AxSYM HoloTC assay is a Microparticle Enzyme Immunoassay (MEIA) for the quantitative determination of holotranscobalamin (HoloTC) in human scrum and plasma on the AxSYM System. HoloTC is used as an aid in the diagnosis and treatment of vitamin B12 deficiency.

The AxSYM HoloTC Standard Calibrators are for the standard calibration of the AxSYM System when used for the quantitative determination of holotranscobalmin (HoloTC) in human serum and plasma.

The AxSYM HoloTC Controls are for the use in quality control to monitor the accuracy and precision of the HoloTC assay when used for the quantitative determination of holotranscobalamin (HoloTC) in human serum and plasma on the AxSYM System.

For in vitro diagnostic use.

Device Description

AxSYM HoloTC is based on Microparticle Enzyme Immunoassay (MEIA) technology. The AxSYM HoloTC reagents and sample are pipetted in the following sequence:

SAMPLING CENTER

Sample and all AxSYM HoloTC reagents required for one test are pipetted by the . Sampling Probe into various wells of a Reaction Vessel (RV).
. A reaction mixture is formed by combining diluted sample and microparticles coated with Anti-HoloTC monoclonal antibody in the sample well of the RV.
. When human HoloTC antigen is present in the sample, it binds to the coated microparticles, forming antigen-antibody complexes on the microparticles.
. The Anti-TC Antibody:Alkaline Phosphatase Conjugate is pipetted into a second well of the RV.
발 The HoloTC Wash Buffer is pipetted into a third well of the RV.
파 The Matrix Cell Wash is pipetted into a fourth well of the RV.

The RV is immediately transferred into the Processing Center. Further pipetting is done in the Processing Center by the Processing Probe.

PROCESSING CENTER

. An aliquot of the reaction mixture, containing microparticles and bound antigenantibody complex, is transferred to the Matrix Cell. The microparticles bind irreversibly to the glass fiber matrix.
B The Matrix Cell is washed to remove materials not bound to the microparticles.
t The Anti-TC Antibody:Alkaline Phosphatase Conjugate is dispensed onto the Matrix Cell and it binds with the antigen-antibody complexes.
" The Matrix Cell is washed to remove conjugate not bound to the microparticles.
.. The substrate, 4-Methylumbelliferyl Phosphate, is added to the Matrix Ccll. The alkaline phosphatase-labeled conjugate catalyzes the removal of a phosphate group from the substrate, yielding the fluorescent product, 4-Methylumbelliferone. This fluorescent product is measured by the MEIA optical assembly.

AI/ML Overview

The AxSYM® HoloTC device is a Microparticle Enzyme Immunoassay (MEIA) intended for the quantitative determination of holotranscobalamin (HoloTC) in human serum and plasma to aid in the diagnosis and treatment of vitamin B12 deficiency.

Acceptance Criteria and Reported Device Performance

The acceptance criteria for the AxSYM® HoloTC assay are based on demonstrating substantial equivalence to its legally marketed predicate device, the Axis-Shield HoloTC Radioimmunoassay (K#030655). The key performance metrics evaluated were precision, linearity, interferences, stability, and method comparison, with specific acceptance thresholds for these parameters not explicitly detailed in the provided summary. However, the study concludes that the device successfully met these criteria.

Acceptance Criteria Category	Reported Device Performance (AxSYM® HoloTC vs. Axis-Shield HoloTC RIA)
Precision	Substantially equivalent
Linearity	Substantially equivalent
Interferences	Substantially equivalent
Stability	Substantially equivalent
Method Comparison	Correlation coefficient of 0.90

Study Information:

Sample Size Used for Test Set and Data Provenance:
- The document does not explicitly state the sample size used for the test set.
- The document implies the use of "human serum and plasma," but the country of origin or whether the data was retrospective or prospective is not specified.
Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications:
- This information is not provided in the summary. For an in vitro diagnostic device, "ground truth" often refers to a reference method or clinical diagnosis established through various means, not necessarily expert consensus in the same way it would be for an imaging AI.
Adjudication Method for the Test Set:
- This information is not applicable/provided for this type of in vitro diagnostic device study as it's not based on reader interpretation requiring adjudication.
Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No MRMC comparative effectiveness study was done as this is an in vitro diagnostic assay, not an AI for medical image analysis where human reader performance is typically evaluated.
Standalone Performance (Algorithm Only without Human-in-the-Loop Performance):
- Yes, the performance evaluated in this submission is the standalone performance of the AxSYM® HoloTC assay as an automated laboratory test. There is no human-in-the-loop component being evaluated for its performance.
Type of Ground Truth Used:
- The "ground truth" for this device's performance evaluation is established by comparison to a legally marketed predicate device: the Axis-Shield HoloTC Radioimmunoassay (RIA). The predicate device's results serve as the reference for determining the "substantial equivalence" of the new AxSYM® HoloTC assay. This falls under a form of comparative reference method rather than expert consensus, pathology, or outcomes data directly.
Sample Size for the Training Set:
- This information is not provided and is generally not applicable in the context of traditional in vitro diagnostic assays like MEIA, which do not typically involve machine learning 'training sets' in the same way AI algorithms do. Their 'training' involves optimizing reagents and protocols.
How the Ground Truth for the Training Set Was Established:
- As there is no "training set" in the context of an AI algorithm, this question is not applicable. The "ground truth" for method development and calibration would have been established through a rigorous process of analytical validation, using internal reference materials, spiked samples, and comparison to established methods, though the specifics are not detailed in this summary.

Summary

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Ka62467

AxSYM® HoloTC 510(K) SUMMARY (Summary of Safety and Effectiveness)

NOV 2 2 2006

This summary of the 510(k) safety and effectiveness information is being submitted in accordance with the requirements of CFR.

Preparation Date: 15th August 2006

Dr Erica Conway Regulatory Affairs Manager Axis-Shield Diagnostics, Ltd. The Technology Park Dundee DD2 1XA, Scotland, UK

Device Name:

Reagents:

Classification Name: HoloTC test system Trade Name: AxSYM® HoloTC Immunoassay Common Name: Holotranscobalamin test Governing Regulation: 862.1810 Device Classification: Class II Classification Panel: Chemistry Product Code: CDD

Calibrators:

Classification Name: Calibrator, Secondary Trade Name: AxSYM® HoloTC Standard Calibrators Common Name: Calibrator Governing Regulation: 862.1150 Device Classification: Class II Classification Panel: Clinical Chemistry Product Code: JIT

Controls:

Classification Name: Single (specified) analyte controls (assayed and unassayed) Trade Name: AxSYM® HoloTC Control Common Name: Control Governing Regulation: 862.1660 Device Classification: Class I Product Code: JJX

Legally marketed device to which equivalency is claimed:

Axis-Shield HoloTC Radioimmunoassay (K#030655)

AxSYM IloloTC 510(k) Summary ADMIN 4.0 510(k) Summary 15th August 2006

Page 1 of 3

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Intended Use of Device:

The AxSYM HoloTC Standard Calibrators are for the standard calibration of the AxSYM System when used for the quantitative determination of holotranscobalmin (HoloTC) in human serum and plasma.

Description of Device:

AxSYM HoloTC is based on Microparticle Enzyme Immunoassay (MEIA) technology. The AxSYM HoloTC reagents and sample are pipetted in the following sequence:

SAMPLING CENTER

Sample and all AxSYM HoloTC reagents required for one test are pipetted by the . Sampling Probe into various wells of a Reaction Vessel (RV).
. A reaction mixture is formed by combining diluted sample and microparticles coated with Anti-HoloTC monoclonal antibody in the sample well of the RV.
. When human HoloTC antigen is present in the sample, it binds to the coated microparticles, forming antigen-antibody complexes on the microparticles.
. The Anti-TC Antibody:Alkaline Phosphatase Conjugate is pipetted into a second well of the RV.
발 The HoloTC Wash Buffer is pipetted into a third well of the RV.
파 The Matrix Cell Wash is pipetted into a fourth well of the RV.

The RV is immediately transferred into the Processing Center. Further pipetting is done in the Processing Center by the Processing Probe.

PROCESSING CENTER

. An aliquot of the reaction mixture, containing microparticles and bound antigenantibody complex, is transferred to the Matrix Cell. The microparticles bind irreversibly to the glass fiber matrix.
B The Matrix Cell is washed to remove materials not bound to the microparticles.
t The Anti-TC Antibody:Alkaline Phosphatase Conjugate is dispensed onto the Matrix Cell and it binds with the antigen-antibody complexes.
" The Matrix Cell is washed to remove conjugate not bound to the microparticles.
.. The substrate, 4-Methylumbelliferyl Phosphate, is added to the Matrix Ccll. The alkaline phosphatase-labeled conjugate catalyzes the removal of a phosphate group from the substrate, yielding the fluorescent product, 4-Methylumbelliferone. This fluorescent product is measured by the MEIA optical assembly.

AxSYM HoloTC 510(k) Summary ADMIN 4.0 510(k) Summary 15th August 2006

Page 2 of 3

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Comparison of Technological Characteristics:

The AxSYM HoloTC assay is a Microparticle Enzyme Immunoassay (MEIA) for the quantitative determination of HoloTC in human scrum and plasma. The Axis-Shield HoloTC RIA is a competitive binding radioassay which uses a specific transcobalamin antibody to capture transcobalamin from the patient sample. The vitamin B12 bound to the captured transcobalamin is then measured by procedures commonly used in vitam to B12 assays.

Summary of Non-Clinical Performance:

The AxSYM HoloTC assay is substantially equivalent to the Axis-Shield HoloTC RIA radioassay in terms of precision, linearity, interferences and stability as demonstrated in non-clinical performance data in this 510(k) submission.

Summary of Clinical Performance:

The AxSYM HoloTC assay demonstrated substantially equivalent performance to the Axis-Shield HoloTC RIA radioassay indicated by a mcthod comparison with a correlation coefficient of 0.90.

Page 3 of 3

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DEPARTMENT OF HEALTH & HUMAN SERVICES

Image /page/3/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three overlapping wing-like shapes. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" is arranged in a circular pattern around the eagle.

Public Health Service

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Dr. Erica Conway Regulatory Affairs Manager Axis-Shield Diagnostics, Ltd. The Technology Park Dundee DD2 1XA, Scotland, UK

NOV 2 2 2006

Re: K062467

Trade/Device Name: AxSYM® HoloTC REAGENTS, AxSYM® HoloTC STANDARD CALIBRATORS (A-F) and AxSYM® HoloTC CONTROLS (LOW and HIGH) Regulation Number: 21 CFR 862.1810 Regulation Name: Vitamin B12 test system Regulatory Class: Class II Product Code: CDD, JIT, JJX Dated: August 21, 2006 Received: August 24, 2006

Dear Dr. Conway:

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 Foedd, Or o and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA), You may, therefore, market the device, subject to the general controls provisions of the Act . The general controls provisions of the Act include requirements for annual registration, into no of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your drivice can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing pratic requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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Page 2 –

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to Ilegally marketed predicate device results in a classification for your device and thus, perroits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (240) 276-0484. Also, please nother regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its tolloffree mobile (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.

Sincerely yours,

Alberto Gutt

Alberto Gutierrez, Ph.D. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Product Classification - Indications for Use Statement ADMIN 5.0

510(k) Number (if known):

Device Name: AxSYM® HoloTC REAGENTS, AxSYM® HoloTC STANDARD CALIBRATORS (A-F) and AxSYM® HoloTC CONTROLS (LOW and HIGH)

Indications for Use:

Reagents

AxSYM HoloTC assay is a Microparticle Enzyme Immunoassay (MEIA) for the quantitative determination of holotranscobalamin (vitamin B12 bound to transcobalamin) in human serum and plasma on the AxSYM System. HoloTC is used as an aid in the diagnosis and treatment of vitamin B12 deficiency.

Calibrators

The AxSYM HoloTC Standard Calibrators are for the standard calibration of the AxSYM System when used for the quantitative determination of holotranscobalmin (HoloTC) in human serum and plasma.

Controls

For in vitro diagnostic use.

Prescription Use _____________________________________________________________________________________________________________________________________________________________ (Part 21 CFR 801 Subpart D) OR

Over-The-Counter Use (21 CFR 807 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

Carol C. Benson
Division Sign-Off

Division Sign-Off

Office of In Vitro Diagnostic Device Evaluation and Safety

062467

Regulation Number and Section

§ 862.1810 Vitamin B

12 test system.(a)
Identification. A vitamin B12 test system is a device intended to measure vitamin B12 in serum, plasma, and urine. Measurements obtained by this device are used in the diagnosis and treatment of anemias of gastrointestinal malabsorption.(b)
Classification. Class II.