The ADVIA Centaur Active-B12 (Holotranscobalamin)(AB12) assay is for in vitro diagnostic use in the quantitative measurement of holotranscobalamin (holoTC) in human serum using the ADVIA Centaur XP system. Active-B12 (holotranscobalamin) is used as an aid in the diagnosis and treatment of vitamin B12 deficiency.

Device Description

The ADVIA Centaur AB12 assay is a fully automated, two-step direct immunoassay using chemiluminescent technology. The assay utilizes an acridinium ester-labeled anti-transcobalamin antibody as the Lite Reagent. The Solid Phase consists of biotinylated anti-holotranscobalamin antibody coupled to streptavidin-coated magnetic latex microparticles.

AI/ML Overview

Here's an analysis of the provided text regarding the ADVIA Centaur Active-B12 (Holotranscobalamin) (AB12) assay, structured to address your specific questions about acceptance criteria and the supporting study:

It's important to note that this document is a 510(k) summary, which is a high-level overview. It describes a modification to an already cleared device (K160757), primarily focusing on a change in calibration traceability. Therefore, detailed study protocols and raw data are not typically included in this summary. The summary focuses on demonstrating that the modified device is substantially equivalent to the predicate device and that the modification did not negatively impact its performance.

Since this is a summary of a modification intended to show substantial equivalence, the "acceptance criteria" discussed are largely in the context of ensuring the modification did not degrade performance.

1. Table of Acceptance Criteria and Reported Device Performance

The document states that "The device passed all of the tests based on pre-determined Pass/Fail criteria." However, the specific numerical acceptance criteria for each test are not explicitly provided in this 510(k) summary. It lists the types of tests performed and implies that the results were satisfactory.

Test Type	Acceptance Criteria (Implied)	Reported Device Performance
Accuracy by correlation	Performance comparable to predicate / within acceptable limits	Passed
Dilution Linearity	Performance comparable to predicate / within acceptable limits	Passed
20-day precision (repeatability and within-run)	Performance comparable to predicate / within acceptable limits	Passed
Detection capability (Limit of blank / detection / quantification)	Performance comparable to predicate / within acceptable limits	Passed (Limit of Quantitation: 5.0 pmol/L)
Dilution recovery of WHO IRP (NIBSC 03/178)	Accurate recovery of the WHO Standard	Passed
Proficiency sample testing	Performance comparable to predicate / within acceptable limits	Passed
Reference range / expected value for asymptomatic population	Comparable to predicate / clinically acceptable reference interval	Mean: 90.24 pmol/L (95% CI: 27.24 to 169.62 pmol/L) - Comparable to predicate (81.91 pmol/L, 95% CI: 28.96 to 168.90 pmol/L)

2. Sample Size Used for the Test Set and Data Provenance

The summary does not explicitly state the sample sizes used for the various validation tests (Accuracy, Linearity, Precision, Detection Limits, Recovery, Proficiency, or Reference Range).

Data Provenance: Not explicitly stated, but the reference range study provides a mean and 95% central reference interval for an "asymptomatic population," implying human serum samples. The device itself is for in vitro diagnostic use in human serum. The data would have been collected in the course of validating the device. The manufacturer is Axis-Shield Diagnostics Ltd. in Scotland, UK, so it's plausible the data collection occurred there or in other regions where they conducted studies. The study is retrospective in the sense that these tests are performed after the device (or its modification) has been developed, but the sample collection itself for the reference range could be prospective.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications of Those Experts

This type of information is not applicable and not provided in the context of this device. This is an in vitro diagnostic (IVD) assay that measures a biomarker (holotranscobalamin) directly. The "ground truth" for the test set is established by the analytical reference methods or reference materials (like the WHO International Standard), not by human experts interpreting images or complex clinical scenarios.

4. Adjudication Method for the Test Set

This is not applicable for this type of IVD device. Adjudication methods (like 2+1, 3+1) are typically used in studies involving human interpretation of medical images or clinical data where there might be inter-reader variability. For an IVD assay, the result is a quantitative measurement, and the "ground truth" is based on the accuracy and precision of the analytical measurement itself, often against a validated reference method or material.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study was not done. This type of study is for evaluating human performance, often with and without AI assistance, especially in radiology or pathology. This device is an automated IVD assay, not an AI-assisted human interpretation tool.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

This device is a standalone algorithm/assay in the sense that it performs the measurement automatically without human intervention during the measurement process. The "performance" mentioned (accuracy, linearity, precision, etc.) are all standalone performance metrics of the assay itself. There is no "human-in-the-loop" once the sample is loaded onto the ADVIA Centaur XP system for this specific measurement.

7. The Type of Ground Truth Used

The ground truth for evaluating the performance of this IVD assay is primarily based on:

Reference Materials: Specifically, the WHO International Standard for Holotranscobalamin (NIBSC Code 03/178) is highlighted as the new traceability standard for calibration. This serves as a primary ground truth for accurate measurement.
Comparative Methods: The "Accuracy by correlation" likely involved comparing results from the modified device with those obtained using a reference method or the predicate device.
Defined Concentrations: For tests like dilution linearity, precision, and detection capability, samples with precisely known or established concentrations of holotranscobalamin are used.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" sample size as this is not a machine learning or AI algorithm in the contemporary sense that would require a separate training phase with a distinct dataset for model building. The calibration process implicitly "trains" the device to measure correctly against known standards. The calibration itself uses "2-point Calibration using 2 level calibrators" (Low – 19 pmol/L, High - 121 pmol/L). However, this is not a "training set" in the context of complex ML models.

9. How the Ground Truth for the Training Set Was Established

Given that there isn't a traditional "training set" for a machine learning model, the "ground truth" for the calibration materials (which serve a similar function of establishing correct performance parameters) is established through:

Reference to the WHO International Standard (NIBSC Code 03/178): The primary modification in this 510(k) is to make the calibration traceable to this international standard. This standard itself would have been value-assigned through a rigorous international collaborative study.
Internal Reference Material: The predicate device used an "Internal reference material; recombinant holotranscobalamin and phosphate buffer with protein (bovine) stabilizers." This internal standard would have been characterized and assigned values through the manufacturer's own internal assay development and validation processes, likely against an existing recognized reference method or material.

In summary, this 510(k) pertains to a minor modification (calibration traceability) of an existing in vitro diagnostic test. The evaluation focuses on ensuring the modification did not alter the fundamental performance characteristics, and the "acceptance criteria" are implied to be that the modified device performs comparably to the predicate and meets standard analytical performance requirements for IVDs. The "study" refers to a series of analytical verification and validation tests rather than clinical trials with human readers or AI algorithms.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002 October 27, 2017

AXIS-SHIELD DIAGNOSTICS LTD. CLAIRE DORA REGULATORY AFFAIRS MANAGER LUNA PLACE THE TECHNOLOGY PARK DUNDEE, SCOTLAND DD2 1XA UK

Re: K172133

Trade/Device Name: ADVIA Centaur Active-B12 (Holotranscobalamin) (AB12) assay Regulation Number: 21 CFR 862.1810 Regulation Name: Vitamin B12 test system Regulatory Class: II Product Code: CDD Dated: September 26, 2017 Received: September 28, 2017

Dear Dr. Claire Dora:

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 (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, 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.

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); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the

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electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely yours,

Kellie B. Kelm -S

Courtney H. Lias, Ph.D. for Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K172133

Device Name

ADVIA Centaur Active-B12 (Holotranscobalamin)(AB12) assay

Indications for Use (Describe)

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)

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510(k) Summary

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.

The assigned 510(k) number is K172133

Submission correspondent:

Dr Claire Dora Regulatory Affairs Manager Axis-Shield Diagnostics Ltd. The Technology Park Dundee, DD2 1XA, Scotland, UK Telephone: +44(0) 1382 422000 Fax: +44(0) 1382 422088 510k summary prepared date: 25th October 2017

Device Name:

ADVIA Centaur® Active-B12 (Holotranscobalamin) (AB12) Assay

Reagents:

Classification Name: Vitamin B12 test system Trade Name: ADVIA Centaur® Active-B12 (Holotranscobalmin) (AB12) assay Common Name: B12 test Governing Regulation: 21CFR 862.1810 Device Classification: Class II Classification Panel: Clinical Chemistry Product Code: CDD

Legally marketed device to which equivalency is claimed:

ADVIA Centaur Active-B12 (Holotranscobalamin) (AB12) assay, K160757

Intended Use of Device:

The ADVIA Centaur Active-B12 (Holotranscobalamin) (AB12) assay is for in vitro diagnostic use in the quantitative measurement of holotranscobalamin (holoTC) in human serum using the ADVIA Centaur XP system. Active-B12 (holotranscobalamin) is used as an aid in the diagnosis and treatment of vitamin B12 deficiency.

Description of Device:

Centaur AB12 assay is a fully automated, two-step direct immunoassay The ADVIA using chemiluminescent technology. The assay utilizes an acridinium ester-labeled anti-transcobalamin antibody as the Lite Reagent. The Solid Phase consists of biotinylated anti-holotranscobalamin antibody coupled to streptavidin-coated magnetic latex microparticles.

Comparison of Technological Characteristics:

The modified ADVIA Centaur AB12 assay is being compared to the cleared ADVIA Centaur AB12 assay (K160757) for the quantitative measurement of holotranscobalamin (holoTC) in human serum.

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Modification of Device:

The special 510k modification ADVIA Centaur AB12 assay consisted of a change to the calibration to be traceable to the WHO International Standard for Holotranscobalamin.

Comparison of the subject device with the predicate device:

The modified ADVIA Centaur® AB12 assay is being compared to the cleared ADVIA Centaur® AB12 assay (K160757).

Parameter	NEWADVIA Centaur®AB12(Modified Device)	PREDICATEADVIA Centaur®AB12(K160757 cleared device)
Intended use	Same	For in vitro diagnostic use in the quantitativemeasurement of holotranscobalamin (holoTC) inhuman serum using the ADVIA Centaur XP system.Active-B12 (holotranscobalamin) is used as an aid inthe diagnosis and treatment of vitamin B12deficiency.
Assay Technology /System	Same	Chemiluminescent microparticleimmunoassay ADVIA Centaur XP/XPT system
Reagents	Same	Lite Reagent:anti-transcobalamin (TC) monoclonal Ab 3-11(0.5 µg/mL) labeled with acridinium ester inbuffer with surfactant and preservativesSolid Phase Reagent:streptavidin coated paramagnetic mPpreformed with biotinylated anti-holoTCmonoclonal antibody 3C4(~0.4 mg/mL) in buffer with surfactant
Calibration	Same	2-point Calibration using 2 level calibrators
Calibration Range	Same	0 to 146.0 pmol/L
Calibration Frequency	Same	44 days
Levels	Same	2 LevelsLow – 19 pmol/LHigh - 121 pmol/L
Fill volume	Same	4.0 mL
Calibration MaterialsFormulation/ Matrix	Same	recombinant holotranscobalamin, bovineserum albumin and sodium azide (< 0.1%)
Standardization	World Health Organization(WHO) International Standard forholotranscobalamin; NIBSC Code03/178	Internal reference material; recombinantholotranscobalamin and phosphate bufferwith protein (bovine) stabilizers
Traceability ofcalibration materials	WHO International StandardNIBSC Code 03/178	Internal (in-house)reference standard
Parameter	NEWADVIA Centaur®AB12(Modified Device)	PREDICATEADVIA Centaur®AB12(K160757 cleared device)
Expected Values inAsymptomaticPopulation	The mean holoTCconcentration for the group wasestablished at 90.24 pmol/L with a95% central reference intervalfrom 27.24 to 169.62 pmol/L	The mean holoTC concentration for the group wasestablished at 81.91 pmol/L with a 95% centralreference interval from 28.96 to 168.90 pmol/L
Analytical measuringrange	Same	5.0 to 146.0 pmol/L
Limit of Quantitation	Same	5.0 pmol/L
Quality Controls:Level 1 (Low) Control	Same	15.60 pmol/L
Quality Controls:Level 2 (High) Control	Same	60.40 pmol/L

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Summary of Non-Clinical Performance

Based on the risk analysis, the modifications to the Active-B12 (Holotranscobalamin) (AB12) assay could affect the accuracy, linearity, precision, and detection limits of the assay as well as the reference range.

Verification, validation and testing activities were conducted to establish performance of the modified device, which included:

Accuracy by correlation Dilution Linearity 20-day precision – repeatability and within-run Detection capability - Limit of blank / detection / quantification Dilution recovery of WHO IRP (NIBSC 03/178) Proficiency sample testing Reference range / expected value for asymptomatic population

The device passed all of the tests based on pre-determined Pass/Fail criteria.

Conclusion:

The results presented in this 510(k) premarket submission demonstrate that the candidate assay (ADVIA Centaur® Active-B12 (Holotranscobalamin)(AB12) assay is substantially equivalent to the predicate device.

Substantial equivalence of the modified device, ADVIA Centaur AB12 assay is claimed to the predicate device cleared in K160757. The modification to the assay calibration has not changed use, as described in the labelling, nor has it altered the fundamental assay technology of the device.

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.