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.

Device Description

Competition principle. Total duration of assay: 18 minutes, 37*C. Competition principic. Total adalabating the sample (15 mL) with the •] * incubation (9 immutes). By metreatment 2 (15 mL), bound Vitamin B12 is liberated into the serum.

·2nd incubation (9 minutes): By incubating the pretreated sample with the •2nd incubation (9 innutes): Dy most, and immunocomplex is formed, the ruthenylated" * " intrilisic Tactor (70 this), " = " = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = · 3rd incubation (9 minutes): After addition of of streptaviding of a streptaviding of the still, •3rd incubation (9 mL) and Vitamin B12 labeled with biotin (60 mL), the still-

microparticles (30 mL) and Vitalini Dr.2 recorder become occupied, with the vacant sites of the ruthenylated Intrinst For and B12 biotin complex.
formation of an ruthenylated Intrinsic Factor-Viraming of biotin formation of an rutherrylated markisto i actor-phase via interaction of biotin.
The entire complex becomes bound to the solid phase via interaction of biotin. and streptavidin.

·The reaction mixture is aspirated into the measuring cell where the · I he reaction inixture is aspirated onto the surface of the electrode. microparticles are then removed with Procell. Application of a voltage Unbound substances are then removed was a secure in which is measured
to the electrode then induces chemiluminescent emission which is measured by a photomultiplier (0.4 second read frame).

·Results are determined via a calibration curve which is instrument-· Results are 'delemined ' via- a 'culturation and a master curve provided via the reagent bar code.

**Tris(2,2'-bipyridyl)ruthenium(II) complex (Ru(bpy)**3)

AI/ML Overview

The provided document is a 510(k) Summary for the Boehringer Mannheim Elecsys Vitamin B12 Assay. It describes the device, its intended use, and compares its performance characteristics to a predicate device.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated in terms of pass/fail thresholds for the Elecsys Vitamin B12 assay. Instead, the document presents performance characteristics of the Elecsys Vitamin B12 assay and the predicate device (BioRad Quantaphase II B12/Folate Radioassay) for comparison, implying that the Elecsys device's performance should be comparable or superior. The specific performance metrics reported are:

Feature	Elecsys Vitamin B12 (Reported Performance)	BioRad Quantaphase II B12/Folate Radioassay (Predicate Performance)	Implied Acceptance Criteria (e.g., comparable to predicate)
Precision (Within-Run)			Comparable %CV and SD to predicate
Level 1 Sample Mean	203.27 pg/mL (Pool 1)	127 pg/mL (Level I)
Within-run SD	14.11 pg/mL	8.9 pg/mL
Within-run %CV	6.94	4.10
Level 2 Sample Mean	481.02 pg/mL (Pool 2)	273 pg/mL (Level II)
Within-run SD	20.38 pg/mL	15.7 pg/mL
Within-run %CV	4.24	4.1
Level 3 Sample Mean	1499.36 pg/mL (Pool 3)	622 pg/mL (Level III)
Within-run SD	41.23 pg/mL	51.7 pg/mL
Within-run %CV	2.75	5.9
Level 4 Sample Mean	N/A (Elecsys)	1325 pg/mL (Level IV)
Within-run SD	N/A (Elecsys)	52.8 pg/mL
Within-run %CV	N/A (Elecsys)	4.0
Precision (Total)			Comparable %CV and SD to predicate
Level 1 Sample Mean	203.27 pg/mL (Pool 1)	127 pg/mL (Level I)
Total SD	15.41 pg/mL	8.6 pg/mL
Total %CV	7.58	6.8
Level 2 Sample Mean	481.02 pg/mL (Pool 2)	429 pg/mL (Level II)
Total SD	21.08 pg/mL	29.3 pg/mL
Total %CV	4.38	6.8
Level 3 Sample Mean	1499.36 pg/mL (Pool 3)	807 pg/mL (Level III)
Total SD	47.78 pg/mL	36.2 pg/mL
Total %CV	3.19	4.5
Level 4 Sample Mean	N/A (Elecsys)	1314 pg/mL (Level IV)
Total SD	N/A (Elecsys)	75.3 pg/mL
Total %CV	N/A (Elecsys)	5.7
Precision (Additional)
Level 1 Sample Mean	1119.49 pg/mL	N/A
Within run %CV	2.79	N/A
Total %CV	3.23	N/A
Level 2 Sample Mean	471.30 pg/mL	N/A
Within run %CV	5.48	N/A
Total %CV	5.68	N/A
Lower Detection Limit	30 pg/ml	20 pg/ml	Comparable (Elecsys is slightly higher, but within acceptable range for the intended use)
Linearity	30 - 2000 pg/ml	20 - 2000 pg/ml	Comparable
Method Comparison	Vs BioRad Quantaphase II:	Vs Commercially available radioimmunoassay:
Number of Samples (N)	346	84	Strong correlation (r value close to 1) and agreement (slope close to 1, intercept close to 0) to predicate/established methods.
Least Squares (y=mX+b)	y = 1.02X + 6.5, r = 0.9751	y = 1.01x + 44, r = 0.933
Passing Bablock (y=mX+b)	y = 1.06X - 9.5, r = 0.9751	N/A
Interfering Substances (No interference at:)	(within 30 pg/ml at Vitamin B12 level <300 pg/ml or within ±10% at Vitamin B12 level > 300 pg/ml)		Comparable or improved resistance to interferents
Bilirubin	80 mg/dL	20 mg/dL unconjugated, 20 mg/dL conjugated
Hemoglobin	1800 mg/dL	500 mg/dL
Lipemia	2500 mg/dL	3000 mg/dL
Rheumatoid Factor	500 IU/mL	N/A
Dysproteinemia	8.8 g/dL	N/A
Biotin	50 pg/ml	N/A
Reference Range	Normal: 243 - 894 pg/ml	Normal: 130 - 770 pg/ml	Clinically acceptable reference ranges
	Indeterminant: 175 - 244 pg/ml	Deficient: <204 pg/ml
	Deficient: <174 pg/ml
% Cross-reactivity			Low cross-reactivity for related substances
Cobinamide	0.024	0.1

Study Proving Acceptance Criteria:

The study proving the device meets the acceptance criteria is detailed in the "Performance Characteristics" section of the 510(k) Summary. It's a comparative study against a predicate device.

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

Precision Studies (Within-run and Total):
- For the Elecsys Vitamin B12 assay, N=60 for each of the three pools/levels tested.
- For the BioRad Quantaphase II, N=40 for each of the four levels tested.
Method Comparison:
- For the comparison of Elecsys to BioRad Quantaphase II B12/Folate Radioassay, the sample size was N=346.
- For the comparison of the predicate BioRad Quantaphase II to a commercially available radioimmunoassay, the sample size was N=84.

The document does not specify the country of origin of the data or whether it was retrospective or prospective. Given the context of a 510(k) submission for a diagnostic device, such studies are typically prospective clinical performance evaluations.

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

This type of information (number and qualifications of experts) is generally not applicable for the ground truth establishment in analytical performance studies of quantitative in vitro diagnostic (IVD) assays like a Vitamin B12 assay.

For an IVD measuring an analyte concentration:

The "ground truth" for method comparison and precision is usually an independent, highly accurate reference method or a carefully characterized reference material (e.g., control pools with assigned values).
For reference ranges, the "ground truth" comes from statistical analysis of a healthy population.
Interfering substances are tested experimentally by adding known concentrations of potential interferents to samples with known analyte concentrations.

Therefore, expert consensus, as might be used for image classification, is not the mechanism for establishing ground truth in this context.

4. Adjudication Method for the Test Set

Adjudication methods (e.g., 2+1, 3+1) are typically used in studies where human interpretation of data (e.g., medical images) is involved and discrepancies need resolution. For a quantitative in vitro diagnostic assay, the "adjudication method" is not applicable in the same sense. The results are numerical values, and any discrepancies would be resolved through re-testing, statistical analysis protocols, or review of instrument performance, rather than expert adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Improvement with AI vs. without AI Assistance

This section is not applicable because the device described, the Elecsys Vitamin B12 Assay, is an automated in vitro diagnostic (IVD) immunoassay. It does not involve human readers interpreting cases or AI assistance in a diagnostic workflow. It generates quantitative results directly.

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

This question is also not truly applicable in the context of this device. The Elecsys Vitamin B12 Assay is a standalone analytical instrument/reagent system designed to automatically measure Vitamin B12 concentrations. Its performance characteristics (precision, linearity, method comparison, interference) represent its "standalone" performance without direct human interpretation of the analytical signal. Human involvement typically comes in operating the instrument, performing calibration, quality control, and interpreting the numerical result in a clinical context, not in interpreting the raw assay signal.

7. The Type of Ground Truth Used

The ground truth used for these studies generally falls into these categories:

Reference Method / Predicate Device Comparison: For the method comparison study, the results from the BioRad Quantaphase II B12/Folate Radioassay (and another commercially available radioimmunoassay for the predicate) served as the comparative "ground truth" to establish substantial equivalence.
Known Concentrations: For precision, linearity, and interference studies, samples with accurately known or established concentrations of Vitamin B12 (e.g., control pools, spiked samples, diluted samples) were used to assess the device's accuracy and robustness.
Clinical Population Data: For the establishment of reference ranges, concentrations measured in a population determined to be healthy or having specific conditions (deficient, indeterminate) would have been used.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of device development. For an IVD assay like this, "training" primarily refers to:

Calibration: The instrument is calibrated using calibrators with known concentrations, which are fundamental to its operation.
Reagent Development and Optimization: Early development likely involves numerous experiments and samples to optimize reagent formulations and assay parameters.

The N=346 and N=84 for method comparison and N=60 and N=40 for precision studies represent the performance validation or test sets for demonstrating the device's characteristics against a predicate or general standards, not a training set in the machine learning sense. Statistical parameters (like calibration curves) are internal to the instrument, derived from known calibrators and master curves.

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

As "training set" in the machine learning sense is not explicitly described or directly applicable here, the establishment of "ground truth" relates to the calibration of the system and optimization during development, rather than a distinct training phase with a labelled dataset:

Calibrators: For calibration, the "ground truth" for the calibrator values is established through highly accurate reference methods or certified reference materials, ensuring the accurate assignment of concentration values to the calibrator solutions. These calibrators are then used by the Elecsys instrument to create its internal calibration curve.
Master Curve: The document mentions "Results are 'delemined' via- a 'culturation and a master curve provided via the reagent bar code." This "master curve" is pre-established by the manufacturer using extensive studies with reference materials and multiple reagent lots, effectively serving as programmatic "ground truth" for the instrument's calculations.

Summary

{0}------------------------------------------------

Image /page/0/Picture/0 description: The image shows a sequence of handwritten digits. The digits appear to be '4973702'. The numbers are written in black ink on a white background. The handwriting is somewhat stylized, with some numbers appearing more rounded than others.

NOV 1 3 1997

	510(k) Summary
Introduction	According to the requirements of 21 CFR 807.92, the following informationprovides sufficient detail to understand the basis for a determination ofsubstantial equivalence.
1.Submittername,address,contact	Boehringer Mannheim Corporation4300 Hacienda DrivePleasanton, CA 94588-2722(510) 730 - 8413Contact Person: Yvette LloydDate Prepared: September 24, 1997
2. Device name	Proprietary name: Elecsys Vitamin B12 AssayCommon name: Electrochemiluminescent immunoassay for the determinationof Vitamin B12.Classification name: System, Test, Vitamin B12
3. Predicatedevice	The Boehringer Mannheim Elecsys Vitamin B12 is substantially equivalent toother products in commercial distribution intended for similar use. Mostnotably it is substantially equivalent to the currently marketed BioRadQuantaphase II B12/Folate Assay (K935286).

{1}------------------------------------------------

10(k) Summary, Continued

Device Description Competition principle. Total duration of assay: 18 minutes, 37*C. Competition principic. Total adalabating the sample (15 mL) with the •] * incubation (9 immutes). By metreatment 2 (15 mL), bound Vitamin B12 is liberated into the serum.

·Results are determined via a calibration curve which is instrument-· Results are 'delemined ' via- a 'culturation and a master curve provided via the reagent bar code.

**Tris(2,2'-bipyridyl)ruthenium(II) complex (Ru(bpy)**3)

{2}------------------------------------------------

	510(k) Summary, Continued
5.Intended use	Assay for the in vitro quantitative determination of Vitamin B12 in human serum and plasma.
6.Comparison to predicate device	The Boehringer Mannheim Elecsys Vitamin B12 Assay is substantially equivalent to other products in commercial distribution intended for similar use. Most notably it is substantially equivalent to the currently marketed BioRad Quantaphase II B12/Folate Assay (K935286).
	The following table compares the Elecsys Vitamin B12 Assay with the predicate device, BioRad Quantaphase II B12/Folate Assay. Specific data on the performance of the test have been incorporated into the draft labeling in attachment 5. Labeling for the predicate device is provided in attachment 6.
	Similarities:
	Intended Use: Assay for the in vitro quantitative determination of Vitamin B12Sample type: Serum and plasmaAssay range: 0- 2000 pg/mLSame binding protein: Porcine Intrinsic Factor

{3}------------------------------------------------

10(k) Summary, Continued

1 1 1 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

Comparison to predicate device cont.

Differences:

Feature	ElecsysVitamin B12	Biorad Quantaphase IIB12/Folate radioassay
Reaction testprinciple	Electrochemiluminescence	Radiobinding assay using57Co
Instrumentrequired	Elecsys 2010	Gamma Counter

Performance Characteristics:

Feature	Elecsys Vitamin B12Modified NCCLS (pg/ml):	BioRad Quantaphase IIB12/Folate RadioassayWithin-Run and Total Precision(pg/ml):
PrecisionLevel	Pool 1	I
	Pool 2	II
	Pool 3	III
		IV
N	60	40
	60	40
	60	40
		40
Mean	203.27	127
	481.02	273
	1499.36	622
		1325
Within run SD	14.11	8.9
	20.38	15.7
	41.23	51.7
		52.8
%CV	6.94	4.10
	4.24	4.1
	2.75	5.9
		4.0
Mean	203.27	127
	481.02	429
	1499.36	807
		1314
Total SD	15.41	8.6
	21.08	29.3
	47.78	36.2
		75.3
%CV	7.58	6.8
	4.38	6.8
	3.19	4.5
		5.7
Level	Level 1
	Level 2
N	60
	60
Mean	1119.49
	471.30
Within run	31.28
	25.84
%CV	2.79
	5.48
Mean	1119.49
	471.30
Total	36.20
	26.77
%CV	3.23
	5.68

{4}------------------------------------------------

10(k) Summary, Continued

Image /page/4/Picture/1 description: The image shows the logo for Boehringer Mannheim Corporation. The text is stacked on top of each other in a bold, sans-serif font. The words are all capitalized and in black.

Performance Characteristics:

Comparison
to predicate
device, (cont.)

Performance Characteristics:

Feature	Elecsys Vitamin B12	BioRad Quantaphase IIB12/Folate Radioassay
LowerDetectionLimit	30 pg/ml	20 pg/ml
Linearity	30 - 2000 pg/ml	20 - 2000 pg/ml
MethodComparison	Vs BioRad Quantaphase IIB12/Folate RadioassayLeast Squares$y =1.02X + 6.5$$r=0.9751$$N=346$Passing Bablock:$y=1.06X - 9.5$$r=0.9751$$N=346$	Vs Commercially availableradioimmunoassay$y =1.01x + 44$$r=0.933$$N=84$

{5}------------------------------------------------

10(k) Summary, Continued RPORATIC

o.
Comparison
to predicate
device, (cont.)

Performance Characteristics:

Feature	Elecsys Vitamin B12	BioRad Quantaphase IIB12/Folate Radioassay
Interferingsubstances	No interference at:(within 30 pg/ml atVitamin B12 level <300pg/ml or within ±10% atVitamin B12 level > 300pg/ml.)	No interference at:
Bilirubin	80 mg/dL	20 mg/dL unconjugated20 mg/dL conjugated
Hemoglobin	1800 mg/dL	500 mg/dL
Lipemia	2500 mg/dL	3000 mg/dL
Rheumatoid Factor	500 IU/mL	N/A
Dysproteinemia	8.8 g/dL	N/A
Biotin	50 pg/ml	N/A
ReferenceRangeVitamin B12,pg/ml	Normal: 243 - 894Indeterminant:175 - 244Deficient:<174	Normal: 130 - 770Deficient:<204
	% Cross-reactivity	% Cross-reactivity
Cobinamide	0.024	0.1

page 31

{6}------------------------------------------------

Image /page/6/Picture/1 description: The image shows the words "Public Health Service" in bold, black font. The words are stacked on one line. The words are clearly legible and the image is simple.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

Ms. Yvette Lloyd Boehringer Mannheim Corporation 4300 Hacienda Drive Pleasanton, California 94588-2722

NOV 1 3 1997

Re: K973702 Elecsys Vitamin B12 Assay Trade Name: Tier: II Requlatory Class: II Product Code: CDD Dated: September 24, 1997 September 26, 1997 Received:

Dear Ms. Lloyd:

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 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 A substantially equivalent determination assumes compliance to 895. with the current Good Manufacturing Practice requirement, 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.

{7}------------------------------------------------

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 at (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html"

Sincerely yours,

Steven Autman

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

{8}------------------------------------------------

10:38

510(k) Number (if known): N/A

Device Name: Elecsys Vitamin B12 Assay

Indications For Use:

Concurrence of CDRH, Office of Device Evaluation (ODE)

Prescription Use	✓
(Per 21 CFR 801.109)

Over-The-Counter Use
(Optional Format 1-2-96)

(Division Sign-Off)
Division of Clinical Laboratory Devices.
510(k) Number K973702

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.