(86 days)
The Access anti-HBc IgM assay is a paramagnetic particle, chemiluminescent immunoassay for the in vitro qualitative detection of IgM antibodies to hepatitis B virus core antigen (anti-HBc IgM) in human pediatric (3 through 21 years) and adult serum and serum separator tubes or plasma [lithium heparin, lithium heparin separator tubes, dipotassium (K2) EDTA, tripotassium (K3) EDTA, sodium citrate, acid citrate dextrose (ACD), and citrate phosphate dextrose (CPD)] using the DxI 9000 Access Immunoassay Analyzer.
The Access anti-HBc IgM assay results may be used as an aid in the laboratory diagnosis of acute or recent hepatitis B virus (HBV) infection in individuals with signs and symptoms of hepatitis, when used in conjunction with other serological and clinical information.
The Access anti-HBc IgM assay is for use on the DxI 9000 Access Immunoassay Analyzer only.
This assay is not intended for the screening of blood, plasma, and cell or tissue donors.
The Access anti-HBc IgM assay is a two-step enzyme immunoassay. Paramagnetic particles coated with anti-human IgM monoclonal antibody and prediluted sample are added to a reaction vessel. After incubation, material bound to the solid phase is held in a magnetic field while unbound materials are washed away. HBc antigen complexed to anti-HBc monoclonal antibody alkaline phosphatase conjugate is added and the conjugate binds to the IgM antibodies captured on the particles. A second separation and wash step remove unbound conjugate.
A chemiluminescent substrate is then added to the vessel and light generated by the reaction is measured with a luminometer. The light production is compared to the cutoff value defined during calibration of the instrument. The qualitative assessment is automatically determined from a stored calibration.
The Access anti-HBc IgM Calibrator is used to establish calibration (determine the cutoff value) for the Access anti-HBc IgM assay. By comparing the light intensity generated by a sample to the cutoff value, the presence or absence of IgM antibodies to hepatitis B virus core antigen (anti-HBc IgM) in the sample is determined.
N/A
FDA 510(k) Clearance Letter - Access anti-HBc IgM
Page 1
U.S. Food & Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
www.fda.gov
Doc ID # 04017.08.04
March, 13, 2026
Beckman Coulter, Inc.
Veronica Colinayo
Staff Regulatory Affairs
250 S. Kraemer Blvd.
Brea, California 92821
Re: K254059
Trade/Device Name: Access anti-HBc IgM
Regulation Number: 21 CFR 21 CFR 866.3173
Regulation Name: Hepatitis B Virus (HBV) Antibody Assay
Regulatory Class: Class II
Product Code: SEI
Dated: December 17, 2025
Received: December 17, 2025
Dear Veronica Colinayo:
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.
Page 2
K254059 - Veronica Colinayo 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 Management System Regulation (QMSR) (21 CFR Part 820), which includes, but is not limited to, ISO 13485 clause 7.3 (Design controls), ISO 13484 clause 8.3 (Nonconforming product), and ISO 13485 clause 8.5 (Corrective and preventative action). Please note that regardless of whether a change requires premarket review, the QMSR requires device manufacturers to review and approve changes to device design and production (ISO 13485 clause 7.3 and 21 CFR 820.70) and document changes and approvals in the Medical Device File (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 Management System Regulation (QMSR) (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.
Page 3
K254059 - Veronica Colinayo Page 3
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-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,
Uwe Scherf -S
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): K254059
Device Name: Access anti-HBc IgM
Indications for Use (Describe)
The Access anti-HBc IgM assay is a paramagnetic particle, chemiluminescent immunoassay for the in vitro qualitative detection of IgM antibodies to hepatitis B virus core antigen (anti-HBc IgM) in human pediatric (3 through 21 years) and adult serum and serum separator tubes or plasma [lithium heparin, lithium heparin separator tubes, dipotassium (K2) EDTA, tripotassium (K3) EDTA, sodium citrate, acid citrate dextrose (ACD), and citrate phosphate dextrose (CPD)] using the DxI 9000 Access Immunoassay Analyzer.
The Access anti-HBc IgM assay results may be used as an aid in the laboratory diagnosis of acute or recent hepatitis B virus (HBV) infection in individuals with signs and symptoms of hepatitis, when used in conjunction with other serological and clinical information.
The Access anti-HBc IgM assay is for use on the DxI 9000 Access Immunoassay Analyzer only.
This assay is not intended for the screening of blood, plasma, and cell or tissue donors.
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
510(k) Summary
Access anti-HBc IgM 510(k) Summary Page 1 of 15
Confidential - Company Proprietary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
510(k) Number: K254059
Date Prepared: March 11, 2026
Submitter Name and Address:
Beckman Coulter, Inc
250 S. Kraemer Boulevard
Brea, CA 92821
Primary Contact:
Veronica V. Colinayo, Ph.D.
Staff Regulatory Affairs
Email: vvcolinayo@beckman.com
Device Trade Name: Access anti-HBc IgM
Device Classification Name: Qualitative Hepatitis B virus antibody assay
Classification Regulation: 21 CFR 866.3173
Class: II
Classification Product Code: SEI
Predicate Device
Device Name: ARCHITECT CORE-M
510(k) Numbers: P060035
Purpose for Submission: New device market clearance of Access anti-HBc IgM assay for use on the DxI 9000 Immunoassay Analyzer
Device Description
The Access anti-HBc IgM assay is a two-step enzyme immunoassay. Paramagnetic particles coated with anti-human IgM monoclonal antibody and prediluted sample are added to a reaction vessel. After incubation, material bound to the solid phase is held in a magnetic field while unbound materials are washed away. HBc antigen complexed to anti-HBc monoclonal antibody alkaline phosphatase conjugate is added and the conjugate binds to the IgM antibodies captured on the particles. A second separation and wash step remove unbound conjugate.
A chemiluminescent substrate is then added to the vessel and light generated by the reaction is measured with a luminometer. The light production is compared to the cutoff value defined during calibration of the instrument. The qualitative assessment is automatically determined from a stored calibration.
The Access anti-HBc IgM Calibrator is used to establish calibration (determine the cutoff value) for the Access anti-HBc IgM assay. By comparing the light intensity generated by a sample to the cutoff value, the presence or absence of IgM antibodies to hepatitis B virus core antigen (anti-HBc IgM) in the sample is determined.
Page 6
Access anti-HBc IgM 510(k) Summary Page 2 of 15
Proprietary and Confidential – For Registration Purposes Only
Quality control (QC) materials simulate the characteristics of patient samples and are essential for monitoring the system performance of the Access anti-HBc IgM immunoassay. In addition, they are an integral part of good laboratory practices. When performing assays with Access reagents for anti-HBc IgM, include quality control materials to validate the integrity of the assays. The assayed values should fall within the acceptable range if the test system is working properly.
The Access anti-HBc IgM reagents are provided in liquid ready-to-use format designed for optimal performance on the Beckman Coulter DxI 9000 Access Immunoassay Analyzer only. Each reagent kit contains two reagent packs. The Access anti-HBc IgM Calibrator kit contains one vial, and the Access anti-HBc IgM QC kit contains three vials each of QC1 (negative for anti-HBc IgM) and QC2 (positive for anti-HBc IgM). Other items needed to run the assay include Lumi-Phos PRO (chemiluminescent substrate) and UniCel DxI Wash Buffer II.
Intended Use
The Access anti-HBc IgM assay is a paramagnetic particle, chemiluminescent immunoassay for the in vitro qualitative detection of IgM antibodies to hepatitis B virus core antigen (anti-HBc IgM) in human pediatric (3 through 21 years) and adult serum and serum separator tubes or plasma [lithium heparin, lithium heparin separator tubes, dipotassium (K2) EDTA, tripotassium (K3) EDTA, sodium citrate, acid citrate dextrose (ACD), and citrate phosphate dextrose (CPD)] using the DxI 9000 Access Immunoassay Analyzer.
The Access anti-HBc IgM assay results may be used as an aid in the laboratory diagnosis of acute or recent hepatitis B virus (HBV) infection in individuals with signs and symptoms of hepatitis, when used in conjunction with other serological and clinical information.
The Access anti-HBc IgM assay is for use on the DxI 9000 Access Immunoassay Analyzer only.
This assay is not intended for the screening of blood, plasma, and cell or tissue donors.
Substantial Equivalence Information
The Access anti-HBc IgM and ARCHITECT CORE-M reagents employ prepackaged reagents for use on automated test systems. A comparison of the key device features, including similarities and differences of these assays, is shown in the following table.
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Access anti-HBc IgM 510(k) Summary Page 3 of 15
Proprietary and Confidential – For Registration Purposes Only
Comparison Table
| Features / Characteristics | Candidate Device Access anti-HBc IgM | Predicate Device ARCHITECT CORE-M (P060035) | Comment |
|---|---|---|---|
| Reagent Intended Use and Clinical Indications | The Access anti-HBc IgM assay is a paramagnetic particle, chemiluminescent immunoassay for the in vitro qualitative detection of IgM antibodies to hepatitis B virus core antigen (anti-HBc IgM) in human pediatric (3 through 21 years) and adult serum and serum separator tubes or plasma [lithium heparin, lithium heparin separator tubes, dipotassium (K2) EDTA, tripotassium (K3) EDTA, sodium citrate, acid citrate dextrose (ACD), and citrate phosphate dextrose (CPD)] using the DxI 9000 Access Immunoassay Analyzer. The Access anti-HBc IgM assay results may be used as an aid in the laboratory diagnosis of acute or recent hepatitis B virus (HBV) infection in individuals with signs and symptoms of hepatitis, when used in conjunction with other serological and clinical information. The Access anti-HBc IgM assay is for use on the DxI 9000 Access Immunoassay Analyzer only. This assay is not intended for the screening of blood, plasma, and cell or tissue donors. | The ARCHITECT CORE-M assay is a chemiluminescent microparticle immunoassay (CMIA) used for the qualitative detection of IgM antibody to hepatitis B core antigen (IgM anti-HBc) in human adult and pediatric serum or plasma (dipotassium EDTA, lithium heparin, and sodium heparin) and neonatal serum on the ARCHITECT i System. The ARCHITECT CORE-M assay is to be used as an aid in the diagnosis of acute or recent hepatitis B virus (HBV) infection in conjunction with other laboratory results and clinical information. | Similar |
| Calibrator and QC Intended Use | Calibrator: The Access anti-HBc IgM Calibrator is intended to calibrate the Access anti-HBc IgM assay for the in vitro qualitative detection of IgM antibodies to hepatitis B virus core antigen (anti-HBc IgM) in human serum and plasma using the DxI 9000 Access Immunoassay Analyzer. QC: The Access anti-HBc IgM QC is intended for monitoring system performance of the Access anti-HBc IgM assay. The Access anti-HBc IgM QC is for use on the DxI 9000 Access Immunoassay Analyzer. | Calibrator: The ARCHITECT CORE-M Calibrators are used for the calibration of the ARCHITECT i System when the system is used for the qualitative detection of IgM antibody to hepatitis B core antigen (IgM anti-HBc) using the ARCHITECT CORE-M Reagent Kit. The performance of the ARCHITECT CORE-M Calibrators has not been established with any other IgM anti-HBc assays. QC: The ARCHITECT CORE-M Controls are used for monitoring the performance of the ARCHITECT i System when used for the qualitative detection of lgM antibody to hepatitis B core antigen (IgM anti-HBc) in human adult serum and plasma when using the ARCHITECT CORE-M Reagent Kit. The performance of the ARCHITECT CORE-M Controls has not been established with any other IgM anti-HBc assays. | Similar |
Page 8
Access anti-HBc IgM 510(k) Summary Page 4 of 15
Proprietary and Confidential – For Registration Purposes Only
| Features / Characteristics | Candidate Device Access anti-HBc IgM | Predicate Device ARCHITECT CORE-M (P060035) | Comment |
|---|---|---|---|
| Operating Principle | Two-step immunoassay | Same | Same |
| Analyte Measured | anti-HBc IgM | Same | Same |
| Assay Type | Qualitative | Same | Same |
| Detection Method | Automated, Chemiluminescence immunoassay | Automated, Chemiluminescent microparticle immunoassay (CMIA) | Similar |
| Reagent, Calibrator, and QC format | Liquid, ready-to-use | Same | Same |
| Calibrator(s) | 1 level C1 (positive) | 2 levels Calibrator 1 (negative) Calibrator 2 (positive) | Different |
| Control(s) | 2 levels 1 Negative (QC1) 1 Positive (QC2) | 2 levels 1 Negative Control 1 Positive Control | Same |
| Sample Type | Serum and Plasma | Same | Same |
| Compatible Anticoagulants | Serum, Serum separator tube, Plasma [Lithium Heparin, Lithium Heparin separator tube, Dipotassium (K2) EDTA, Tripotassium (K3) EDTA Sodium Citrate, Acid Citrate Dextrose (ACD),Citrate Phosphate Dextrose (CPD)] | Human serum, plasma (dipotassium EDTA, Lithium Heparin, Sodium Heparin) | Similar |
| Sample Volume | 10 μL+ dead volume | 64 µL + dead volume | Different |
| Instrumentation | DxI 9000 Access Immunoassay Analyzer | ARCHITECT i Systems | Different |
| Test Result Reporting | • < 1.00 S/CO - Nonreactive • ≥ 1.00 S/CO - Reactive | • < 0.80 S/CO - Nonreactive • 0.80 to < 1.21 S/CO - Grayzone, re-test at approximately one-week intervals • ≥ 1.21 S/CO - Reactive | Different |
| Traceability/ Standardization | Calibrator is traceable to the manufacturer's working calibrator. | Calibrator 2 is traceable to the Reference Standard of the Paul Ehrlich Institute, HBc Referenzserum IgM 84 (IgM anti-HBc). | Different |
| Time to Result | ~ 29 minutes | ~ 30 minutes | Different |
| Reagent Storage and Stability | Unopened at 2 to 10°C up to stated expiration date | Unopened at 2 to 8°C up to stated expiration date | Similar |
| Reagent In-use (On-board) Stability | 56 days | 30 days | Different |
| Calibration Frequency | 56 days | 30 days | Different |
Page 9
Access anti-HBc IgM 510(k) Summary Page 5 of 15
Proprietary and Confidential – For Registration Purposes Only
Summary of Studies
Clinical Performance
Study Overview
A multi-center study was conducted using the DxI 9000 Access Immunoassay Analyzer to evaluate the performance of the Access anti-HBc IgM assay to detect anti-HBc IgM in plasma and serum samples from the intended use population. The overall study population included 2,537 specimens, consisting of 2,281 that were prospectively collected, and an additional 256 retrospective samples. Of the 2,281 specimens prospectively collected, 1,955 were from non-pregnant adults classified as increased risk for hepatitis due to lifestyle, behavior, occupation, or known exposure events, or individuals with signs and symptoms of hepatitis. 171 prospective specimens were from the pregnant population with increased risk and/or showed signs and symptoms of hepatitis. Specimens from the pregnant population included 71 from the first trimester, 67 from the second trimester, and 33 from the third trimester. In addition, 163 prospective and retrospective specimens were collected from the pediatric (ages 9-21) increased risk and/or sign & symptoms population. The table below summarizes the number of specimens in each population.
| Cohort | Adult (Non-Pregnant) (n =2,203) | Pregnant (n =171) | Pediatric (Non-Pregnant) (n =163) |
|---|---|---|---|
| S&S | IR | Retrospective | |
| Prospective (n=2,281) | 192 | 1,763 | 0 |
| Retrospective (n=256) | 0 | 0 | 248 |
| Total (n=2,537) | 192 | 1,763 | 248 |
S&S = Signs and Symptoms, IR = Increased Risk
Expected Results
The prospective study population was 61.25% White, 26.30% Black or African American, 1.49% Asian, 1.89% American Indian or Alaska Native, 0.13% Native Hawaiian or other Pacific Islander, and 8.94% from unknown/other or unwilling to answer. 34.41% of the prospective study population was of Hispanic ethnicity. The majority of patients were female (59% female and 41% male). Patients in the prospective population were collected from the United States (US) in the following states: Arizona (585, 25.65%), California (26, 1.14%), Connecticut (123, 5.39%), Florida (284, 12.45%), Georgia (61, 2.67%), Idaho (71, 3.11%), Minnesota (68, 2.98%), North Carolina (1, 0.04%), New Jersey (91, 3.99%), New York (445, 19.51%), Ohio (8, 0.35%), Pennsylvania (59, 2.59%), South Carolina (33, 1.45%), Tennessee (40, 1.75%), Texas (381, 16.70%) and Virginia (5, 0.22%). The retrospective study population was comprised of US samples and samples collected outside the US (Spain). Each sample was tested at one of three clinical sites located in Minneapolis, MN; Louisville, KY; or Baltimore, MD using the Access anti-HBc IgM assay and commercially available anti-HBc IgM assays.
The Access anti-HBc IgM results for the prospective population for all clinical trial sites combined by age group and gender are summarized in the table below. Samples were considered nonreactive if S/CO was ˂ 1.00 and reactive if S/CO was ≥ 1.00.
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Access anti-HBc IgM 510(k) Summary Page 6 of 15
Proprietary and Confidential – For Registration Purposes Only
Distribution of Access anti-HBc IgM Reactive and Nonreactive Results Among the Prospective Cohort by Age Group and Sex
| Age Range (years) | Sex | Access anti-HBc IgM | Total | |
|---|---|---|---|---|
| Nonreactive | Reactive | |||
| N | % | N | ||
| 9-12 | Female | 6 | 0.26 | 0 |
| Male | 11 | 0.48 | 0 | |
| 13-18 | Female | 34 | 1.49 | 0 |
| Male | 24 | 1.05 | 0 | |
| 19-21 | Female | 73 | 3.20 | 0 |
| Male | 28 | 1.23 | 0 | |
| 22-29 | Female | 301 | 13.20 | 0 |
| Male | 108 | 4.73 | 0 | |
| 30-39 | Female | 276 | 12.10 | 0 |
| Male | 129 | 5.66 | 0 | |
| 40-49 | Female | 190 | 8.33 | 0 |
| Male | 150 | 6.58 | 1 | |
| 50-59 | Female | 253 | 11.09 | 0 |
| Male | 225 | 9.86 | 1 | |
| 60-69 | Female | 153 | 6.71 | 0 |
| Male | 178 | 7.80 | 2 | |
| 70-79 | Female | 52 | 2.28 | 0 |
| Male | 55 | 2.41 | 0 | |
| 80-89 | Female | 9 | 0.39 | 0 |
| Male | 16 | 0.70 | 0 | |
| 90+ | Female | 1 | 0.04 | 0 |
| Male | 5 | 0.22 | 0 | |
| Total | 2,277 | 99.82 | 4 |
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Access anti-HBc IgM 510(k) Summary Page 7 of 15
Proprietary and Confidential – For Registration Purposes Only
Results by Specimen Classification
The HBV classification was determined by serological assessment for all prospective and retrospective specimens (n= 2,537) based on the reactivity patterns of six (6) HBV serological marker results (HBsAg, HBeAg, anti-HBc IgM, anti-HBc Total, anti-HBe, and anti-HBs) as illustrated in the table below. This testing was performed using FDA approved assays following the manufacturers' instructions for use.
| Classification | HBsAg | HBeAg | anti-HBc IgM | anti-HBc Total | anti-HBe | anti-HBs |
|---|---|---|---|---|---|---|
| Acute | + | + | + | + | - /+ | - |
| + | + | - /+ | - | - | - | |
| + | - | - | - | - | - | |
| + | + | eq | + | -/+ | - | |
| + | - | + | + | - | - | |
| + | - | eq | + | + | - | |
| Acute (late) | + | - | + | + | + | - /+ |
| Chronic | + | + | + | + | + | + |
| + | - | - | + | + | -/+ | |
| + | - | - | + | eq | - | |
| + | - | - | + | - | -/+ | |
| + | + | + | + | - | + | |
| + | + | - | + | - | -/+ | |
| + | + | - | + | + | - | |
| Early Recovery | - | - | - | + | -/+ | - |
| - | - | + | + | - | -/+ | |
| - | - | + | + | + | -/+ | |
| Recovery | - | - | - | -/+ | + | + |
| - | - | - | + | + | eq | |
| Recovered or Immune due to Natural Infection | - | - | - | + | - | +, eq |
| HBV Vaccine Response | - | - | - | - | - | + |
| Possible HBV Vaccination Response | - | - | - | - | - | eq |
| Not Previously Infected | - | - | - | - | - | - |
| Not Interpretable | - | + | - | + | - | + |
| - | - | - | - | + | - | |
| - | + | - | + | + | - | |
| - | + | - | - | - | -, eq, + |
Notes: The symbols (+) and (-) refer to a final status of reactive and nonreactive, respectively. The symbol eq refers to equivocal.
Due to volume limitations, two (2) samples were classified with four serological markers (HBsAg, anti-HBc IgM, anti-HBc T and anti-HBs) as "susceptible" and "recovered or immune due to natural infection".
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Access anti-HBc IgM 510(k) Summary Page 8 of 15
Proprietary and Confidential – For Registration Purposes Only
Comparison of Results
All samples were tested by the Access anti-HBc IgM assay and anti-HBc IgM comparator assays with a final sample status determined by the Composite Reference Method (CRM) for Access anti-HBc IgM as outlined in table below.
Composite Reference Method (CRM) Status
| Reference anti-HBc IgM | Comparator 1 | Comparator 2 | CRM Status |
|---|---|---|---|
| Reactive | Reactive | Reactive | Reactive |
| Reactive | Reactive | Nonreactive | Reactive |
| Reactive | Nonreactive | Reactive | Reactive |
| Reactive | Nonreactive | Nonreactive | Nonreactive |
| Equivocal | Reactive | Reactive | Reactive |
| Equivocal | Reactive | Nonreactive | Indeterminate* |
| Equivocal | Nonreactive | Reactive | Indeterminate* |
| Equivocal | Nonreactive | Nonreactive | Nonreactive |
| Nonreactive | Not tested | Not tested | Nonreactive |
*Final indeterminate results were excluded from analysis
Comparison of Results by HBV Classification Category
Access anti-HBc IgM results for each HBV classification were compared with the final interpretation from the CRM anti-HBc IgM assays in the table above. The positive and negative percent agreement (PPA and NPA) between the Access anti-HBc IgM assay results and CRM status from the reference and comparator anti-HBc IgM assays for the prospective population, based on HBV classification, is summarized in the following table.
| HBV Classification | Total | PPA | NPA | ||
|---|---|---|---|---|---|
| % (n/N) | 95% CI | % (n/N) | 95% CI | ||
| Acute | 4 | 100.0 (2/2) | 34.2-100.0 | 100.0 (2/2) | 34.2-100.0 |
| Chronic | 20 | N/A (0/0) | N/A | 95.00 (19/20) | 76.4-99.1 |
| Early Recovery | 70 | 25.00 (1/4)** | 4.6-69.9 | 100.0 (66/66) | 94.5-100.0 |
| HBV Vaccine Response | 769 | N/A (0/0) | N/A | 100.0 (769/769) | 99.5-100.0 |
| Not Previously Infected | 1,098 | N/A (0/0) | N/A | 100.0 (1,098/1,098) | 99.7-100.0 |
| Possible HBV Vaccination Response | 73 | N/A (0/0) | N/A | 100.0 (73/73) | 95.0-100.0 |
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Access anti-HBc IgM 510(k) Summary Page 9 of 15
Proprietary and Confidential – For Registration Purposes Only
| HBV Classification | Total | PPA | NPA | ||
|---|---|---|---|---|---|
| % (n/N) | 95% CI | % (n/N) | 95% CI | ||
| Recovered or Immune due to Natural Infection | 121* | N/A (0/0) | N/A | 100.0 (121/121) | 96.9-100.0 |
| Recovery | 121 | N/A (0/0) | N/A | 100.0 (121/121) | 96.9-100.0 |
| Susceptible | 1* | N/A (0/0) | N/A | 100.0 (1/1) | 20.7-100.0 |
| Not Interpretable | 4 | N/A (0/0) | N/A | 100.0 (4/4) | 51.0-100.0 |
| Total | 2,281 | 50.00 (3/6) | 18.8-81.2 | 99.96 (2,274/2,275) | 99.8-100.0 |
*One subject classified with four-marker classification.
** All four early recovery samples produced signals very close to the cutoff values of Access anti-HBc IgM and the reference and comparator anti-HBc IgM assays; two of the discordant samples produced results in concordance with the Access anti-HBc IgM upon re-testing (re-test results not used in performance calculations).
The PPA between the Access anti-HBc IgM assay results and CRM status from the reference and comparator anti-HBc IgM assays for the retrospective population, based on HBV classification, is summarized in the following table.
| HBV Classification | Total | PPA | |
|---|---|---|---|
| % (n/N) | 95% CI | ||
| Acute | 52 | 98.08 (51/52) | 89.9-99.7 |
| Acute (Late) | 85 | 100.0 (85/85) | 95.7-100.0 |
| Chronic | 5 | 100.0 (5/5) | 56.6-100.0 |
| Early Recovery | 52 | 90.38 (47/52) | 79.4-95.8 |
| Not Interpretable | 7 | 42.86 (3/7) | 15.8-75.0 |
| Total | 201 | 95.02 (191/201) | 91.1-97.3 |
Comparison of Results for Pregnant Women
One hundred and seventy-one (171) serum samples were prospectively collected from an increased risk and/or signs and symptoms U.S. pregnant population. The NPA between the Access anti-HBc IgM assay results and CRM status from the reference and comparator anti-HBc IgM assays for the pregnant women population by HBV classification is summarized in the following table. This population included 21 pregnant subjects of pediatric age (range 18 - 21 years). There were 71 subjects in the first trimester, 67 subjects in the second trimester and 33 subjects in the third trimester in this study.
| HBV Classification | Total | NPA | |
|---|---|---|---|
| % (n/N) | 95% CI | ||
| Chronic | 1 | 100.0 (1/1) | 20.65-100.0 |
| HBV Vaccine Response | 77 | 100.0 (77/77) | 95.25-100.0 |
| Not Previously Infected | 82 | 100.0 (82/82) | 95.52-100.0 |
| Possible HBV Vaccination Response | 9 | 100.0 (9/9) | 70.09-100.0 |
| Recovery | 2 | 100.0 (2/2) | 34.24-100.0 |
| Total | 171 | 100.0 (171/171) | 97.80-100.0 |
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Because no anti-HBc IgM positive samples were identified in the pregnant cohort, a spiking study was conducted to evaluate the results when pregnant samples are tested with the Access anti-HBc IgM assay. A total of thirty-one pregnant and control adult serum samples were spiked with a unique native anti-HBc IgM positive sample. The results showed that there were no significant differences between spiked pregnant samples versus control samples, indicating that the Access anti-HBc IgM assay detects anti-HBc IgM comparably between pregnant and non-pregnant adult populations.
Comparison of Results for Pediatric Population
One hundred and fifty-five (155) prospective and eight (8) retrospective specimens were collected with risk factors and/or signs and symptoms from a pediatric (non-pregnant) population (9-21 years). The PPA and NPA between the Access anti-HBc IgM assay results and CRM status from the reference and comparator anti-HBc IgM assays for the prospective pediatric population, based on HBV classification, is summarized in the following table.
| HBV Classification | Total | PPA | NPA | ||
|---|---|---|---|---|---|
| % (n/N) | 95% CI | % (n/N) | 95% CI | ||
| Early Recovery | 1 | 0.00 (0/1) | 0.0-79.3 | N/A | N/A |
| HBV Vaccine Response | 53 | N/A | N/A | 100.0 (53/53) | 93.2-100.0 |
| Not Previously Infected | 95 | N/A | N/A | 100.0 (95/95) | 96.1-100.0 |
| Possible HBV Vaccination Response | 3 | N/A | N/A | 100.0 (3/3) | 43.9-100.0 |
| Recovered or Immune due to Natural Infection | 2 | N/A | N/A | 100.0 (2/2) | 34.2-100.0 |
| Not Interpretable | 1 | N/A | N/A | 100.0 (1/1) | 20.7-100.0 |
| Total | 155 | 0.00 (0/1) | 0.0-79.3 | 100.0 (154/154) | 97.6-100.0 |
The PPA between the Access anti-HBc IgM assay results and CRM status from the reference and comparator anti-HBc IgM assays for the retrospective pediatric population, based on HBV classification, is summarized in the following table.
| HBV Classification | Total | PPA | |
|---|---|---|---|
| % (n/N) | 95% CI | ||
| Acute | 2 | 100.0 (2/2) | 34.2-100.0 |
| Acute (Late) | 2 | 100.0 (2/2) | 34.2-100.0 |
| Early Recovery | 4 | 100.0 (4/4) | 51.0-100.0 |
| Total | 8 | 100.0 (8/8) | 67.6-100.0 |
Because few anti-HBc IgM positives were identified in the pediatric cohort, a spiking study was conducted to evaluate the results when pediatric samples are tested with the Access anti-HBc IgM assay. A total of thirty-one pediatric (age 3–21 years) and control adult serum samples were spiked with a unique native anti-HBc IgM positive sample. The results showed that there were no significant differences in results of spiked pediatric samples versus control samples, indicating the Access anti-HBc IgM assay detects anti-HBc IgM comparably between pediatric and adult populations.
Seroconversion
Commercially available patient seroconversion panels were tested using the Access anti-HBc IgM assay and a reference assay to determine the seroconversion sensitivity of the assay. Equivalent detection with
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no difference in bleed number was observed in 3 of the 6 panels and earlier detection by the Access anti-HBc IgM assay was observed in 3 panels. The results are summarized in the table below.
| Panel ID | First anti-HBc IgM Positive Result from Initial Draw Date | Access anti-HBc IgM assay vs Reference assay | |
|---|---|---|---|
| Access anti-HBc IgM assay (days) | Reference assay (days) | Difference in bleed number for the first reactive bleed* | |
| HBV-6281 | 43 | 43 | 0 |
| HBV-9092 | 85 | 92 | -1 |
| HBV-9093 | 49 | 49 | 0 |
| HBV-001 | 36 | 43 | -1 |
| HBV-002 | 59 | 59 | 0 |
| HBV-004 | 71 | 76 | -1 |
*The difference in bleed number is compared to the reference assay. For example, -1 indicates that the reference assay required 1 additional bleed before reactivity was determined compared to the Access anti-HBc IgM assay.
Imprecision
The imprecision of the Access anti-HBc IgM assay was evaluated in a study based on CLSI EP05-A3 guidance. The study design included two test runs per day over a minimum of 20 test days. A ten-member panel of serum (S1-S4) and plasma (P1-P4) patient samples, and the Access anti-HBc IgM QC1 and QC2 were assayed in each run in triplicate. Three lots of Access anti-HBc IgM reagent and two lots of Access anti-HBc IgM calibrator were tested on three DxI 9000 Access Immunoassay Analyzers for the study. The results for all reagents lots combined are summarized in the following table.
| Sample | N | Mean (S/CO) | Repeatability (Within-Run) | Between-Run | Between-Day | Between-Lot | Between-Instrument | Within-Laboratory (Overall) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD (S/CO) | %CV | SD (S/CO) | %CV | SD (S/CO) | %CV | SD (S/CO) | %CV | SD (S/CO) | %CV | SD (S/CO) | %CV | |||
| QC1 | 2,160 | 0.01 | 0.000 | N/A | 0.001 | N/A | 0.001 | N/A | 0.001 | N/A | 0.000 | N/A | 0.002 | N/A |
| QC2 | 2,160 | 2.84 | 0.062 | 2.2 | 0.052 | 1.8 | 0.039 | 1.4 | 0.047 | 1.7 | 0.022 | 0.8 | 0.104 | 3.7 |
| S1 | 2,160 | 0.01 | 0.000 | N/A | 0.000 | N/A | 0.000 | N/A | 0.001 | N/A | 0.000 | N/A | 0.001 | N/A |
| S2 | 2,160 | 0.73 | 0.018 | 2.5 | 0.018 | 2.5 | 0.008 | 1.1 | 0.018 | 2.5 | 0.006 | 0.9 | 0.033 | 4.5 |
| S3 | 2,160 | 1.13 | 0.028 | 2.5 | 0.033 | 2.9 | 0.015 | 1.3 | 0.036 | 3.1 | 0.01 | 0.9 | 0.059 | 5.2 |
| S4 | 2,160 | 4.45 | 0.102 | 2.3 | 0.097 | 2.2 | 0.063 | 1.4 | 0.092 | 2.1 | 0.034 | 0.8 | 0.183 | 4.1 |
| P1 | 2,160 | 0.01 | 0.001 | N/A | 0.000 | N/A | 0.000 | N/A | 0.001 | N/A | 0.000 | N/A | 0.001 | N/A |
| P2 | 2,160 | 0.71 | 0.019 | 2.7 | 0.015 | 2.1 | 0.014 | 2 | 0.018 | 2.5 | 0.004 | 0.5 | 0.034 | 4.7 |
| P3 | 2,160 | 1.08 | 0.03 | 2.8 | 0.018 | 1.7 | 0.031 | 2.9 | 0.038 | 3.6 | 0.008 | 0.8 | 0.061 | 5.7 |
| P4 | 2,160 | 3.84 | 0.099 | 2.6 | 0.054 | 1.4 | 0.085 | 2.2 | 0.11 | 2.9 | 0.047 | 1.2 | 0.185 | 4.8 |
Note: %CV are not meaningful when S/CO approaches zero. Results are noted as N/A.
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Reproducibility
A 5-day reproducibility study was performed on the DxI 9000 Access Immunoassay Analyzer based on CLSI EP05-A3 guidance. A twelve-member panel of patient samples, including serum (S1-S6) and plasma (P1-P6) samples, were assayed at three clinical sites, using one lot of Access anti-HBc IgM reagent kit, on three instruments (one instrument per site). Each panel member was assayed in replicates of three at two separate times per day. The results are summarized in the following table.
| Sample | N | Mean (S/CO) | Repeatability (Within-Run) | Between-Run | Between-Day | Between-Site | Reproducibility | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD (S/CO) | %CV | SD (S/CO) | %CV | SD (S/CO) | %CV | SD (S/CO) | %CV | SD (S/CO) | %CV | |||
| S1 | 90 | 0.01 | 0 | N/A | 0 | N/A | 0 | N/A | 0 | N/A | 0 | N/A |
| S2 | 90 | 0.32 | 0.009 | 2.7 | 0.003 | 1.0 | 0 | 0 | 0.011 | 3.6 | 0.015 | 4.5 |
| S3 | 90 | 0.55 | 0.015 | 2.7 | 0.015 | 2.8 | 0 | 0 | 0.017 | 3.0 | 0.027 | 4.9 |
| S4 | 90 | 0.76 | 0.018 | 2.4 | 0.009 | 1.2 | 0.003 | 0.4 | 0.024 | 3.2 | 0.032 | 4.2 |
| S5 | 90 | 1.19 | 0.030 | 2.5 | 0.027 | 2.2 | 0 | 0 | 0.032 | 2.6 | 0.051 | 4.3 |
| S6 | 90 | 4.52 | 0.108 | 2.4 | 0.068 | 1.5 | 0.049 | 1.1 | 0.087 | 1.9 | 0.162 | 3.6 |
| P1 | 90 | 0.01 | 0 | N/A | 0 | N/A | 0 | N/A | 0 | N/A | 0 | N/A |
| P2 | 90 | 0.33 | 0.008 | 2.5 | 0.007 | 2.0 | 0.004 | 1.1 | 0.009 | 2.7 | 0.014 | 4.3 |
| P3 | 90 | 0.53 | 0.013 | 2.6 | 0.012 | 2.2 | 0 | 0 | 0.017 | 3.2 | 0.025 | 4.7 |
| P4 | 90 | 0.74 | 0.019 | 2.6 | 0.013 | 1.8 | 0 | 0 | 0.021 | 2.8 | 0.031 | 4.2 |
| P5 | 90 | 1.12 | 0.024 | 2.1 | 0.029 | 2.6 | 0 | 0 | 0.035 | 3.1 | 0.052 | 4.6 |
| P6 | 90 | 3.95 | 0.097 | 2.5 | 0.081 | 2.1 | 0.042 | 1.1 | 0.073 | 1.8 | 0.152 | 3.8 |
Note: %CV are not meaningful when S/CO approached zero. Results are noted as N/A.
Interfering Substances
The Access anti-HBc IgM assay was evaluated for interference consistent with CLSI document EP07 3rd Edition. Testing was performed using one negative and two reactive samples (one low positive and one moderate positive) with substances at the concentrations indicated. Of the compounds tested, none were found to cause interference using the highest test concentrations indicated in the following table.
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| Potential Interferent | Highest Concentration Added |
|---|---|
| Hemoglobin | 1,000 mg/dL |
| Total Protein | 15 g/dL |
| Bilirubin Conjugated | 40 mg/dL |
| Bilirubin Unconjugated | 40 mg/dL |
| Biotin | 3,510 ng/mL |
| Cholesterol | 400 mg/dL |
| Triglycerides (Intralipid) | 37 mmol/L (3,854 mg/dL) |
| Aspirin (acetylsalicylic acid) | 167 µmol/L |
| Salicylic acid | 207 µmol/L |
| Acetaminophen (paracetamol) | 1,030 µmol/L |
| Ibuprofen | 1,060 µmol/L |
| Atorvastatin | 1.34 µmol/L |
| Lisinopril | 0.607 µmol/L |
| Levothyroxine | 0.552 µmol/L |
| Metformin | 92.9 µmol/L |
| Amlodipine | 0.183 µmol/L |
| Omeprazole | 24.3 µmol/L |
| Sertraline | 3.03 µmol/L |
Cross Reactivity
Cross-reactivity was evaluated by testing samples for potentially cross-reacting conditions. No cross-reactivity was observed. The results are summarized in the following table.
| Category | Number of samples tested | Number of Reactive samples | Number of Nonreactive samples |
|---|---|---|---|
| Epstein-Barr virus (EBV IgM or VCA IgG) | 10 | 0 | 10 |
| Cytomegalovirus (CMV) | 10 | 0 | 10 |
| Herpes simplex virus (HSV 1/2) | 10 | 0 | 10 |
| Human immunodeficiency virus (HIV) | 10 | 0 | 10 |
| Hepatitis A virus (HAV) | 10 | 0 | 10 |
| Hepatitis C virus (HCV) | 10 | 0 | 10 |
| Hepatitis E virus (HEV) | 10 | 0 | 10 |
| Alcoholic liver disease | 10 | 0 | 10 |
| Primary biliary cirrhosis | 10 | 0 | 10 |
| Flavivirus (Zika) | 10 | 0 | 10 |
| Flavivirus (Dengue) | 10 | 0 | 10 |
| Flavivirus (West Nile) | 10 | 0 | 10 |
| Influenza post-vaccination | 10 | 0 | 10 |
| HAMA | 10 | 0 | 10 |
| Anti-nuclear antibody (ANA) | 10 | 0 | 10 |
| Rheumatoid Factor | 10 | 0 | 10 |
| Systemic lupus erythematosus (SLE) | 10 | 0 | 10 |
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| Category | Number of samples tested | Number of Reactive samples | Number of Nonreactive samples |
|---|---|---|---|
| Multiple myeloma | 10 | 0 | 10 |
| Pregnancy multipara | 10 | 0 | 10 |
| Pregnancy first trimester | 10 | 0 | 10 |
| Pregnancy second trimester | 10 | 0 | 10 |
| Pregnancy third trimester | 10 | 0 | 10 |
| Syphilis | 10 | 0 | 10 |
| Toxoplasmosis | 10 | 0 | 10 |
| Transplant recipient | 10 | 0 | 10 |
| Dialysis patients | 10 | 0 | 10 |
| Hemophiliac / Clotting factor deficiency | 10 | 0 | 10 |
| anti-E. coli (including E. coli urinary infection) | 10 | 0 | 10 |
| Rubella | 10 | 0 | 10 |
| Varicella Zoster Virus (VZV) | 10 | 0 | 10 |
| Measles | 10 | 0 | 10 |
| Mumps | 10 | 0 | 10 |
Matrix Equivalence
A matrix equivalence study was performed using a protocol based on CLSI EP09c, 3rd Edition. Matched donor sets consisting of nine specimen types each were used for the evaluation. Serum (without gel) served as the reference sample type. The results from the study demonstrate the equivalency between the reference sample type, serum (without gel) and the eight serum/plasma matrices evaluated. The results support use of human serum (without gel), serum separator tubes, or plasma (lithium heparin, lithium heparin with gel, dipotassium (K2) EDTA, tripotassium (K3) EDTA, sodium citrate, acid citrate dextrose (ACD), and citrate phosphate dextrose (CPD)) sample types.
Sample Stability
Sample Handling Stability
Sample handling and freeze/thaw stability was established for the Access anti-HBc IgM assay on the DxI 9000 Access Immunoassay Analyzer.
The study verified the following sample handling claims:
- Up to 72 hours when stored at 20-25°C
- Up to 7 days when stored at 2-8°C
- Up to 30 days, thaw samples no more than 5 times when stored at ≤ -20°C or colder.
Reagent Stability Studies
Access anti-HBc IgM reagents shelf-life dating was established based on real time stability (RTS) studies for the Access anti-HBc IgM Reagent Pack, Access anti-HBc IgM Calibrator, and Access anti-HBc IgM QC. The studies were performed to determine the shelf-life at the recommended storage condition (2-10°C), using a protocol based on CLSI EP25-ED2 guideline.
In-use studies were also performed using a protocol based on CLSI EP25-ED2 guideline. Each study included evaluation stability following simulated winter and summer transport stresses on the reagent packs, Calibrator, and QC.
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Intra-Assay Carryover
Testing was conducted to assess the sample-to-sample and sample-to-reagent pack carryover on the Access anti-HBc IgM assay. Test procedures were based on CSI EP10-A3 AMD guideline. No intra-assay carryover was observed with the Access anti-HBc IgM assay tested on the DxI 9000 Access Immunoassay Analyzer.
Hook Effect
A hook study was performed to evaluate if high levels of analyte in patient specimens result in a hook effect that changes the reported results of the Access anti-HBc IgM assay on the DxI 9000 Access Immunoassay Analyzer. The study was performed using a ten-dilution series originating from three anti-HBc IgM positive samples. No hook effect (no change in result interpretation) was observed for this assay.
Substantial Equivalence Comparison Conclusion
The results from the nonclinical and clinical studies demonstrate that the Access anti-HBc IgM assay is as safe, as effective, and performs as well as the predicate device.
§ 866.3173 Hepatitis B virus antibody assays.
(a)
Identification. A hepatitis B virus (HBV) antibody assay is identified as an in vitro diagnostic device intended for prescription use in the detection of antibodies to HBV in human serum, plasma, or other matrices, and as a device that aids in the diagnosis of HBV infection in persons with signs and symptoms of hepatitis and in persons at risk for hepatitis B infection. Results from assays may be qualitative or quantitative, such as quantitative anti-HBs. In addition, results from an anti-HBc IgM (IgM antibodies to core antigen) assay indicating the presence of anti-HBc IgM are indicative of recent HBV infection. Anti-HBs (antibodies to surface antigen) assay results may be used as an aid in the determination of susceptibility to HBV infection in individuals prior to or following HBV vaccination or when vaccination status is unknown. The assay is not intended for screening of blood, plasma, cells, or tissue donors. The assay is intended as an aid in diagnosis in conjunction with clinical findings and other diagnostic procedures.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10(b) of this chapter must include:
(i) A prominent statement that the assay is not intended for the screening of blood, plasma, cells, or tissue donors.
(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. The limitations must include statements that indicate:
(A) When appropriate, performance characteristics of the assay have not been established in populations of immunocompromised or immunosuppressed patients or other special populations where assay performance may be affected.
(B) Detection of HBV antibodies to a single viral antigen indicates a present or past infection with hepatitis B virus, but does not differentiate between acute, chronic, or resolved infection.
(C) The specimen types for which the device has been cleared, and that use of the assay with specimen types other than those specifically cleared for this device may result in inaccurate assay results.
(D) Diagnosis of hepatitis B infection should not be established on the basis of a single assay result but should be determined by a licensed healthcare professional in conjunction with the clinical presentation, history, and other diagnostic procedures.
(E) A non-reactive assay result may occur early during acute infection, prior to development of a host antibody response to infection, or when analyte levels are below the limit of detection of the assay.
(F) Results obtained with this assay may not be used interchangeably with results obtained with a different manufacturer's assay.
(v) For devices intended for the quantitative detection of HBV antibodies (anti-HBs), in addition to the special controls listed in paragraphs (b)(1) and (2) of this section, labeling required under § 809.10(b) of this chapter must include:
(A) The assay calibrators' traceability to a standardized reference material that FDA has determined is appropriate (
e.g., a recognized consensus standard) and the limit of blank (LoB), limit of detection (LoD), limit of quantitation (LoQ), linearity, and precision to define the analytical measuring interval.(B) Performance results of the analytical sensitivity study testing a standardized reference material that FDA has determined is appropriate (
e.g., a recognized consensus standard).(2) Design verification and validation must include the following:
(i) Detailed device description, including all parts that make up the device, ancillary reagents required but not provided, an explanation of the device methodology, and design of the antigen(s) and capture antibody(ies) sequences, rationale for the selected epitope(s), degree of amino acid sequence conservation of the target, and the design and composition of all primary, secondary and subsequent standards used for calibration.
(ii) Documentation and characterization (
e.g., supplier, determination of identity, and stability) of all critical reagents (including description of the antigen(s) and capture antibody(ies)), and protocols for maintaining product integrity throughout its labeled shelf life.(iii) Risk analysis and management strategies, such as Failure Modes Effects Analysis and/or Hazard Analysis and Critical Control Points summaries and their impact on assay performance.
(iv) Final release criteria to be used for manufactured assay lots with appropriate evidence that lots released at the extremes of the specifications will meet the identified analytical and clinical performance characteristics as well as stability.
(v) Stability studies for reagents must include documentation of an assessment of real-time stability for multiple reagent lots using the indicated specimen types and must use acceptance criteria that ensure that analytical and clinical performance characteristics are met when stability is assigned based on the extremes of the acceptance range.
(vi) All stability protocols, including acceptance criteria.
(vii) When applicable, analytical sensitivity of the assay that is the same or better than that of other cleared or approved assays.
(viii) Analytical performance studies and results for determining the limit of blank (LoB), limit of detection (LoD), cutoff, precision (reproducibility), including lot-to-lot and/or instrument-to-instrument precision, interference, cross reactivity, carryover, hook effect, seroconversion panel testing, matrix equivalency, specimen stability, reagent stability, and cross-genotype antibody detection sensitivity, when appropriate.
(ix) For devices intended for the detection of antibodies for which a standardized reference material (that FDA has determined is appropriate) is available, the analytical sensitivity study and results testing the standardized reference material. Detailed documentation of that study and its results must be provided, including the study protocol, study report, testing results, and all statistical analyses.
(x) For devices with associated software or instrumentation, documentation must include a detailed description of device software, including software applications and hardware-based devices that incorporate software. The detailed description must include documentation of verification, validation, and hazard analysis and risk assessment activities, including an assessment of the impact of threats and vulnerabilities on device functionality and end users/patients as part of cybersecurity review.
(xi) Detailed documentation of clinical performance testing from a clinical study with an appropriate number of HBV reactive and non-reactive samples in applicable risk categories and conducted in the appropriate settings by the intended users. Performance must be analyzed relative to an FDA cleared or approved HBV antibody assay or a comparator that FDA has determined is appropriate. Additional relevant patient groups must be validated as appropriate. The samples must include prospective (sequential) samples for each identified specimen type and, as appropriate, additional characterized clinical samples. Samples must be sourced from geographically diverse areas.
(3) For any HBV antibody assay intended for quantitative detection of anti-HBV antibodies, the following special controls, in addition to those special controls listed in paragraphs (b)(1) and (2) of this section, also apply:
(i) Detailed documentation of the metrological calibration traceability hierarchy to a standardized reference material that FDA has determined is appropriate.
(ii) Detailed documentation of the following analytical performance studies conducted, as appropriate to the technology, specimen types tested, and intended use of the device, including upper and lower limits of quantitation (UloQ and LloQ, respectively), linearity using clinical samples, and an accuracy study using the recognized international standard material.