(84 days)
The Alinity m HCV assay is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for both the detection and quantitation of hepatitis C virus (HCV) RNA, in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals. The assay is intended for use as an aid in the diagnosis of active HCV infection in individuals with antibody evidence of HCV infection, and to aid in the management of patients with known active HCV infection, including Sustained Virologic Response (SVR) determination.
The results from the Alinity m HCV assay must be interpreted within the context of all relevant clinical and laboratory findings.
The Alinity m HCV assay is not intended to be used in screening blood, plasma, serum, tissue or tissue donors for HCV.
Alinity m HCV is an in vitro polymerase chain reaction (PCR) assay for both the detection and quantitation of HCV RNA in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals.
This device is similar to the predicate device originally approved (PMA P190025) with the exception that the subject device may use a new DNA Polymerase as an alternative to the original DNA Polymerase and a new Reverse Transcriptase as an alternative to the original Reverse Transcriptase in the reagent formulation of the assay. This formulation difference does not introduce any changes to sample processing, assay procedure, or data reduction.
Additional studies were initiated to support the formulation of the assay with alternative DNA Polymerase and Reverse Transcriptase. Supplemental data from these studies were used with data previously obtained from the analytical and clinical testing studies submitted in P190025.
The steps of the Alinity m HCV assay consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. All steps of the Alinity m HCV assay procedure are executed automatically by the Alinity m System. Manual dilutions may be performed for low-volume specimens to meet the minimum volume requirement and for high-titer specimens above the upper limit of quantitation (ULoQ). The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m HCV assay in parallel with other Alinity m assays on the same instrument.
Alinity m HCV requires three separate assay specific kits as follows:
-
Alinity m HCV AMP Kit (List No. 08N50-095), consisting of 2 types of multi-well assay trays. The amplification trays (AMP Trays) contain lyophilized, unit-dose RT-PCR amplification/detection reagents and lyophilized, unit-dose IC in separate wells, and the activation trays (ACT Trays) contain liquid activation reagent. The intended storage condition for the Alinity m HCV AMP Kit is 2°C to 8°C.
-
Alinity m HCV CTRL Kit (List No. 08N50-085), consisting of negative controls, low positive controls, and high positive controls, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m HCV CTRL Kit is –25°C to –15°C.
-
Alinity m HCV CAL Kit (List No. 08N50-075), consisting of 2 calibrator levels, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m HCV CAL Kit is –25°C to –15°C.
HCV RNA from human plasma or serum is extracted automatically on-board in the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash, and elution. The resulting purified nucleic acids are then combined with liquid unit-dose Alinity m HCV activation reagent and lyophilized unit-dose Alinity m HCV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification, and real-time fluorescence detection of HCV targets.
At the beginning of the Alinity m HCV sample preparation process, a lyophilized unit-dose IC on the AMP Tray is rehydrated by the Alinity m System and delivered into each sample preparation reaction. The IC is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators, and controls to demonstrate proper sample processing and validity.
The Alinity m HCV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable reverse transcription, polymerization, and detection.
An HCV calibration curve is required for determination of HCV RNA concentration. Two levels of calibrators are processed through sample preparation and RT-PCR to generate the calibration curve. The concentration of HCV RNA in specimens and controls is then calculated from the stored calibration curve.
Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remains satisfactory. During each control event, a negative control, a low-positive control, and a high-positive control are processed through sample preparation and RT-PCR procedures that are identical to those used for specimens.
The Alinity m HCV assay also utilizes the following:
- Alinity m HCV Application Specification File, (List No. 08N50-03B)
- Alinity m System and System Software (List No. 08N53)
- Alinity m Sample Prep Kit 2 (List No. 09N12-001)
- Alinity m Specimen Dilution Kit I (List No. 09N50-001)
- Alinity m System Solutions, (List No. 09N20):
- Alinity m Lysis Solution (List No. 09N20-001)
- Alinity m Diluent Solution (List No. 09N20-003)
- Alinity m Vapor Barrier Solution, (List No. 09N20-004)
- Alinity m Tubes and Caps (List No. 09N49):
- Alinity m LRV Tube (List No. 09N49-001)
- Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
- Alinity m Transport Tube (List No. 09N49-011)
- Alinity m Pierceable Cap (List No. 09N49-012)
- Alinity m Aliquot Tube (List No. 09N49-013)
N/A
FDA 510(k) Clearance Letter - Alinity m HCV
Page 1
U.S. Food & Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
www.fda.gov
Doc ID # 04017.08.00
September 25, 2025
Abbott Molecular Inc.
Jennifer Peterson
Associate Director Regulatory Affairs
1350 East Touhy Avenue
Des Plaines, Illinois 60018
Re: K252102
Trade/Device Name: Alinity m HCV
Regulation Number: 21 CFR 866.3170
Regulation Name: Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Tests
Regulatory Class: Class II
Product Code: MZP
Dated: July 2, 2025
Received: July 3, 2025
Dear Jennifer Peterson:
We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
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K252102 - Jennifer Peterson Page 2
Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reporting-combination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.
All medical devices, including Class I and unclassified devices and combination product device constituent parts are required to be in compliance with the final Unique Device Identification System rule ("UDI Rule"). The UDI Rule requires, among other things, that a device bear a unique device identifier (UDI) on its label and package (21 CFR 801.20(a)) unless an exception or alternative applies (21 CFR 801.20(b)) and that the dates on the device label be formatted in accordance with 21 CFR 801.18. The UDI Rule (21 CFR 830.300(a) and 830.320(b)) also requires that certain information be submitted to the Global Unique Device Identification Database (GUDID) (21 CFR Part 830 Subpart E). For additional information on these requirements, please see the UDI System webpage at https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/unique-device-identification-system-udi-system.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-devices/medical-device-safety/medical-device-reporting-mdr-how-report-medical-device-problems.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-
Page 3
K252102 - Jennifer Peterson Page 3
assistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Bhawna Poonia -S
for
Uwe Scherf, M.Sc., Ph.D.
Director
Division of Microbiology Devices
OHT7: Office of In Vitro Diagnostics
Office of Product Evaluation and Quality
Center for Devices and Radiological Health
Enclosure
Page 4
FORM FDA 3881 (8/23) Page 1 of 1
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Indications for Use
Form Approved: OMB No. 0910-0120
Expiration Date: 07/31/2026
See PRA Statement below.
510(k) Number (if known): K252102
Device Name: Alinity m HCV
Indications for Use (Describe)
The Alinity m HCV assay is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for both the detection and quantitation of hepatitis C virus (HCV) RNA, in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals. The assay is intended for use as an aid in the diagnosis of active HCV infection in individuals with antibody evidence of HCV infection, and to aid in the management of patients with known active HCV infection, including Sustained Virologic Response (SVR) determination.
The results from the Alinity m HCV assay must be interpreted within the context of all relevant clinical and laboratory findings.
The Alinity m HCV assay is not intended to be used in screening blood, plasma, serum, tissue or tissue donors for HCV.
Type of Use (Select one or both, as applicable)
☒ Prescription Use (Part 21 CFR 801 Subpart D)
☐ Over-The-Counter Use (21 CFR 801 Subpart C)
CONTINUE ON A SEPARATE PAGE IF NEEDED.
This section applies only to requirements of the Paperwork Reduction Act of 1995.
DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.
The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:
Department of Health and Human Services
Food and Drug Administration
Office of Chief Information Officer
Paperwork Reduction Act (PRA) Staff
PRAStaff@fda.hhs.gov
"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."
Page 5
Alinity m HCV 510(k) K252102
September 2025
Attachment 022_Alinity m HCV_510(k) Summary_mw006 Page 1 of 25
510(k) Summary
Table of Contents
1.0 510(k) Summary ...................................................................................................... 2
- 1.1 Submitter.......................................................................................................... 2
- 1.2 Device Information.......................................................................................... 2
- 1.3 Predicate Device .............................................................................................. 2
- 1.4 Device Description .......................................................................................... 3
- 1.5 Intended Use .................................................................................................... 6
- 1.6 Similarities and Differences to Predicate Device ............................................ 6
- 1.7 Performance Data ............................................................................................ 9
- 1.8 Conclusions Drawn from the Studies............................................................ 25
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Attachment 022_Alinity m HCV_510(k) Summary_mw006 Page 2 of 25
1.0 510(k) Summary
This 510(k) summary of safety and effectiveness information is being submitted in accordance with the requirement of 21 CFR Section 807.92(c).
1.1 Submitter
Applicant Name and Address: Abbott Molecular Inc.
1300 E. Touhy Avenue
Des Plaines, IL 60018
Contact Person: Jennifer Peterson
Associate Director Regulatory Affairs
Abbott Molecular, Inc.
1300 E. Touhy Avenue
Des Plaines, IL 60018
Phone: 224-361-7081
Mobile: 224-651-7305
Fax: 224-361-7269
Date Prepared: July 2025
1.2 Device Information
| Trade Name | Regulation Name | Product Code | Regulation No. | Class |
|---|---|---|---|---|
| Alinity m HCV | Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Test | MZP | 21 CFR 866.3170 | II |
1.3 Predicate Device
| Device Name | Predicate Device | PMA | Approved |
|---|---|---|---|
| Alinity m HCV | Alinity m HCV | P190025 | 03/23/2020 |
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Attachment 022_Alinity m HCV_510(k) Summary_mw006 Page 3 of 25
1.4 Device Description
Alinity m HCV is an in vitro polymerase chain reaction (PCR) assay for both the detection and quantitation of HCV RNA in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals.
This device is similar to the predicate device originally approved (PMA P190025) with the exception that the subject device may use a new DNA Polymerase as an alternative to the original DNA Polymerase and a new Reverse Transcriptase as an alternative to the original Reverse Transcriptase in the reagent formulation of the assay. This formulation difference does not introduce any changes to sample processing, assay procedure, or data reduction.
Additional studies were initiated to support the formulation of the assay with alternative DNA Polymerase and Reverse Transcriptase. Supplemental data from these studies were used with data previously obtained from the analytical and clinical testing studies submitted in P190025.
The steps of the Alinity m HCV assay consist of sample preparation, real-time PCR assembly, amplification/detection, result calculation, and reporting. All steps of the Alinity m HCV assay procedure are executed automatically by the Alinity m System. Manual dilutions may be performed for low-volume specimens to meet the minimum volume requirement and for high-titer specimens above the upper limit of quantitation (ULoQ). The Alinity m System is designed to be a random-access analyzer that can perform the Alinity m HCV assay in parallel with other Alinity m assays on the same instrument.
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Attachment 022_Alinity m HCV_510(k) Summary_mw006 Page 4 of 25
Alinity m HCV requires three separate assay specific kits as follows:
-
Alinity m HCV AMP Kit (List No. 08N50-095), consisting of 2 types of multi-well assay trays. The amplification trays (AMP Trays) contain lyophilized, unit-dose RT-PCR amplification/detection reagents and lyophilized, unit-dose IC in separate wells, and the activation trays (ACT Trays) contain liquid activation reagent. The intended storage condition for the Alinity m HCV AMP Kit is 2°C to 8°C.
-
Alinity m HCV CTRL Kit (List No. 08N50-085), consisting of negative controls, low positive controls, and high positive controls, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m HCV CTRL Kit is –25°C to –15°C.
-
Alinity m HCV CAL Kit (List No. 08N50-075), consisting of 2 calibrator levels, each supplied as liquid in single-use tubes. The intended storage condition for the Alinity m HCV CAL Kit is –25°C to –15°C.
HCV RNA from human plasma or serum is extracted automatically on-board in the Alinity m System using the Alinity m Sample Prep Kit 2, Alinity m Lysis Solution, and Alinity m Diluent Solution. The Alinity m System employs magnetic microparticle technology to facilitate nucleic acid capture, wash, and elution. The resulting purified nucleic acids are then combined with liquid unit-dose Alinity m HCV activation reagent and lyophilized unit-dose Alinity m HCV amplification/detection reagents and transferred into a reaction vessel. Alinity m Vapor Barrier Solution is then added to the reaction vessel which is then transferred to an amplification/detection unit for PCR amplification, and real-time fluorescence detection of HCV targets.
At the beginning of the Alinity m HCV sample preparation process, a lyophilized unit-dose IC on the AMP Tray is rehydrated by the Alinity m System and delivered into each sample preparation reaction. The IC is then processed through the entire sample preparation and real-time PCR procedure along with the specimens, calibrators, and controls to demonstrate proper sample processing and validity.
The Alinity m HCV amplification/detection reagents consist of enzymes, primers, probes, and activation reagents that enable reverse transcription, polymerization, and detection.
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Attachment 022_Alinity m HCV_510(k) Summary_mw006 Page 5 of 25
An HCV calibration curve is required for determination of HCV RNA concentration. Two levels of calibrators are processed through sample preparation and RT-PCR to generate the calibration curve. The concentration of HCV RNA in specimens and controls is then calculated from the stored calibration curve.
Assay controls are tested at or above an established minimum frequency to help ensure that instrument and reagent performance remains satisfactory. During each control event, a negative control, a low-positive control, and a high-positive control are processed through sample preparation and RT-PCR procedures that are identical to those used for specimens.
The Alinity m HCV assay also utilizes the following:
- Alinity m HCV Application Specification File, (List No. 08N50-03B)
- Alinity m System and System Software (List No. 08N53)
- Alinity m Sample Prep Kit 2 (List No. 09N12-001)
- Alinity m Specimen Dilution Kit I (List No. 09N50-001)
- Alinity m System Solutions, (List No. 09N20):
- Alinity m Lysis Solution (List No. 09N20-001)
- Alinity m Diluent Solution (List No. 09N20-003)
- Alinity m Vapor Barrier Solution, (List No. 09N20-004)
- Alinity m Tubes and Caps (List No. 09N49):
- Alinity m LRV Tube (List No. 09N49-001)
- Alinity m Transport Tubes Pierceable Capped (List No. 09N49-010)
- Alinity m Transport Tube (List No. 09N49-011)
- Alinity m Pierceable Cap (List No. 09N49-012)
- Alinity m Aliquot Tube (List No. 09N49-013)
Page 10
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Attachment 022_Alinity m HCV_510(k) Summary_mw006 Page 6 of 25
1.5 Intended Use
The Alinity m HCV assay is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for both the detection and quantitation of hepatitis C virus (HCV) RNA, in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals. The assay is intended for use as an aid in the diagnosis of active HCV infection in individuals with antibody evidence of HCV infection, and to aid in the management of patients with known active HCV infection, including Sustained Virologic Response (SVR) determination.
The results from the Alinity m HCV assay must be interpreted within the context of all relevant clinical and laboratory findings.
The Alinity m HCV assay is not intended to be used in screening blood, plasma, serum, tissue or tissue donors for HCV.
1.6 Similarities and Differences to Predicate Device
The primary functional components of the Alinity m HCV assay are substantially equivalent to the current on-market Alinity m HCV assay (PMA 190025), which is a legally marketed Nucleic Acid-Based Hepatitis C Virus Ribonucleic Acid Test.
The Alinity m HCV assay has the same intended use as the predicate device. The subject device and predicate device differ only in the DNA polymerase and Reverse Transcriptase enzymes that may be used in manufacture of the assay; this formulation difference does not raise new types of safety or effectiveness questions.
These devices are similar in that they are designed to prepare nucleic acids for amplification, amplify specific HCV RNA sequences, detect the amplified products, and report quantitative results.
The primary similarities and differences between the Alinity m HCV assay and the predicate device are shown in Table 1 and Table 2.
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Table 1. Similarities Between Alinity m HCV and Predicate Device
| Description | Subject Device | Predicate Device |
|---|---|---|
| Alinity m HCV | Alinity m HCV (PMA 190025) | |
| Intended Use | Same | The Alinity m HCV assay is an in vitro reverse transcription-polymerase chain reaction (RT-PCR) assay for both the detection and quantitation of hepatitis C virus (HCV) RNA, in human plasma (EDTA, Acid Citrate Dextrose) or serum, from HCV antibody positive individuals. The assay is intended for use as an aid in the diagnosis of active HCV infection in individuals with antibody evidence of HCV infection, and to aid in the management of patients with known active HCV infection, including Sustained Virologic Response (SVR) determination.The results from the Alinity m HCV assay must be interpreted within the context of all relevant clinical and laboratory findings.The Alinity m HCV assay is not intended to be used in screening blood, plasma, serum, tissue or tissue donors for HCV. |
| Assay Type | Same | Quantitative |
| Assay Targets | Same | highly conserved sequence within the 5' untranslated region (5'utr) of the HCV genome |
| Specimen Types | Same | ACD Plasma, EDTA Plasma, Serum |
| Sample Preparation Procedure | Same | Automated liquid handling and robotic manipulation platform |
| Amplification Technology | Same | Real-time polymerase chain reaction |
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Table 1. Similarities Between Alinity m HCV and Predicate Device (continued)
| Description | Subject Device | Predicate Device |
|---|---|---|
| Alinity m HCV | Alinity m HCV (PMA 190025) | |
| Assay Controls | Same | • Negative Control• Low Positive Control• High Positive Control• Internal Control (IC) |
Table 2. Differences Between Alinity m HCV and Predicate Device
| Feature | Current Application | Predicate Device |
|---|---|---|
| Alinity m HCV | Alinity m HCV (P190025) | |
| Amplification Enzymes | Original DNA Polymerase or alternative DNA Polymerase enzyme used for DNA amplification.Original or alternative enzyme to convert target RNA to complimentary DNA (cDNA). | Original DNA Polymerase enzyme used for DNA amplification.Original enzyme to convert target RNA to complimentary DNA (cDNA). |
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1.7 Performance Data
The following performance data were provided in support of substantial equivalence determination of the device.
1.7.1 Specific Performance Characteristics
The subject device is similar to the predicate device originally approved (P190025) with the exception that the subject device may use a new DNA Polymerase as an alternative to the original DNA Polymerase and a new Reverse Transcriptase as an alternative to the original Reverse Transcriptase in the reagent formulation of the assay. Apart from the DNA polymerase and Reverse Transcriptase enzymes used, the reagent formulation, including all oligonucleotide primers and probes (components and concentrations) is identical between the subject device and predicate device. There are no differences in the intended use, end-user workflow, instrument workflow, assay software, reagent manufacturing, or final product release specifications.
Additional analytical performance studies listed in Table 3 were conducted to confirm the ability of the Alinity m HCV assay formulated with alternative DNA Polymerase and alternative Reverse Transcriptase (subject device) to meet the performance claims established in the corresponding studies submitted in P190025 for the Alinity m HCV assay formulated with the original DNA Polymerase and the original Reverse Transcriptase (predicate device).
Table 3. Additional Supporting Studies (Alternate Enzymes Formulation)
| Study Description / Performance Characteristic | 510(k) Summary Section |
|---|---|
| Limit of Detection | 1.7.1.1 |
| Linear Range | 1.7.1.2 |
| Precision | 1.7.1.3 |
| Lower Limit of Quantitation | 1.7.1.4 |
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All other specific performance characteristics of the subject device are supported by the studies submitted in P190025. Refer to Table 4.
Table 4. Supporting Studies Submitted in P190025
| Study Description / Performance Characteristic | Reference |
|---|---|
| Traceability to the WHO Standard | Original submission |
| Genotype Limit of Detection | Original submission |
| Genotype Linearity | Original submission |
| Analytical Specificity – Potential Cross-Reactants | Original submission |
| Analytical Specificity – Potentially Interfering Substances | Original submission |
| Carryover | Original submission |
| Alinity m HCV Testing Using Dilution Procedure | Original submission |
| Precision of Alinity m HCV Using Dilution Procedure | Original submission |
| Confirmation of LLoQ Using Dilution Procedure | Original submission |
1.7.1.1 Limit of Detection
A limit of detection (LoD) study was conducted previously to support the approval of P190025. Please refer to the decision summary for P190025.
An additional study was conducted to confirm the LoD claim of Alinity m HCV (12 IU/mL) for the formulation of the assay using the alternative enzymes.
The LoD for HCV was evaluated by testing dilutions of a World Health Organization (WHO) HCV Standard (NIBSC code 18/184) prepared in HCV negative human plasma. Testing for each HCV DNA concentration was performed with 3 lots of amplification reagents across multiple days.
The data from the study demonstrated that the Alinity m HCV assay formulated with the alternative DNA Polymerase and the alternative Reverse Transcriptase had an overall detection rate of 98.6% at 12 IU/mL. Refer to Table 5.
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Attachment 022_Alinity m HCV_510(k) Summary_mw006 Page 11 of 25
Table 5. Alinity m HCV (Alternate Enzymes Formulation) Limit of Detection (LoD) Results
| Target Concentration (IU/mL) | AMP Kit Reagent Lot | Number of Total Replicates | Number of Replicates Detected | Detection Rate (%) | 95% Score Confidence Interval (%) |
|---|---|---|---|---|---|
| 9 | 1 | 48 | 46 | 95.8 | (86.0, 98.8) |
| 2 | 48 | 45 | 93.8 | (83.2, 97.9) | |
| 3 | 48 | 47 | 97.9 | (89.1, 99.6) | |
| All Combined | 144 | 138 | 95.8 | (91.2, 98.1) | |
| 12ᵃ | 1 | 48 | 48 | 100.0 | (92.6, 100.0) |
| 2 | 48 | 46 | 95.8 | (86.0, 98.8) | |
| 3 | 47 | 47 | 100.0 | (92.4, 100.0) | |
| All Combined | 143 | 141 | 98.6 | (95.0, 99.6) | |
| 16 | 1 | 47 | 47 | 100.0 | (92.4, 100.0) |
| 2 | 48 | 48 | 100.0 | (92.6, 100.0) | |
| 3 | 45 | 45 | 100.0 | (92.1, 100.0) | |
| All Combined | 140 | 140 | 100.0 | (97.3, 100.0) |
ᵃ Alinity m HCV assay limit of detection (LoD) claim
1.7.1.2 Linear Range
A linearity study was conducted previously to support the approval of P190025. Please refer to the decision summary for P190025.
An additional study was conducted to confirm that the Alinity m HCV assay formulated with the alternative DNA Polymerase and the alternative Reverse Transcriptase was linear across the claimed quantitation range (12 IU/mL [1.08 Log IU/mL] to 100,000,000 IU/mL [8.00 Log IU/mL]).
Linearity was evaluated by testing 12 panel members that spanned the intended quantitation range of the assay(12 IU/mL to 100,000,000 IU/mL), including a panel member below the expected Lower Limit of Quantification (LLoQ) at 10 IU/mL and a panel member exceeding the expected Upper Limit of Quantification (ULoQ) at 200,000,000 IU/mL. Refer to Table 6.
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Table 6. Panel Members for Linearity
| Panel Member | Targeted HCV Concentration | Source | |
|---|---|---|---|
| IU/mL | Log IU/mL | ||
| 01 | 200,000,000 | 8.30 | aRNA |
| 02 | 10,000,000 | 7.00 | aRNA |
| 03 | 1,000,000 | 6.00 | aRNA |
| 04 | 100,000 | 5.00 | aRNA |
| 05 | 10,000 | 4.00 | Clinical Sample |
| 06 | 5,000 | 3.70 | aRNA |
| 07 | 1,000 | 3.00 | Clinical Sample |
| 08 | 500 | 2.70 | aRNA |
| 09 | 100 | 2.00 | Clinical Sample |
| 10 | 50 | 1.70 | aRNA |
| 11ᵃ | 12 | 1.08 | Clinical Sample |
| 12 | 10 | 1.00 | Clinical Sample |
ᵃ The assay's claimed LLoQ is 12 IU/mL per package insert.
The data from the study demonstrated that the Alinity m HCV assay formulated with the alternative DNA Polymerase and the alternative Reverse Transcriptase was linear across the quantitative range from 12 IU/mL to 100,000,000 IU/mL (1.08 Log IU/mL to 8.00 Log IU/mL). Results for Alinity m HCV linearity performance are shown in Figure 1.
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Figure 1. Alinity m HCV (Alternate Enzymes Formulation) Linearity
[THIS IS FIGURE: A scatter plot showing linearity data with Expected Concentration (Log IU/mL) on x-axis (0-9) and Alinity HCV (Log IU/mL) on y-axis (0-9). The plot shows a strong linear relationship with r = 1.000 and data points following a diagonal line from approximately (1,1) to (8,8).]
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1.7.1.3 Precision
A precision study was conducted previously to support the approval of P190025. Please refer to the decision summary for P190025.
An additional study was conducted to confirm the precision claim of Alinity m HCV (as follows) for the alternative DNA Polymerase and the alternative Reverse Transcriptase formulation of the assay:
- Within-laboratory standard deviation (SD) of ≤ 0.25 Log IU/mL for samples between 100 IU/mL to 200,000,000 IU/mL (2.00 Log IU/mL to 8.30 Log IU/mL) HCV RNA
- Within-laboratory SD of ≤ 0.35 Log IU/mL for samples with target concentrations from the claimed LLoQ to 3x LLoQ (12 IU/mL to 36 IU/mL or 1.08 Log IU/mL to 1.56 Log IU/mL) HCV RNA
Precision was evaluated by testing 8 panel members with HCV concentrations ranging from 12 IU/mL to 200,000,000 IU/mL (1.08 Log IU/mL to 8.30 Log IU/mL). Panel members were prepared by diluting HCV positive specimen or armored RNA (aRNA) in human EDTA plasma. aRNA was only used for panel members with high concentrations (> 5.00 Log IU/mL).
Three lots of Alinity m HCV amplification reagents manufactured with the alternative DNA Polymerase and the alternative Reverse Transcriptase were run on 1 Alinity m System. Three replicates of each panel member were run twice each day for 15 days for each lot with a minimum separation of 2 hours between successive runs of a panel member.
The overall precision analysis summary for the Alinity m HCV assay formulated with the alternative enzymes is presented in Table 7.
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The results demonstrated that the Alinity m HCV assay has a within-laboratory SD of 0.25 Log IU/mL or less for samples targeted between 100 IU/mL to 200,000,000 IU/mL (2.00 Log IU/mL to 8.30 Log IU/mL) HCV RNA, and a within-laboratory SD of 0.35 Log IU/mL or less for samples with target concentrations from the claimed LLoQ to 3x LLoQ (12 IU/mL to 36 IU/mL or 1.08 Log IU/mL to 1.56 Log IU/mL) HCV RNA
Table 7. Alinity m HCV (Alternate Enzymes Formulation) Precision Analysis – All Reagent Lots
| Panel | N | Mean Concentration (Log IU/mL) | Within-Run Component | Between-Run Component | Between-Day Component | Within-Laboratory ᵃ | Between-Lot Component | Total ᵇ |
|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | |||
| 01 | 269 | 0.96 | 0.24 | 24.6 | 0.00 | 0.0 | 0.10 | 10.2 |
| 02 | 270 | 1.61 | 0.14 | 8.8 | 0.06 | 3.5 | 0.00 | 0.0 |
| 03 | 270 | 1.80 | 0.11 | 6.2 | 0.06 | 3.1 | 0.00 | 0.0 |
| 04 | 270 | 2.88 | 0.09 | 3.0 | 0.05 | 1.6 | 0.00 | 0.0 |
| 05 | 270 | 3.78 | 0.07 | 1.9 | 0.04 | 1.1 | 0.00 | 0.0 |
| 06 | 270 | 5.85 | 0.06 | 1.1 | 0.02 | 0.3 | 0.03 | 0.5 |
| 07 | 270 | 6.89 | 0.04 | 0.5 | 0.02 | 0.2 | 0.00 | 0.0 |
| 08 | 270 | 8.26 | 0.04 | 0.5 | 0.01 | 0.1 | 0.02 | 0.2 |
ᵃ Within-Laboratory includes Within-Run, Between-Run, and Between-Day Components.
ᵇ Total includes Within-Run, Between-Run, Between-Day, and Between-Lot Components.
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The Total SD and Total %CV for each panel member in this study were compared with the Total SD and Total %CV from the original precision study submitted in P190025. Refer to Table 8.
Table 8. Equivalence Evaluation of Total SD and Total %CV (New ᵃ vs. Original ᵇ)
| Panel Member | Mean Concentration | Total SD | Total %CV | Ratios and 95% CI | ||||
|---|---|---|---|---|---|---|---|---|
| New ᵃ Mean (Log IU/mL) | Original ᵇ Mean (Log IU/mL) | New ᵃ SD | Original ᵇ SD | New ᵃ % CV | Original ᵇ % CV | SD | %CV | |
| 01 | 0.96 | 1.07 | 0.27 | 0.21 | 28.2 | 19.7 | 1.28 (1.01, 1.63) | 1.43 (1.12, 1.81) |
| 02 | 1.61 | 1.42 | 0.17 | 0.18 | 10.6 | 12.6 | 0.96 (0.68, 1.34) | 0.85 (0.60, 1.19) |
| 03 | 1.80 | 1.91 | 0.15 | 0.17 | 8.1 | 8.7 | 0.88 (0.53, 1.46) | 0.94 (0.57, 1.55) |
| 04 | 2.88 | 2.88 | 0.12 | 0.17 | 4.1 | 5.8 | 0.71 (0.40, 1.26) | 0.71 (0.40, 1.26) |
| 05 | 3.78 | 3.94 | 0.10 | 0.14 | 2.7 | 3.6 | 0.73 (0.47, 1.12) | 0.76 (0.49, 1.16) |
| 06ᶜ | 5.85 | 6.14 | 0.09 | 0.11 | 1.5 | 1.8 | 0.77 (0.33, 1.80) | 0.81 (0.35, 1.89) |
| 07ᵈ | 6.89 | 7.11 | 0.07 | 0.16 | 1.1 | 2.3 | 0.45 (0.22, 0.92) | 0.47 (0.23, 0.95) |
| 08ᵉ | 8.26 | 8.55 | 0.11 | 0.16 | 1.3 | 1.9 | 0.69 (0.17, 2.87) | 0.72 (0.17, 2.97) |
ᵃ "New" Mean, SD, and %CV data for Alinity m HCV assay formulated with alternative DNA Polymerase and alternative Reverse Transcriptase.
ᵇ "Original" Mean, SD, and %CV data for Alinity m HCV assay formulated with original DNA Polymerase and original Reverse Transcriptase (per P190025)
ᶜ Panel 06 in the New Precision protocol targeting 6.0 Log IU/mL is compared to panel 07 in the Original Precision protocol targeting 6.0 Log IU/mL
ᵈ Panel 07 in the New Precision protocol targeting 7.0 Log IU/mL is compared to panel 08 in the Original Precision protocol targeting 7.0 Log IU/mL.
ᵉ Panel 08 in the New Precision protocol targeting 8.3 Log IU/mL is compared to panel 09 in the Original Precision protocol targeting 8.3 Log IU/mL.
NOTE: Panel 06 in the Original Precision protocol targeting 5.0 Log IU/mL is not analyzed for comparison.
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1.7.1.4 Lower Limit of Quantitation (LLoQ)
A lower limit of quantitation (LLoQ) study was conducted previously to support the approval of P190025. Please refer to the decision summary for P190025.
An additional study was conducted to confirm the LLoQ claim of Alinity m HCV (12 IU/mL) for the alternative DNA Polymerase and alternative Reverse Transcriptase formulation of the assay.
The LLoQ is defined as the lowest concentration at which HCV RNA is reliably quantitated within an acceptable total error. Total error was estimated for detected samples from the LoD study (Section 1.7.1.1), the Linearity study (Section 1.7.1.2), and the Precision study (Section 1.7.1.3) by 2 methods:
- Total Analytical Error (TAE) = |bias| + 2 × SD, (where bias = mean concentration – assigned target concentration)
and
- Total Error (TE) = SQRT(2) × 2 × SD
Panel members were dilutions of a World Health Organization (WHO) HCV Standard (NIBSC code 18/184) prepared in HCV negative human plasma.
The results of the calculations are shown in Table 9.
The results of these analyses support a claimed LLoQ of 12 IU/mL (1.08 Log IU/mL), with an acceptable level of accuracy and precision (ie, TAE and TE less than or equal to 1.00 Log IU/mL).
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Table 9. Alinity m HCV (Alternate Enzyme Formulation) TAE and TE
| Study | Panel | Target (IU/mL) | N | Target (Log IU/mL) | Mean (Log IU/mL) | Bias (Log IU/mL) | SD | TAE | TE |
|---|---|---|---|---|---|---|---|---|---|
| Linearity | 11 | 12 | 24 | 1.08 | 0.90 | -0.18 | 0.27 | 0.72 | 0.76 |
| 12 | 10 | 24 | 1.00 | 0.72 | -0.28 | 0.32 | 0.93 | 0.92 | |
| Precision | 01 | 12 | 269 | 1.08 | 0.96 | -0.12 | 0.26 | 0.63 | 0.73 |
| Sensitivity | 1 | 9 | 138 | 0.95 | 0.77 | -0.18 | 0.26 | 0.70 | 0.74 |
| 2 | 12 | 141 | 1.08 | 0.85 | -0.23 | 0.27 | 0.77 | 0.76 | |
| 3 | 16 | 140 | 1.20 | 1.06 | -0.15 | 0.21 | 0.57 | 0.59 |
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1.7.1 Performance Characteristics
1.7.1.1 Reproducibility
A reproducibility study was conducted previously to support the approval of P190025. Please refer to the decision summary for P190025.
An additional study was conducted to evaluate the reproducibility of the Alinity m HCV assay formulated with alternative DNA Polymerase and alternative Reverse Transcriptase.
Reproducibility performance of Alinity m HCV was evaluated by testing an 11-member reproducibility panel, which included 10 positive panel members and 1 negative panel member. Panel members were prepared in base-matrix (EDTA plasma) and spanned the linear range of Alinity m HCV assay. One panel member was negative for HCV. Ten positive panel members represented the two different genotypes 1a & 2. Panel members were prepared by diluting HCV positive clinical specimen or HCV armored RNA (aRNA) in HCV negative plasma. HCV aRNA was only used for panel members with high concentrations (>5.0 Log IU/mL).
One lot each of Alinity m HCV AMP Kit, Alinity m HCV CAL Kit, Alinity m HCV CTRL Kit, and Alinity m Sample Prep Kit 2 lots were used. Testing was performed at 3 clinical sites on 5 non-consecutive days with 2 runs per day. Four replicates of each panel member were tested on each of 5 days to ensure a minimum of 3 valid replicates for analysis.
The reproducibility results are summarized in Table 10 (for the positive panel members) and in Table 11 (for the negative panel member).
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Table 10. Alinity m HCV (Alternate Enzymes Formulation) Overall Variance Component Analysis
| Genotype | Panel | N | Mean Concentration (Log IU/mL) | Within-Run Component | Between-Run Component | Between-Day Component | Within-Laboratory ᵃ | Between-Site Component | Total ᵇ |
|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | ||||
| 1a | 1 | 118 | 7.71 | 0.20 | 2.6 | 0.08 | 1.1 | 0.10 | 1.4 |
| 1a | 2 | 115 | 5.72 | 0.06 | 1.1 | 0.05 | 0.8 | 0.00 | 0.0 |
| 1a | 3 | 115 | 3.53 | 0.06 | 1.6 | 0.04 | 1.1 | 0.03 | 0.9 |
| 1a | 4 | 119 | 1.84 | 0.11 | 5.9 | 0.07 | 4.1 | 0.00 | 0.0 |
| 1a | 5 | 116 | 0.89 | 0.21 | 23.8 | 0.07 | 7.4 | 0.01 | 1.4 |
| 1a | 6 | 116 | 0.80 | 0.25 | 31.5 | 0.04 | 5.5 | 0.00 | 0.0 |
| 2 | 7 | 120 | 6.97 | 0.06 | 0.9 | 0.03 | 0.5 | 0.05 | 0.6 |
| 2 | 8 | 116 | 2.99 | 0.08 | 2.6 | 0.02 | 0.8 | 0.03 | 1.1 |
| 2 | 9 | 118 | 1.65 | 0.14 | 8.5 | 0.00 | 0.0 | 0.05 | 2.8 |
| 2 | 10 | 119 | 1.05 | 0.22 | 21.3 | 0.00 | 0.0 | 0.06 | 5.9 |
ᵃ Within-Laboratory includes Within-Run, Between-Run, and Between-Day Variance Components.
ᵇ Total (Overall) includes Within-Run, Between-Run, Between-Day, and Between-Site Variance Components.
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Table 11. Alinity m HCV (Alternate Enzymes Formulation) Overall Negative Agreement Analysis
| Panel | Site | N | Negative Agreement Rate | 95% CI | |
|---|---|---|---|---|---|
| Total | Positive | Negative | |||
| 11 | All | 120 | 0 | 120 | 100.0% |
The Total SD and Total %CV for each panel member in this study were compared with the Total SD and Total %CV from the original reproducibility study submitted in P190025. Refer to Table 12.
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Table 12. Equivalence Evaluation of Total SD and Total %CV (New ᵃ vs. Original ᵇ)
| Genotype | Panel | Mean Concentration | Total SD | Total %CV | Ratios and 95% CI | ||||
|---|---|---|---|---|---|---|---|---|---|
| New Mean (Log IU/mL) | Original Mean (Log IU/mL) | New SD | Original SD | New %CV | Original %CV | SD | %CV | ||
| 1a | 1 | 7.71 | 8.50 | 0.25 | 0.15 | 3.2 | 1.7 | 1.68 (0.97, 2.92) | 1.85 (1.06, 3.21) |
| 1a | 2 | 5.72 | 6.15 | 0.10 | 0.16 | 1.8 | 2.6 | 0.64 (0.44, 0.93) | 0.69 (0.48, 1.00) |
| 1a | 3 | 3.53 | 3.89 | 0.08 | 0.18 | 2.4 | 4.5 | 0.47 (0.36, 0.61) | 0.52 (0.40, 0.68) |
| 1a | 4 | 1.84 | 1.95 | 0.14 | 0.22 | 7.8 | 11.0 | 0.66 (0.52, 0.84) | 0.70 (0.55, 0.90) |
| 1a | 5 | 0.89 | 1.06 | 0.24 | 0.35 | 27.5 | 33.0 | 0.70 (0.53, 0.94) | 0.83 (0.63, 1.11) |
| 1a | 6 | 0.80 | 0.65 | 0.26 | 0.37 | 32.9 | 56.8 | 0.71 (0.58, 0.87) | 0.58 (0.47, 0.71) |
| 2 | 7 | 6.97 | 7.30 | 0.09 | 0.11 | 1.3 | 1.5 | 0.83 (0.59, 1.16) | 0.87 (0.62, 1.21) |
| 2 | 8 | 2.99 | 3.06 | 0.09 | 0.21 | 3.0 | 6.7 | 0.44 (0.36, 0.54) | 0.45 (0.36, 0.56) |
| 2 | 9 | 1.65 | 1.44 | 0.16 | 0.24 | 9.7 | 17.0 | 0.66 (0.51, 0.85) | 0.57 (0.44, 0.74) |
| 2 | 10 | 1.05 | 0.88 | 0.24 | 0.30 | 23.1 | 34.2 | 0.80 (0.66, 0.98) | 0.67 (0.55, 0.83) |
ᵃ "New" Mean Concentration, Total SD, and Total %CV data for Alinity m HCV assay formulated with alternative enzymes.
ᵇ "Original" Mean Concentration, Total SD, and Total %CV data for on-market Alinity m HCV assay (submitted in P190025).
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1.7.1.2 Method Comparison
A method comparison study was conducted with the Alinity m HCV assay formulated with the alternative DNA Polymerase and the alternative Reverse Transcriptase to demonstrate equivalence to the FDA-approved (on-market) Alinity m HCV assay formulated with the original DNA Polymerase and the original Reverse Transcriptase (P190025).
Regression and bias analysis included a total of 222 samples with results that were within the common quantitation range of both the Alinity m HCV assay formulated with alternative enzymes formulation (Alinity m HCV IUO) and the comparator assay (on-market Alinity m HCV). Figure 2 shows the results of the Deming regression analysis with a slope of 1.01, an intercept of 0.03, and a correlation coefficient of 0.996.
The mean bias between Alinity m HCV IUO and the comparator (Alinity m HCV IUO minus comparator) was 0.06 Log IU/mL with a 95% Confidence Interval of (0.04, 0.09).
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Figure 2. Deming Regression Analysis
[THIS IS FIGURE: A scatter plot showing the correlation between Comparator HCV Quantitation (Log IU/mL) on x-axis and Alinity m HCV IUO Quantitation (Log IU/mL) on y-axis. The plot shows a strong linear relationship with the equation y = 1.01x + 0.03, r = 0.996, n = 222. Data points range from approximately 1 to 8 on both axes, following a tight linear pattern.]
The Systematic difference between Alinity m HCV assay formulated with alternate enzymes and the on-market Alinity m HCV assay (comparator) at 4 selected viral load levels is shown in Table 13.
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Table 13. Systematic Difference at Selected Viral Load Levels
| Target Viral Load Level (per comparator) | Systematic Difference | 95% CI (Log IU/mL) |
|---|---|---|
| 1.08 Log IU/mL | 0.04 Log IU/mL | (-0.00, 0.09) |
| 1.40 Log IU/mL | 0.05 Log IU/mL | (0.00, 0.09) |
| 3.60 Log IU/mL | 0.06 Log IU/mL | (0.04, 0.09) |
| 5.80 Log IU/mL | 0.08 Log IU/mL | (0.05, 0.11) |
1.8 Conclusions Drawn from the Studies
The additional analytical and clinical study results demonstrate that the Alinity m HCV assay formulated with the alternative DNA Polymerase and the alternative Reverse Transcriptase performs comparably to the FDA approved Alinity m HCV assay formulated with the original DNA Polymerase and the original Reverse Transcriptase. The results support a substantial equivalence decision for Alinity m HCV formulated with the alternative DNA Polymerase and the alternative Reverse Transcriptase.
§ 866.3170 Nucleic acid-based hepatitis C virus ribonucleic acid tests.
(a)
Identification. A nucleic acid-based hepatitis C virus (HCV) ribonucleic acid (RNA) test is identified as an in vitro diagnostic device intended for prescription use as an aid in the diagnosis of HCV infection in specified populations, and/or as an aid in the management of HCV-infected patients including guiding the selection of genotype-specific treatment in individuals with chronic HCV infection. The test is intended for use with human serum or plasma. The test is not intended for use as a donor screening test for the presence of HCV antibodies in blood, blood products, or tissue donors.(b)
Classification. Class II (special controls). The special controls for this device are:(1) For all nucleic acid-based HCV RNA tests, the labeling required under § 809.10(b) of this chapter must include:
(i) A prominent statement that the test is not intended for use as a donor screening test for the presence of HCV RNA from human cells, tissues, and cellular and tissue-based products.
(ii) A detailed explanation of the principles of operation and procedures for performing the assay.
(iii) A detailed explanation of the interpretation of results.
(iv) Limitations, which must be updated to reflect current clinical practice and disease presentation and management. These limitations must include, but are not limited to, statements that indicate:
(A) The specimen types for which the device has been cleared and that use of this test kit with specimen types other than those specifically cleared for this device may result in inaccurate test results.
(B) When applicable, that assay performance characteristics have not been established in populations of immunocompromised or immunosuppressed patients or, other populations where test performance may be affected.
(C) Test results are to be interpreted by qualified licensed healthcare professionals in conjunction with the individual's clinical presentation, history, and other laboratory results.
(2) For all nucleic acid-based HCV RNA tests, the design verification and validation must include:
(i) Detailed device description, including the device components, ancillary reagents required but not provided, and an explanation of the device methodology. Additional information appropriate to the technology must be included such as design of primers and probes, rationale for the selected gene targets, specifications for amplicon size, and degree of nucleic acid sequence conservation.
(ii) For devices with assay calibrators, the design and nature of all primary, secondary, and subsequent quantitation standards used for calibration as well as their traceability to a standardized reference material that FDA has determined is appropriate (
e.g., a recognized consensus standard). In addition, analytical testing must be performed following the release of a new lot of the standard material that was used for device clearance or approval, or when there is a transition to a new calibration standard.(iii) Documentation and characterization (
e.g., determination of the identity, supplier, purity, and stability) of all critical reagents (including nucleic acid sequences for primers and probes) and protocols for maintaining product integrity.(iv) Detailed documentation of analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including, but not limited to, limit of detection (LoD), upper and lower limits of quantitation (ULoQ and LLoQ, respectively), linearity, precision, endogenous and exogenous interferences, cross reactivity, carryover, matrix equivalency, and sample and reagent stability. Samples selected for use in analytical studies or used to prepare samples for use in analytical studies must be from subjects with clinically relevant circulating genotypes in the United States. Cross-reactivity studies must include samples from HCV RNA negative subjects with other causes of liver disease, including autoimmune hepatitis, alcoholic liver disease, chronic hepatitis B virus, primary biliary cirrhosis, and nonalcoholic steatohepatitis, when applicable. The effect of each claimed nucleic-acid isolation and purification procedure on detection must be evaluated.
(v) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on test performance.
(vi) Final release criteria to be used for manufactured test lots with appropriate evidence that lots released at the extremes of the specifications will meet the claimed analytical and clinical performance characteristics as well as the stability claims.
(vii) Multisite reproducibility study that includes the testing of three independent production lots.
(viii) All stability protocols, including acceptance criteria.
(ix) Final release test results for each lot used in clinical studies.
(x) Analytical sensitivity and specificity of the test must be the same or better than that of other cleared or approved tests.
(xi) Lot-to-lot precision studies, as appropriate.
(3) For devices intended for the qualitative detection of HCV RNA, in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, the design verification and validation must include detailed documentation of performance from a multisite clinical study. Performance must be analyzed relative to an FDA cleared or approved qualitative HCV RNA test, or a comparator that FDA has determined is appropriate. This study must be conducted using appropriate patient samples, with appropriate numbers of HCV positive and negative samples in applicable risk categories. Additional genotypes must be validated using appropriate numbers and types of samples. The samples may be a combination of fresh and repository samples, sourced from within and outside the United States, as appropriate. The study designs, including number of samples tested, must be sufficient to meet the following criteria:
(i) Clinical sensitivity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 95 percent.
(ii) Clinical specificity of the test must have a lower bound of the 95 percent confidence interval of greater than or equal to 96 percent.
(4) For devices intended for the quantitative detection of HCV RNA, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:
(i) Labeling required under § 809.10(b) of this chapter must include a prominent statement that the test is not intended as a diagnostic test to confirm the presence of active HCV infection, when applicable.
(ii) Design verification and validation must include the following:
(A) Detailed documentation of the following analytical performance studies conducted as appropriate to the technology, specimen types tested, and intended use of the device, including but not limited to: LoD, ULoQ and LLoQ. LoD, LLoQ, and linearity studies must demonstrate acceptable device performance with all HCV genotypes detected by the device.
(B) Detailed documentation of clinical performance testing from either:
(
1 ) A multisite clinical study with an appropriate number of clinical samples from chronically HCV infected patients in which the results are compared to an FDA-cleared or approved quantitative HCV RNA test, or a comparator that FDA has determined is appropriate. This study must include a sufficient number of HCV positive samples containing an analyte concentration near the LLoQ to describe performance at this level. Clinical samples must cover the full range of the device output and must be consistent with the distribution of these genotypes in the U.S. population. Clinical samples may be supplemented with diluted clinical samples for those viral load concentrations that are not sufficiently covered by natural clinical specimens, or(
2 ) A clinical study with prospectively collected samples demonstrating clinical validity of the device.(C) Detailed documentation of a qualitative analysis near the lower end of the measuring range demonstrating acceptable performance when used as an aid in diagnosis.
(5) For devices intended for HCV RNA genotyping, in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, design verification and validation must include the following:
(i) Detailed documentation of an analytical performance study demonstrating the LoD for all HCV genotypes detected by the device.
(ii) Detailed documentation, including results, of a multisite clinical study that assesses genotyping accuracy (
i.e., the proportion of interpretable results that match with the reference method result) and the genotyping rate (i.e., the proportion of results that were interpretable).(6) For any nucleic acid-based HCV RNA test intended for Point of Care (PoC) use, the following special controls, in addition to those listed in paragraphs (b)(1) and (2) of this section, apply:
(i) Clinical studies must be conducted at PoC sites.
(ii) Additional labeling must include a brief summary of the instructions for use that are appropriate for use in a PoC environment.