The ACS:180 VB12 and ADVIA Centaur assays are competitive assays. Vitamin B12, or cyanocobalamin, is a complex corrinoid compound containing four pyrrole rings that surround a single cobalt atom. Humans obtain vitamin B12 exclusively from animal dietary sources, such as meat, eggs, and milk. Vitamin B12 requires intrinsic factor, a protein secreted by the parietal cells in the gastric mucosa, for absorption. Vitamin B12 and intrinsic factor form a complex that attaches to receptors in the ileal mucosa, where proteins known as trans-cobalamins transport the vitamin B12 from the mucosal cells to the blood and tissues. Most vitamin B12 is stored in the liver as well as in the bone marrow and other tissues. The ACS:180 VB12 and ADVIA Centaur VB12 assays are competitive assays in which vitamin B12 from the patient sample competes with vitamin B12 labeled with acridinium ester in the Lite Reagent, for a limited amount of purified intrinsic factor, which is covalently coupled to paramagnetic particles in the Solid Phase. The assay uses Releasing Agent (sodium hydroxide) and DTT to release the vitamin B12 from the endogenous binding proteins in the sample and cobinamide to prevent rebinding after the Solid Phase is added to the sample.

AI/ML Overview

Here's an analysis of the provided text regarding the acceptance criteria and study for the Bayer Diagnostics ACS:180 VB12 and ADVIA Centaur VB12 assays.

1. Table of Acceptance Criteria and Reported Device Performance

The document provided does not explicitly state "acceptance criteria" through a pass/fail threshold, but rather presents various performance characteristics that would be evaluated for substantial equivalence. I will interpret the reported performance characteristics as meeting the implied acceptance criteria for a device of this type.

Performance Characteristic	Acceptance Criteria (Implied)	Reported Device Performance
Reference Range	Established for normal and deficient populations.	ACS:180 / ADVIA Centaur:Normal (253 samples): 211-911 pg/mL (Median: 382 pg/mL, 95% range)Deficient (45 samples): 32-246 pg/mL (Median: 160 pg/mL)
Assay Reportable Range	Demonstrated ability to measure a specific range of values.	ACS:180 / ADVIA Centaur:Up to 2000 pg/mL (1476 pmol/L)
Minimum Detectable Concentration (Sensitivity)	Demonstrated ability to detect low concentrations.	ACS:180 / ADVIA Centaur:30 pg/mL (22 pmol/L)
Serum vs. Plasma Method Comparison (Correlation)	High correlation (r-value) and close agreement between serum and plasma measurements.	ACS:180:Plasma VB12 = 1.04 (serum VB12) + 9 pg/mL, r = 0.96 (213 pairs)ADVIA Centaur:Plasma VB12 = 1.03 (serum VB12) + 12 pg/mL, r = 0.96 (207 pairs)
Precision (Within-Run & Total %CV)	Low coefficient of variation (CV%) to demonstrate reproducibility.	ACS:180 (n=231 per sample):- 1147 pg/mL: Within-run 2.68% CV, Total 3.44% CV- 661 pg/mL: Within-run 2.70% CV, Total 3.24% CV- 204 pg/mL: Within-run 3.73% CV, Total 4.79% CV- 169 pg/mL: Within-run 5.33% CV, Total 6.28% CVADVIA Centaur (n=72 per sample):- 178.76 pg/mL: Within-run 5.0% CV, Run-to-run 9.2% CV, Total 10.4% CV- 207.22 pg/mL: Within-run 4.0% CV, Run-to-run 4.4% CV, Total 5.9% CV- 608.83 pg/mL: Within-run 2.7% CV, Run-to-run 2.7% CV, Total 3.8% CV- 1343.87 pg/mL: Within-run 2.4% CV, Run-to-run 3.0% CV, Total 3.9% CV

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

Reference Range Determination:
- Sample Size: 298 serum samples (253 from apparently healthy individuals, 45 from physician-diagnosed vitamin B12 deficient patients).
- Data Provenance: Not explicitly stated, but clinical samples are generally considered prospective or retrospective from a patient population within a medical setting (e.g., a hospital or clinic). No country of origin is mentioned.
Serum vs. Plasma Method Comparison:
- ACS:180: 213 pairs of serum and plasma specimens.
- ADVIA Centaur: 207 pairs of serum and plasma specimens.
- Data Provenance: Not explicitly stated. Assumed to be clinical samples.
Precision Studies:
- ACS:180: 4 samples, assayed 3 times in 7 assays on each of 11 systems over 5 days (n=231 for each sample level).
- ADVIA Centaur: 4 samples, assayed 6 times in each of 12 runs on 6 systems over 3 days (n=72 for each sample level).
- Data Provenance: Not explicitly stated, but these are typically controlled laboratory experiments using known samples rather than patient data.

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

Reference Range Determination:
- The "ground truth" for the deficient samples was established by physician-diagnosed vitamin B12 deficient patients. The number of physicians or their specific qualifications are not mentioned.
For the method comparison and precision studies, the "ground truth" is implied to be the actual concentration of vitamin B12 in the samples, measured by the assays themselves or potentially other reference methods, and assessed for consistency. This type of ground truth does not typically involve human expert consensus in the same way image interpretation or diagnostic decisions would.

4. Adjudication Method for the Test Set

For the performance studies described (reference range, method comparison, precision), no human adjudication method (like 2+1 or 3+1 for clinical diagnosis) is mentioned or appears applicable. These are quantitative measurements where the "ground truth" is the measured analyte concentration or a reference range defined by a cohort.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This type of study is typically conducted for diagnostic devices (e.g., imaging devices) where multiple human readers interpret cases with and without AI assistance. The described device is an immunoassay for quantitative determination of a biomarker; its performance is assessed through analytical validation (precision, accuracy, range, correlation) rather than reader studies.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, the entire performance validation for these immunoassay systems can be considered a "standalone" assessment of the device's analytical performance. The device directly measures vitamin B12 concentration, and the studies reported (precision, range, method comparison) evaluate the device's output without direct human interpretation influencing the measurement itself. The human element comes in interpreting the result in a clinical context, but the device's output is independent.

7. The Type of Ground Truth Used

Reference Range Determination:
- For the normal group: Based on a population of "apparently healthy individuals," implying a statistically derived range from a healthy cohort.
- For the deficient group: Based on "physician-diagnosed vitamin B12 deficient patients," indicating a clinical diagnosis as the ground truth.
Method Comparison and Precision: The ground truth is the quantitative concentration of vitamin B12 in the samples, determined by the assays themselves and compared for consistency and agreement. This is an analytical ground truth.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI models. Given that these are immunoassay devices, their development typically involves biochemical optimization and calibration, rather than a machine learning training phase with a distinct training dataset. Therefore, the concept of a training set as understood in AI/ML is not directly applicable here. The development data used for optimizing reagents and protocols would be analogous but not explicitly reported as a "training set" in this context.

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

As mentioned in point 8, the concept of a "training set" in the AI/ML sense doesn't directly apply to these immunoassay devices. The ground truth for their development would involve using reference materials, spiked samples, and clinical samples with known (or previously established) vitamin B12 concentrations to calibrate the assay and optimize its performance characteristics. This is part of the standard assay development and validation process for IVD devices.

Summary

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Image /page/0/Picture/1 description: The image shows a handwritten alphanumeric string. The string is "K993571". The characters are written in a simple, slightly slanted style.

Summary of Safety and Effectiveness

As required by 21 CFR 807.92, the following 510(k) Summary is provided:

1. Submitters Information

Contact person:	Thomas F. FlynnManager of Regulatory Affairs
Address:	Bayer Diagnostics Corporation63 North StreetMedfield, MA 02052
Phone:	508 359-3877
Date Summary Prepared:	October 18, 1999
2. Device Information
Proprietary Name:	Bayer Diagnostics ACS:180 VB12Bayer Diagnostics ADVIA Centaur VB12
Common Name:	Immunoassay for vitamin B12
3. Predicate Device Information
Name:	Current legally marketed device (ACS:180 and ADVIACentaur VB12)

Manufacturer:

Bayer Diagnostics Corporation

4. Device Description

The ACS:180 VB12 and ADVIA Centaur assays are competitive assays.

Vitamin B12, or cyanocobalamin, is a complex corrinoid compound containing four pyrrole rings that surround a single cobalt atom. Humans obtain vitamin B12 exclusively from animal dietary sources, such as meat, eggs, and milk. Vitamin B12 requires intrinsic factor, a protein secreted by the parietal cells in the gastric mucosa, for absorption. Vitamin B12 and intrinsic factor form a complex that attaches to receptors in the ileal mucosa, where proteins known as trans-cobalamins transport the vitamin B12 from the mucosal cells to the blood and tissues. Most vitamin B12 is stored in the liver as well as in the bone marrow and other tissues,

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5. Statement of Intended Use

ACS180 VB12:

In vitro diagnostic use in the quantitative determination of vitamin B12 in serum. heparinized plasma, or EDTA plasma using the ADVIA Centaur System using the ACS:180® Automated Chemiluminescence Systems.

ADVIA Centaur:

In vitro diagnostic use in the quantitative determination of vitamin B12 in serum, heparinized plasma, or EDTA plasma using the ADVIA® Centaur System.

6. Summary of Technological Characteristics

The ACS:180 VB12 and ADVIA Centaur VB12 assays are competitive assays in which vitamin B12 from the patient sample competes with vitamin B12 labeled with acridinium ester in the Lite Reagent, for a limited amount of purified intrinsic factor, which is covalently coupled to paramagnetic particles in the Solid Phase. The assay uses Releasing Agent (sodium hydroxide) and DTT to release the vitamin B12 from the endogenous binding proteins in the sample and cobinamide to prevent rebinding after the Solid Phase is added to the sample.

7. Performance Characteristics

Expected Results:

To determine the reference range for the ACS:180 and ADVIA Centaur VB12 assays, data was obtained on 298 serum samples, including 253 samples from apparently healthy individuals and 45 samples from physician-diagnosed vitamin B12 deficient patients. Ninety-five percent of the serumACS:180 VB12 values for the apparently healthy individuals fell in the range of 211 to 911 pg/mL (156 to 672 pmol/L).

Category	Median(pg/mL)	Range(pg/mL)	Median(pmol/L)	Range(pmol/L)
Normal	382	211–911	282	156-672
Deficient	160	32–246	118	24-181

Sensitivity and Assay Reportable Range:

The ACS:180 and ADVIA Centaur VB12 assays measures vitamin B12 concentrations up to 2000 pg/mL (1476 pmol/L) with a minimum detectable concentration of 30 pg/mL (22 pmol/L).

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Serum Versus Plasma Method Comparison:

ACS 180:

A comparison of values for 213 pairs of serum and plasma specimens in the range of 160 to 1000 pg/mL (118 to 738 pmol/L) yielded the following regression equation: plasma VB12 = 1.04 (serum VB12) + 9 pg/mL, r = 0.96

ADVIA Centaur:

A comparison of values for 207 pairs of serum and plasma specimens in the range of 147 to 1033 pg/mL (108 to 762 pmol/L) yielded the following regression equation: plasma VB12 = 1.03 (serum VB12) + 12 pg/mL, r = 0.96

Precision:

ACS180:

Four samples were assayed 3 times in 7 assays, on each of 11 systems (n=231 for each sample), over a period of 5 days. The following results were obtained:

Mean	Mean	Within-run	Total
(pg/mL)	(pmol/L)	% CV	% CV
1147	846	2.68	3.44
661	488	2.70	3.24
204	151	3.73	4.79
169	125	5.33	6.28

ADVIA Centaur:

Four samples were assayed 6 times, in each of 12 runs, on 6 systems, (n = 72 for each sample), over a period of 3 days. The following results were obtained:

Mean (pg/mL)	Mean(pmol/L)	Within-run %CV	Run-to-run %CV	Total % CV
178.76	131.89	5.0	9.2	10.4
207.22	152.89	4.0	4.4	5.9
608.83	449.19	2.7	2.7	3.8
1343.87	991.51	2.4	3.0	3.9

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Image /page/3/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" arranged around the top half of the circle. Inside the circle is a stylized image of an eagle with three wing-like shapes extending upwards and to the right.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

DEC I 6 1999

Mr. Thomas F. Flynn Manager of Regulatory Affairs Bayer Corporation Business Group Diagnostics 63 North Street Medfield, Massachusetts 02052-1688

K993571 Trade Name: Chiron Diagnostics ACS:180 VB12 Assay Regulatory Class: II Product Code: CDD Dated: October 18, 1999 Received: October 21, 1999

Dear Mr. Flynn:

Re:

We have reviewed your Section 510(k) notification of intent to market the device referenced above and we 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). 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,

If your device is classified (see above) into either class II (Special Controls) or class III (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. A substantially equivalent determination assumes compliance with the Current Good Manufacturing Practice requirements, as set forth in the Quality System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Register. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.

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Page 2

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655.

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

If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification"(21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597, or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html".

Sincerely yours,

Steven Putman

Steven I. Gutman, M.D, M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Page ⊥ of ⊥

4993571 510(k) Number (if known): ____________________________________________________________________________________________________________________________________________________

Device Name: Chiron Diagnostics ACS:180 VB12 Assay

Indications for Use:

In vitro diagnostic use in the quantitative determination of vitamin B12 in serum, heparinized plasma, or EDTA plasma using the ADVIA Centaur System.

Qeen Cooper

Division Sign-Off

ivision of Clinical Laboratory Devices 0(k) Number _ K 99

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

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use	✓
(Per 21 CFR 801.109)

510(k) Number (if known):	K910343 K993571
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Over-The-Counter Use (Optional Format 1-2-96)

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.