | 0.99 | 0.60 | 1.70 |
| GT1a 1.5 x LoD | HCV | 60 | 38.43 | 0.91 | 2.36 | 0.25 | 0.64 | 0.00 | 0.00 | 0.35 | 0.92 | 1.00 | 2.61 |
| GT1a 3.0 x LoD | HCV | 60 | 37.89 | 0.71 | 1.87 | 0.22 | 0.58 | 0.35 | 0.93 | 0.29 | 0.76 | 0.87 | 2.30 |
| GT2b 1.5 x LoD | HCV | 57 | 39.77 | 1.20 | 3.02 | 0.00 | 0.00 | 0.35 | 0.88 | 0.52 | 1.30 | 1.35 | 3.40 |
| GT2b) 3.0 x LoD | HCV | 60 | 38.44 | 0.70 | 1.82 | 0.47 | 1.23 | 0.00 | 0.00 | 0.16 | 0.41 | 0.86 | 2.23 |
| GT3a 1.5 x LoD | HCV | 59 | 38.43 | 0.87 | 2.27 | 0.00 | 0.00 | 0.14 | 0.36 | 0.43 | 1.13 | 0.99 | 2.56 |
| GT3a 3.0 x LoD | HCV | 60 | 37.27 | 0.53 | 1.41 | 0.00 | 0.00 | 0.22 | 0.59 | 0.00 | 0.00 | 0.57 | 1.53 |

ªN is the total number of non-zero Ct values bCV (%) = SD/Mean Ct * 100

Multi-Site Reproducibility Study: The reproducibility of the Xpert HCV test was established through a multicenter (3 CLIA-Waived sites), blinded and randomized study, using a single reagent lot of the Xpert HCV cartridges. The study tested three clinical HCV strains from

9

Genotype (GT) 1a, GT2b, and GT3a and external controls (one positive and one negative). Three analyte levels were tested for each genotype: negative, ~ 1.5x LoD, and ~3.0x LoD. The study was conducted with three untrained operators per site, during 5 independent days of testing, with one run per day (1 run per operator per day), and two replicates per sample per run, using one GeneXpert Xpress System (four module system) with the Hub configuration (GeneXpert Xpress software version 6.4a or higher). The total number of replicates per sample tested was 90. Table 4 summarizes the percent correct for each panel level, and 95% CI using the Wilson score method.

| Target and
Level | Site 1 | | | | Site 2 | | | | Site 3 | | | | Agreement by
Target |
|---------------------|--------|-------|-------|---------------|--------|-------|-------|---------------|--------|-------|-------|---------------|--------------------------|
| | Op1 | Op2 | Op3 | Site
Total | Op1 | Op2 | Op3 | Site
Total | Op1 | Op2 | Op3 | Site
Total | (%; 95%CI) |
| Negative | 100% | 100% | 90% | 96.7% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 98.9%
(94.0% - 99.8%) |
| | 10/10 | 10/10 | 9/10 | 29/30 | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 89/90 |
| GT1a 1.5 x LoD | 100% | 90% | 100% | 96.7% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 98.9%
(94.0% - 99.8%) |
| | 10/10 | 9/10 | 10/10 | 29/30 | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 89/90 |
| GT1a 3.0 x LoD | 100% | 100% | 90% | 96.7% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 98.9%
(94.0% - 99.8%) |
| | 10/10 | 10/10 | 9/10 | 29/30 | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 89/90 |
| GT2b 1.5 x LoD | 100% | 90% | 100% | 96.7% | 100% | 90% | 100% | 96.7% | 100% | 90% | 100% | 96.7% | 96.7%
(90.7% - 98.9%) |
| | 10/10 | 9/10 | 10/10 | 29/30 | 10/10 | 9/10 | 10/10 | 29/30 | 10/10 | 9/10 | 10/10 | 29/30 | 87/90 |
| GT2b 3.0 x LoD | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100%
(95.9% - 100%) |
| | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 90/90 |
| GT3a 1.5 x LoD | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100%
(95.9% - 100%) |
| | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 90/90 |
| GT3a 3.0 x LoD | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100% | 100%
(95.9% - 100%) |
| | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 10/10 | 10/10 | 10/10 | 30/30 | 90/90 |

Table 4. Summary of Reproducibility Percent Agreement Results for the Xpert HCV test

The reproducibility of the Xpert HCV test was also evaluated in terms of the fluorescence signal expressed in Ct values for each target detected. The mean, standard deviation (SD), and coefficient of variation (CV) are provided for each covariate: within-run (repeatability), between-operators, between-days, between-sites, and total reproducibility for each panel member are presented in Table 5.

Table 5. Summary of Ct Variance Components Observed in the Reproducibility Study.

Target and Level	Analyte of Ct Values	Na	Mean Ct	Repeatability (Within Run)		Between Days		Between Operators		Between Sites		Reproducibility
				SD	CV (%)b	SD	CV (%)	SD	CV (%)	SD	CV (%)	SD	CV (%)
Negative	SPC	90	35.05	0.44	1.25	0.00	0.00	0.27	0.76	0.00	0.00	0.51	1.46
GT1a 1.5x LoD	HCV	89	38.42	0.90	2.33	0.00	0.00	0.36	0.95	0.00	0.00	0.97	2.52
GT1a 3.0x LoD	HCV	89	37.63	0.68	1.82	0.00	0.00	0.28	0.74	0.00	0.00	0.74	1.96
GT2b 1.5x LoD	HCV	87	39.53	0.91	2.31	0.45	1.14	0.00	0.00	0.43	1.08	1.10	2.79
GT2b 3.0x LoD	HCV	90	38.43	0.73	1.90	0.08	0.20	0.06	0.17	0.22	0.57	0.77	2.00
GT3a 1.5x LoD	HCV	90	38.18	0.82	2.15	0.20	0.52	0.25	0.67	0.00	0.00	0.88	2.31

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GT3a 3.0x LoD	HCV	90	37.14	0.74	1.99	0.00	0.00	0.22	0.58	0.00	0.00	0.77	2.07
---------------	-----	----	-------	------	------	------	------	------	------	------	------	------	------

aN is the total number of non-zero Ct values

The Xpert HCV test demonstrated acceptable reproducibility across sites, operators, and panel members when testing was performed in a CLIA-waived environment.

1. Linearity:
  Not Applicable.1
1. Analytical Specificity/Interference:
  Analytical Specificity: The analytical specificity of the Xpert HCV test was evaluated by testing a panel of 27 organisms that can be encountered in samples drawn for HCV testing. These organisms were tested at a concentration of 100,000 CFU/mL, copies/mL, or TCID50/mL as applicable. Each organism in the panel was tested in the presence (3-time Limit of Detection (LoD)) and absence of HCV RNA in replicates of 6. Positive and Negative HCV controls tested in replicates of 6 were also included in the study. The study was completed using a single kit lot.

None of the organisms tested in this study (Table 6) showed cross reactivity with the HCV detection using the Xpert HCV test in HCV-positive and HCV-negative samples.

Virus	Bacteria	Fungus
Human Immunodeficiency virus 1 (HIV-1)	Staphylococcus aureus	Candida albicans
Human Immunodeficiency virus 2 (HIV-2)	Streptococcus epidermidis
Human T-cell Lymphotropic virus Type 1
(HTLV-I)

Human T-cell Lymphotropic virus Type 2
(HTLV-II)

Dengue Virus
West Nile Virus
Zika Virus
Banzi Virus
Ilheus Virus
Yellow Fever Virus
Cytomegalovirus
Epstein-Barr Virus (EBV)
Hepatitis A Virus (HAV)
Hepatitis B virus (HBV)
Herpes simplex Virus 1 (HSV-1)
Herpes simplex Virus 2 (HSV-2)
Herpes simplex Virus 6 (HHV-6)
Herpes simplex Virus 8 (HHV-8)
Varicella Zoster Virus (VZV)
BK Human Polyoma Virus

Table 6. List of organisms tested in the analytical specificity study.

1 Linearity study is not applicable to Xpert HCV test because the device is qualitative. Special control (b) (5) (i) applies to quantitative devices only.

11

Human papilloma Virus 16 (HPV-16)
Human papilloma Virus 18 (HPV-18)
St. Louis Encephalitis Virus
Vaccinia Virus

Interference Study: The Xpert HCV test was evaluated for interference in the presence of elevated levels of endogenous and exogenous substances commonly found in fingerstick whole blood specimens from individuals in the intended use population. Endogenous substances, exogenous substances, and autoimmune disease specimens were tested in the presence (300 IU/mL) and absence of HCV RNA. Each endogenous and exogenous substance was tested in replicates of six, and the autoimmune disease specimens in replicates of three. Two controls without any endogenous substance consisting of HCV negative EDTA venous whole blood and HCV negative EDTA venous whole blood spiked with HCV to 300 IU/ml was included and tested in replicates of six. This study was conducted using one kit lot.

None of the substances and autoimmune conditions tested in this study interfere with the Xpert HCV test at the concentrations listed in the tables below.

| Endogenous Substance | Concentration for
Testing |
|----------------------|------------------------------|
| Albumin | 9 g/dL |
| Bilirubin | 20 mg/dL |
| Hemoglobin | 500 mg/dL |
| Human DNA | 0.4 mg/dL |
| Triglycerides | 3,000 mg/dL |

Table 7. Endogenous interferents evaluated with the Xpert HCV test.

	Table 8. Exogenous interferent pools evaluated with the Xpert HCV test.
--	-------------------------------------------------------------------------	--

| Drug Pool | Generic Name | Concentration for
Testing (3xCmax) | Tested as*: |
|-----------|-----------------------|---------------------------------------|-------------|
| Pool 1 | Zidovudine | 6.00 µg/ml | Drug |
| | Abacavir sulfate | 11.67 µg/ml | Drug |
| | Saquinavir | 0.59 µg/ml | Drug |
| | Ritonavir | 44.40 µg/ml | Drug |
| | Interferon 2b | 819.00 IU/ml | Drug |
| Pool 1 | Ombitasvir | 0.20 µg/ml | API |
| | Paritaprevir | 0.79 µg/ml | API |
| | Dasabuvir | 2.00 µg/ml | API |
| | Fosamprenavir | 17.16 µg/ml | Drug |
| Pool 2 | Peginterferon alfa-2a | 0.08 µg/ml | Drug |
| | Peginterferon alfa-2b | 0.00032 µg/ml | Drug |
| | Ribavirin | 10.70 µg/ml | Drug |
| | Ledipsavir | 0.97 µg/ml | API |
| | Sofosbuvir | 1.85 µg/ml | API |
| | Daclatasvir | 4.60 µg/ml | API |
| | Simeprevir | 5.81 µg/ml | API |

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| Pool 3 | Tenofovir disoproxil
fumarate | 1.17 µg/ml | Drug |
|--------|----------------------------------|----------------|------|
| | Lamivudine | 6.00 µg/ml | Drug |
| | Indinavir sulfate | 35.57 µg/ml | Drug |
| | Ganciclovir | 31.20 µg/ml | Drug |
| | Acyclovir | 68.70 µg/ml | Drug |
| | Valganciclovir HCl | 34.44 µg/ml | Drug |
| Pool 4 | Stavudine | 2.05 µg/ml | Drug |
| | Efavirenz | 15.72 µg/ml | Drug |
| | Lopinavir | 40.50 µg/ml | Drug |
| | Enfuvirtide | 18.27 µg/ml | Drug |
| | Ciprofloxacin | 4.77 µg/ml | API |
| | Clarithromycin | 5.10 µg/ml | Drug |
| Pool 5 | Maraviroc | 1.00 µg/ml | Drug |
| | Nevirapine | 7.20 µg/ml | Drug |
| | Nelfinavir | 14100.00 µg/ml | API |
| | Azithromycin | 2.10 µg/ml | Drug |
| | Valacyclovir | 24.06 µg/ml | Drug |

*API: Active Pharmaceutical Ingredient

Table 9. Autoimmune disease samples evaluated with the Xpert HCV test.

Condition	Number of Specimens
SLE / ANA positive	7
SLE /ANA negative	2
SLE / ANA unknown	3
RA / RF positive	8

SLE: Systemic Lupus Erythematosus, ANA: Anti-Nuclear Antibodies RA: Rheumatoid Arthritis, RF: Rheumatoid Factor

4. Assay Reportable Range:

Not applicable

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):

Fingerstick Whole Blood specimen stability: The stability of hepatitis C virus genotype 1a in fingerstick whole blood (FS) was evaluated after storage at 2°C and 30°C for up to five hours. Freshly drawn FS collected from 6 individuals were included in the study. Individuals providing the FS were confirmed HCV-negative using cobas HCV assay. Each individual provided three 250 – 500 µl samples of FS in K2 EDTA microtainer tubes. FS samples from five individual were spiked at a final concentration of 3x LoD with contrived HCV-positive venous whole blood (VWB) samples. FS samples from one individual were spiked with HCV-negative VWB to generate HCV-negative samples.

Samples were stored at 2℃ or 30℃ and tested in singlicate at baseline (T=0 hours), 2 hours, 4 hours, and 5 hours. For each sample at each timepoint, test results were reported as HCV DETECTED and HCV NOT DETECTED.

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The study results support the stability of FS stored for up to 4 hours at 2ºC and 30ºC.

External Controls: the external positive and negative controls are available but not provided with the Xpert HCV test. The external controls for use with the Xpert HCV test include:

NAT troll Hepatitis C Virus Positive Control (ZeptoMetrix Corporation, NATHCV-● 6C-IVD).
NAT troll Hepatitis C Virus Negative Control (ZeptoMetrix Corporation, ● NATHCVNEG-6C-IVD).

The instruction for use recommends that external controls be tested at the frequency noted below:

Each time a new lot of Xpert HCV kits is received. ●
Each time a new shipment of Xpert HCV kits is received even if it is the same lot ● previously received.
. Each time a new operator is performing the test (i.e., operator who has not performed the test recently).
When problems (storage, operator, instrument, or other) are suspected or identified. ●
If otherwise required by your institution's standard Quality Control (OC) procedures.
1. Detection Limit:

The LoD of the Xpert HCV test was determined by testing dilutions of hepatitis C virus RNA for genotypes 1a, 1b, 2b, 3a, 4, 5 and 6 in HCV negative human K2-EDTA fingerstick whole blood. Each panel was tested following the package insert. Probit analysis was used to determine the LoD. Table 10 below summarizes the LoD for each genotype in fingerstick whole blood.

Table 10. Summary of Xpert HCV LoD for genotypes 1a, 1b, 2b, 3a, 4, 5, and 6 in Fingerstick Whole Blood.

| Genotype | Fingerstick whole blood
LoD (IU/mL) | 95% Confidence Interval
(IU/mL) |
|----------|----------------------------------------|------------------------------------|
| 1a | 35.0 | (22.3 - 54.9) |
| 1b | 41.5 | (29.8 - 57.9) |
| 2b | 89.2 | (47.7 - 166.8) |
| 3a | 58.2 | (39.0 - 86.7) |
| 4 | 32.2 | (21.1 - 49.1) |
| 5 | 136.4 | (83.2 - 223.4) |
| 6 | 83.8 | (57.2 - 122.8) |

7. Assay Cut-Off:

Not Applicable

1. Accuracy (Instrument):
  Not Applicable

9. Carry-Over:

14

Not Applicable

B Comparison Studies:

1. Method Comparison:
  Not Applicable
1. Matrix Comparison:
  Not applicable

C Clinical Studies:

1. Clinical Sensitivity:
  Not Applicable
1. Clinical Specificity:
  Not Applicable

3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):

Prospective all-comers blinded clinical study was conducted to evaluate the performance of the Xpert HCV test. The study was conducted at 15 CLIA waived sites from geographically diverse locations in the US with 32 untrained operators. Participants included individuals ≥ 22 years of age who were at risk and/or with signs and symptoms for HCV infection. A total of 1,012 fingerstick whole blood (FS) specimens were obtained from eligible participants for testing with the Xpert HCV test. In addition, serum specimens were tested on an FDA approved HCV RNA test and an FDA approved HCV antibody test to establish the patient infected status (PIS). Patient management continued at the site per the standard practice, independent of investigational test results.

Table 11 below summarizes the total number of participants by risk factor. Available demographic data collected from study participants are presented Table 12.

Risk Factora	n/N (%)
Intravenous drug use	422 / 1012 (41.7%)
Persons who are HIV-positive	148 / 1012 (14.6%)
Blood transfusion or organ transplant received prior to 1992	12 / 1012 (1.2%)
Blood clotting factor for hemophilia received prior to 1987	1 / 1012 (0.1%)
Born between 1945 and 1965	406 / 1012 (40.1%)
Born to an HCV-infected mother	5 / 1012 (0.5%)

Table 11. Categorization of Risk Factors for the Eligible Participants

15

Chronic hemodialysis patients	3 / 1012 (0.3%)
Persons who engage in high-risk sexual behavior	111 / 1012 (11.0%)
Persons with known exposure to HCV, such as Healthcare workers after needle sticks involving HCV-positive blood and Recipients of blood or organs from a donor who tested HCV-positive	53 / 1012 (5.2%)

4 Participants may have reported multiple risk factors.

| Demographic Characteristics | Overall
(N=1012) | |
|----------------------------------------|--------------------------------------------------------|----------------------------|
| Age | >=22 years old 60 | 646 (63.8%)
366 (36.2%) |
| Gender | Male
Female | 544 (53.8%)
468 (46.2%) |
| Racea | Black/African American | 369 (36.5%) |
| | White | 521 (51.5%) |
| | Asian | 10 (1.0%) |
| | Otherb | 93 (9.2%) |
| | Unknown/Prefer not to answer
Missing | 18 (1.8%)
1 (0.1%) |
| Ethnicity | Hispanic Latino | 130 (12.8%) |
| | Not Hispanic Latino | 862 (85.2%) |
| | Unknown/Prefer not to answer
Not Available /Missing | 16 (1.6%)
4 (0.4%) |
| History of HCV infection | Yes | 293 (29.0%) |
| | No | 717 (70.8%) |
| | Missing | 2 (0.2%) |
| Recent HCV antibody test | Yes | 544 (53.8%) |
| | NA | 158 (15.6%) |
| | Never had an HCV antibody test
Missing | 308 (30.4%)
2 (0.2%) |
| Results of recent HCV antibody
test | Reactive | 164 (16.2%) |
| | Not Reactive | 376 (37.2%) |
| | Invalid | 3 (0.3%) |
| | No Resultc | 469 (46.3%) |
| Recent HCV NAAT test | Yes | 204 (20.2%) |
| | Not Available | 196 (19.4%) |
| | Never had an HCV NAAT test
Missing | 611 (60.4%)
1 (0.1%) |
| Result of recent HCV NAAT
Test | Positive | 34 (3.4%) |
| | Negative | 170 (16.8%) |
| | No Resultd | 808 (79.8%) |
| | Yes | 46 (4.5%) |
| HCV Genotype Test | NA | 246 (24.3%) |
| | Never had a HCV genotyping test
Missing | 719 (71.0%)
1 (0.1%) |
| | Genotype Result | 1a
1b |

Table 12. Demographic Data Summary of Participants

16

| Demographic Characteristics | Overall
(N=1012) |
|---------------------------------------------|---------------------|
| 1c | 2 (0.2%) |
| 2b | 2 (0.2%) |
| 3a | 5 (0.5%) |
| No Resulte | 967 (95.6%) |
| Treatment History
Not currently treated | 175 (17.3%) |
| Treatment History
Never been treated | 836 (82.6%) |
| Treatment History
Missing | 1 (0.1%) |
| Symptomatic
Yes | 373 (36.9%) |
| Symptomatic
No | 639 (63.1%) |
| At risk
Yes | 934 (92.3%) |
| At risk
No | 78 (7.7%) |
| Symptomatic and at risk
Yes | 295 (29.2%) |
| Symptomatic and at risk
No | 717 (70.8%) |
| History of injection drug use
Yes | 437 (43.2%) |
| History of injection drug use
No | 575 (56.8%) |
| History of Non-HCV liver
disease Yes | 68 (6.7%) |
| History of Non-HCV liver
disease No | 943 (93.2%) |
| History of Non-HCV liver
disease Missing | 1 (0.1%) |
| HIV Status Positive | 154 (15.2%) |
| HIV Status Negative | 799 (79.0%) |
| HIV Status Unknown (Never tested) | 59 (5.8%) |
| HBV Status Positive | 16 (1.6%) |
| HBV Status Negative | 684 (67.6%) |
| HBV Status Unknown (Never tested) | 311 (30.7%) |
| HBV Status Missing | 1 (0.1%) |

a If more than one race is reported for a participant, they are only captured in one category.

b Other race group includes "American-Indian or Alaskan Native", "More than one race", "Native Hawaiian or Pacific Islander" and "Other"

& Combined category of "Not Available", "Never had a HCV Antibody Test" and "Missing"

d A combined category of "Not Available", "Never had a HCV NAAT Test" and "Missing"

e A combined category of "Not Available", Never had a HCV Genotyping Test" and "Missing"

Of the 1,012 eligible samples, 30 samples were excluded due to the following reasons: 1) protocol deviations (n=15); 2) unresolved ND results for Xpert HCV test (n=11); and 3) nonevaluable comparator test results (n=4). A total of 982 FS samples tested were included in the Xpert HCV test performance calculations. Table 13 summarizes the Xpert HCV test results by patient infected status (PIS).

| HCV Ab | HCV RNA
NAAT | Patient Infection
status | Xpert HCV | N |
|----------|-----------------|-----------------------------|---------------------|-----|
| Reactive | Reactive | Active chronic
infection | HCV
DETECTED | 111 |
| | | | HCV NOT
DETECTED | 6 |
| | Non-reactive | Past/resolved
infection | HCV
DETECTED | 1 |
| | | | HCV NOT
DETECTED | 223 |

Table 13. Summary of samples by infected status (PIS)

17

| Non-reactive | Reactive | Active acute
infection | HCV
DETECTED | 3 |
|--------------|--------------|---------------------------|---------------------|-----|
| | | | HCV NOT
DETECTED | 2 |
| | Non-reactive | Not infected | HCV
DETECTED | 1 |
| | | | HCV
DETECTED | 635 |

The Xpert HCV test performance was compared to a patient infected status (PIS) algorithm based on results from an FDA approved HCV RNA test and an antibody test. Table 14 below summarize the Xpert HCV test performance. The Xpert HCV test demonstrated positive percent agreement (PPA) and negative percent agreement (NPA) of 93.44% and 99.77%, respectively when compared to the PIS.

		Patient Infection Status
		HCV Positivea	HCV Negativeb	Total
Xpert
HCV
test	HCV detected	114	2	116
	HCV not
detected	8	858	866
	Total	122	860	982
	PPA*	93.44%; 95% CI (87.59% – 96.64%)
	NPA*	99.77%; 95% CI (99.16% – 99.94%)

Table 14. Xpert HCV test result according to PIS

ª Active chronic or acute infection.

b Past/resolved infection or not infected.

Two (2) specimens (1 false positive and 1 false negative) with suspicion of specimen handling and testing errors were retested along with 110 additional serum specimens on the HCV RNA NAAT comparator test (15 positive and 95 negative). Retesting confirmed the specimen handling and testing error at the reference laboratory.

4. Non-Determinate Rate

Of the 1,012 Xpert HCV runs performed in the clinical study, 61 resulted in non-determinate ("INSTRUMENT ERROR" or "NO RESULT - REPEAT TEST") results on first attempt. Upon retest of these 61 specimens, 12 remained non-determinate. The initial nondeterminate rate was 6.0 % (61/1,012) and the overall non-determinate rate was 1.2 % (12/1,012).

5. Testing non-viral hepatitis samples

FS samples from individuals with other liver diseases (where active HCV infection was not indicated as the underlying cause) were collected during the clinical study. Samples were tested with an FDA-approved anti-HCV test and an FDA-approved HCV molecular test to confirm the samples were HCV negative. Seventy-eight (78) samples from individuals with non-viral hepatitis were included in the study.

The table below shows subject demographics and liver disease status for the 78 evaluable subjects.

18

Table 15: Non-viral Hepatitis Disease Group Clinical Performance by Disease

| Non-viral
Liver Diseasea | N of Xpert Test
by Disease
Occurrence | N of Xpert
Test
Compared
to PISb | TP | FN | TN | FP | PPA with 95% CI (%) | NPA with 95% CI
(%) |
|----------------------------------------------------------------------------------|---------------------------------------------|-------------------------------------------|----|----|----|----|----------------------------------|----------------------------------|
| Metabolic
Dysfunction-
Associated
Steatotic Liver
Disease
(MASLD) | 28 | 24 | 1 | 0 | 23 | 0 | 100.0%
(95% CI: 20.7 - 100.0) | 100.0%
(95% CI: 85.7- 100.0) |
| NASH | 2 | 1 | 0 | 0 | 1 | 0 | N/A | 100.0%
(95% CI: 20.7 - 100.0) |
| Primary biliary
cirrhosis | 15 | 13 | 2 | 0 | 11 | 0 | 100.0%
(95% CI: 34.2 - 100.0) | 100.0%
(95% CI: 74.1 - 100.0) |
| Chronic HBV | 3 | 2 | 0 | 0 | 2 | 0 | N/A | 100.0%
(95% CI: 34.2 - 100.0) |
| Alcoholic liver
disease | 11 | 10 | 0 | 0 | 10 | 0 | N/A | 100.0%
(95% CI: 72.2 - 100.0) |
| Autoimmune
hepatitis | 3 | 3 | 0 | 0 | 3 | 0 | N/A | 100.0%
(95% CI: 43.9 - 100.0) |
| Other | 16 | 15 | 1 | 0 | 14 | 0 | 100.0%
(95% CI: 20.7 - 100.0) | 100.0%
(95% CI: 78.5 - 100.0) |
| Total | 78 | 68 | 4 | 0 | 64 | 0 | 100.0%
(95% CI: 51.0 - 100.0) | 100.0%
(95% CI: 94.3 - 100.0) |

ª Patients may have multiple non-viral liver diseases

b With both valid Xpert test result and valid PIS results

D Clinical Cut-Off:

Not Applicable

Expected Values/Reference Range: E

Not Applicable

Other Supportive Performance Characteristics Data: F

Not Applicable

Proposed Labeling: VII

The labeling supports the decision to grant the De Novo request for this device.

Identified Risks and Mitigations: VIII

19

Identified Risks to Health	Mitigation Measures
Risks of false test results	Certain labeling information, including
limitations, device descriptions, explanation
of procedures, and results interpretation
information.
	Certain design verification and validation
information, certain analytical studies and
clinical studies, risk analysis strategies, lot
release criteria, flex studies, and stability
studies.
Failure to correctly interpret the results	Certain labeling information, including
limitations, device descriptions, explanation
of procedures, and results interpretation
information.
	Certain design verification and validation
information, including critical reagent
information, risk analysis strategies, lot
release criteria, flex studies, and stability
studies and protocols.
Failure to correctly operate the device	Certain labeling information, including
limitations, device descriptions, and
explanation of procedures.
	Certain design verification and validation
information including critical reagent
information, risk analysis strategies, lot
release criteria, flex studies, and stability
studies.

IX Benefit/Risk Assessment:

A Summary of the Assessment of Benefit:

The benefit of the assay is the ability to detect HCV RNA to aid a clinician in the diagnosis of hepatitis C virus (HCV) infection in individuals with signs and symptoms or risk factors for HCV infection without needing an HCV antibody result. Diagnosis of HCV infection with the aid of this device can occur within one encounter with the healthcare system. Individuals diagnosed with HCV infection with the aid of the candidate device can be treated with indicated antiviral treatment. Treatment of HCV infection helps prevent known complications of undiagnosed and untreated HCV infection, including by symptom alleviation, decreases in allcause mortality, liver disease-related complications and death, hepatocellular carcinoma rates, and need for liver transplantation. Diagnosis of HCV infection can improve patient knowledge of the condition, inform prognosis, and guide the need for additional imaging or laboratory testing. Diagnosis of HCV infection also leads clinicians to evaluate and subsequently treat patients for human immunodeficiency virus (HIV) and hepatitis B virus (HBV), if indicated, as these viruses share common modes of transmission with HCV, and co-infection is widely documented.

20

Diagnosis could also decrease community transmission among other individuals at risk for HCV infection.

B Summary of the Assessment of Risk:

The risks associated with the device, when used as intended, are those related to the risk of false test results (false positive and false negative), failure to correctly interpret the test results, and failure to correctly operate the instrument.

Risks of a false positive test include unnecessary imaging, laboratory testing, and treatment. repeating hepatitis C testing and additional imaging and laboratory evaluations. False positive test results may have psychosocial implications for those tested.

Risks of false negative test results include missed diagnosis of HCV infection. Risks of a false negative test include the failure to treat HCV infection. Failure to diagnose and treat HCV infection will lead to increased all-cause mortality and increased likelihood of liver diseaserelated complications, including cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. A failure to diagnose HCV infection could also lead to increased community transmission and disease burden in individuals at risk for infection. A false negative result may deny a clinician the opportunity to evaluate and treat a patient who is co-infected with HIV or HBV, as these viruses share common modes of transmission with HCV, and patients are often co-infected. Additional risks of false negative test results are unnecessary additional diagnostic procedures in pursuit of a different cause for the patient's hepatitis, which bear known risks such as bleeding and infection for liver biopsies and pharmacological treatment for other etiologies, which have known adverse effects such as hypersensitivity reactions.

Failure to correctly operate the device could lead to invalid results requiring retesting and leading to delayed test results. The risk of a delayed result is minimal, given the short time to results with the device. Failure to correctly interpret results carries the same risks as false results.

C Patient Perspectives:

This submission did not include specific information on patient perspectives for this device.

D Summary of the Assessment of Benefit-Risk:

The risks associated with the device (risk of false test results, failure to correctly interpret the results, and failure to correctly operate the device) are mitigated by labeling information, which will assist the operator in correctly performing the test and will assist healthcare providers in understanding the intended use of the test and evaluating the predictive value of a result based on the analytical and clinical performance of the test. In addition, the risks of false test results and failure to correctly interpret the results are mitigated by certain design verification and validation activities, including analytical and clinical studies and risk analysis strategies to reduce the likelihood of such errors. Such measures help to ensure that errors will be uncommon and will facilitate accurate assay implementation and interpretation of results. In addition, the device's performance observed in the clinical study suggests that errors will be uncommon and that the assay will provide substantial benefits to patients as an aid in the diagnosis of HCV infection in individuals at risk and/or with signs and symptoms of HCV infection with or without antibodies to HCV. There is significant morbidity and mortality associated with the natural history of disease progression of undiagnosed HCV, and barriers exist to initiation of antiviral treatment due to loss-to-follow up with current multi-step HCV testing algorithms over multiple encounters with the healthcare system. Because this test can be used at the point of care and can return a

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result in approximately 60 minutes, the diagnosis of HCV can occur in one encounter with the healthcare system. Risks can be further mitigated by labeling the device as "prescription use only" and by including additional warnings noting limitations of safety information, including populations or situations for which the safety and efficacy of the device has not been evaluated. While general controls alone are insufficient to mitigate the risks associated with the device, given the special controls, the benefits outweigh the risks.

X Conclusion:

The De Novo request is granted, and the device is classified under the following, and subject to the special controls identified in the letter granting the De Novo request:

Product Code(s):	SBP
Device Type:	Simple point-of-care nucleic acid-based hepatitis C virus ribonucleic acid
test
Class:	Class II
Regulation:	21 CFR 866.3171