The ADVIA Centaur® Anti-Müllerian Hormone (AMH) assay is for in vitro diagnostic use in the quantitative determination of anti-Müllerian hormone (AMH) in human serum and plasma (lithium heparin) using the ADVIA Centaur® XP system.

The measurement of AMH is used as an aid in the assessment of the ovarian reserve in women presenting to fertility clinics. This assay is intended to distinguish between women with AFC (antral follicle count) values > 15 (high ovarian reserve) and women with AFC values ≤ 15 (normal or diminished ovarian reserve).

This assay is intended to be used in conjunction with other clinical and laboratory findings, such as AFC, before starting fertility therapy. This assay is not intended to be used for monitoring women undergoing controlled ovarian stimulation in an Assisted Reproduction Technology program.

Device Description

The ADVIA Centaur AMH assay is a sandwich immunoassay using direct acridinium ester-based chemiluminometric technology. Two monoclonal anti-AMH antibodies are employed in the assay. The first antibody in the Lite Reagent is a mouse monoclonal anti-AMH antibody labeled with acridinium ester. The second antibody is a biotinylated mouse monoclonal anti-AMH antibody coupled to streptavidin-coated magnetic particles in the Solid Phase.

A direct relationship exists between the amount of AMH present in the patient sample and the amount of relative light units detected by the system. Dose concentration results (ng/mL) are calculated based on a 2-point calibration from a pre-defined master curve.

Materials include:
ADVIA Centaur AMH ReadyPack® primary reagent pack: Solid Phase (Streptavidin-coated paramagnetic microparticles with biotinylated mouse monoclonal anti-human AMH antibody in buffer; sodium azide (< 0.1%); blocker (bovine); surfactant; preservatives)
ADVIA Centaur AMH ReadyPack® ancillary reagent pack: Ancillary Reagent (Mouse monoclonal anti-human AMH antibody labeled with acridinium ester in buffer (~0.6 µg/mL); sodium azide (<0.1%); blocker (bovine, murine); stabilizers; surfactant; preservatives)
AMH CAL: After reconstitution, low and high levels of AMH antigen (bovine) in defibrinated human plasma; sodium azide (< 0.1%); preservatives

AI/ML Overview

Here's the detailed breakdown of the acceptance criteria and study information for the ADVIA Centaur® Anti-Müllerian Hormone (AMH) assay, based on the provided FDA 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

Performance Characteristic	Acceptance Criteria (Design Goal)	Reported Device Performance
Detection Capability
Limit of Blank (LoB)	(Implicitly compared to predicate LoB of ≤ 0.01 ng/mL)	0.010 ng/mL (0.071 pmol/L)
Limit of Detection (LoD)	(Implicitly compared to predicate LoD of ≤ 0.02 ng/mL)	0.020 ng/mL (0.143 pmol/L)
Limit of Quantitation (LoQ)	(Implicitly compared to predicate LoQ of ≤ 0.08 ng/mL)	0.043 ng/mL (0.307 pmol/L)
Precision (Total CV)	≤ 10% CV for concentration ≥ 0.100 ng/mL	Ranges from 2.5% to 4.4% for samples at various AMH concentrations (0.112 ng/mL to 16.4 ng/mL). For controls, ranges from 2.9% to 3.3% (0.955 ng/mL to 14.1 ng/mL). All reported total CVs are ≤ 4.4% at or above 0.112 ng/mL, meeting the criterion.
Reproducibility (Total CV)	(Implicitly compared to predicate Total CV of ≤ 10% for concentration ≥ 0.16 ng/mL)	Ranges from 2.1% to 3.1% for samples at various AMH concentrations (0.199 ng/mL to 17.0 ng/mL). For controls, ranges from 2.6% to 2.9% (1.01 ng/mL to 14.4 ng/mL). All reported reproducibility CVs are ≤ 3.1% at or above 0.199 ng/mL, meeting the likely implied criterion.
Linearity	Linear for the measuring interval of 0.043-24.0 ng/mL	Linear for the measuring interval of 0.043-24.0 ng/mL (0.307-171 pmol/L).
Assay Comparison	Correlation coefficient ≥ 0.950, slope of 1.00 ± 0.10, intercept of ± 0.035 ng/mL (vs. commercial AMH assay)	Serum: Correlation coefficient (r) = 0.994 Regression Equation: y = 1.04x - 0.032 ng/mL (Slope: 1.04, Intercept: -0.032 ng/mL). This meets the criteria for correlation, slope (within 1.00 ± 0.10), and intercept (within ± 0.035 ng/mL).
Specimen Equivalence	Correlation coefficient ≥ 0.950, slope of 0.90-1.10, intercept of ± 0.035 ng/mL (vs. serum)	Gel-barrier tube (serum) vs. Serum: Correlation coefficient (r) = 0.997 Regression Equation: y = 1.00x + 0.003 ng/mL (Slope: 1.00, Intercept: +0.003 ng/mL). Meets criteria. Plasma, lithium heparin vs. Serum: Correlation coefficient (r) = 0.997 Regression Equation: y = 1.08x - 0.004 ng/mL (Slope: 1.08, Intercept: -0.004 ng/mL). Meets criteria.
Interferences (HIL)	Bias due to substances not to exceed 10% at specified AMH concentrations	Hemoglobin: No interference (1000 mg/dL). Bilirubin, conjugated: No interference (66.0 mg/dL). Bilirubin, unconjugated: No interference up to 39.0 mg/dL; however, >10% bias observed at ≥ 40 mg/dL (10.6% bias at 6.79 ng/mL AMH, 11.4% bias at 0.936 ng/mL AMH). Lipemia (Intralipid): No interference (2000 mg/dL).
Interferences (Other Substances)	Bias due to substances not to exceed 10% at specified AMH concentrations	Acetaminophen, Acetylcysteine, Acetylsalicylic Acid, Ampicillin sodium, L-Ascorbic acid, Biotin, Cefoxitin sodium salt, Cholesterol, Cyclosporine, Doxycycline hyclate, Folic acid, Gonapeptyl, Heparin, Human IgA, Human IgG, Human IgM, Ibuprofen, Levodopa, Levothyroxine, Metformin hydrochloride, Methyldopa, Metronidazole, Phenylbutazone, Rheumatoid Factor, Rifampicin, Theophylline, Total Protein, Uric acid: All showed no interference (bias ≤ 10%) at tested concentrations.
Cross-Reactivity	Bias does not exceed 10%	Activin A, Activin B, Activin AB, Inhibin A, Inhibin B, TGF b-1: ≤ 0.1% cross-reactivity. Follicle stimulating hormone (FSH) at 500 mIU/mL: Not Detectable, 0.2% bias. Luteinizing hormone (LH) at 500 mIU/mL: Not Detectable, 2.9% bias. All considered insignificant.
Stability (On-board Reagents)	Reagents stable for 70 days	Determined to be 70 days.
Stability (Calibrators)	Calibrators stable at 2-8°C and ≤ -20°C for 90 days after reconstitution	Determined to be stable at 2-8°C and ≤ -20°C for 90 days after reconstitution.
High Dose Hook	(No explicit criterion given, but predicate states no hook effect up to 1000 ng/mL)	No hook effect observed up to 1151 ng/mL (8218 pmo/L). This exceeds the predicate.
Clinical Performance (Overall)	(Aid in distinguishing AFC > 15 vs ≤ 15 in fertility clinics)	Sensitivity: 90.5% (256/283) (95% CI: 86.47, 93.36) Specificity: 52.0% (130/250) (95% CI: 45.82, 58.12) PPV: 68.1% (256/376) (95% CI: 63.21, 72.59) NPV: 82.8% (130/157) (95% CI: 76.13, 87.90)
Clinical Performance (Age < 35)	(Aid in distinguishing AFC > 15 vs ≤ 15 in fertility clinics for this age group)	Prevalence (AFC > 15): 67.4% PPV: 73.6% (67.47, 78.88) NPV: 65.1% (50.17, 77.58)
Clinical Performance (Age ≥ 35)	(Aid in distinguishing AFC > 15 vs ≤ 15 in fertility clinics for this age group)	Prevalence (AFC > 15): 38.4% PPV: 59.7% (51.71, 67.27) NPV: 89.5% (82.50, 93.88)

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

Detection Capability (LoB, LoD, LoQ): Not explicitly stated, but determined as described in CLSI protocol EP17-A2. These are typically derived from analytical studies involving numerous replicates of blank, low-concentration, and relevant samples.
Precision and Reproducibility:
- Precision: 480 measurements per sample/control (replicates of 2, 2 runs/day, 20-day protocol). This was across 2 instruments and 3 reagent lots.
- Reproducibility: 90 measurements per sample/control (triplicate, 2 runs/day, 5 days) across 3 sites and 1 reagent lot.
Assay Comparison: 120 samples (serum) vs. a commercial AMH assay.
Specimen Equivalence: 88 samples for Gel-barrier tube (serum) vs. Serum, and 88 samples for Plasma (lithium heparin) vs. Serum.
Interferences: The number of samples tested for each substance is not specified, but the testing was performed in accordance with CLSI Document EP07-ed3 and EP37-ed1.
Cross-Reactivity: Number of samples not specified, performed in accordance with CLSI Document EP07-ed3.
Stability: Not sample-based but rather experimental conditions and time points.
Expected Values (Reference Intervals):
- Females (18–25 years): 209 samples
- Females (26–30 years): 122 samples
- Females (31–35 years): 123 samples
- Females (36–40 years): 126 samples
- Females (41–45 years): 152 samples
- Females (46–50 years): 121 samples
- Females (51 years and older): 139 samples
Clinical Sensitivity and Specificity: 533 women.
Data Provenance:
- Clinical Study: Prospectively collected from women presenting to fertility clinics for evaluation.
- Country of Origin: 11 sites across the United States.
- Expected Values: Samples were collected retrospectively or prospectively from "apparently healthy subjects," but the exact nature (retrospective/prospective) and location of collection is not explicitly detailed beyond "apparently healthy subjects". Given the clinical study provenance, it's likely linked, but not explicitly stated.

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

For the clinical performance study (Clinical Sensitivity and Specificity), the ground truth for ovarian reserve was established by Antral Follicle Count (AFC) values determined by transvaginal ultrasound.

The document does not specify the number of experts (e.g., sonographers, radiologists) who performed or interpreted these ultrasounds.
It also does not specify the individual qualifications (e.g., years of experience, board certification) of these experts. It only states that the AFC result was determined by transvaginal ultrasound.

4. Adjudication Method for the Test Set

The document does not explicitly describe an adjudication method (such as 2+1, 3+1) for establishing the ground truth (AFC values). The AFC results were simply stated as being "determined by transvaginal ultrasound." This suggests that the individual AFC measurements were taken as the singular truth, without a multi-reader review or adjudication process outlined to resolve discrepancies, if any.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

No, an MRMC comparative effectiveness study involving human readers and AI assistance was not conducted. This device is an in vitro diagnostic (IVD) assay that quantitatively measures a biomarker (AMH) in serum/plasma. It does not involve interpretation of medical images or other data by human readers, and thus, AI assistance in the context of human reading is not applicable here.

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

Yes, the studies reported are essentially "standalone" performance evaluations of the ADVIA Centaur® Anti-Müllerian Hormone (AMH) assay itself. The clinical performance study evaluates the assay's ability to distinguish between high and normal/diminished ovarian reserve based on AMH measurements, against the ground truth of AFC. This is the performance of the device (the assay) as an algorithm or test method, independent of subsequent human interpretation enhancements.

7. The Type of Ground Truth Used

Analytical Studies (Detection Capability, Precision, Linearity, Interference, Cross-reactivity, Stability, Hook Effect): The ground truth for these studies is typically derived from highly characterized reference materials, spiked samples with known concentrations, or established analytical methods.
Expected Values (Reference Intervals): Established by collecting samples from "apparently healthy subjects" and calculating statistical percentiles (90th and 95th reference intervals). The ground truth here is the statistical distribution of AMH levels in a healthy population defined by age.
Clinical Sensitivity and Specificity: The ground truth for ovarian reserve was Antral Follicle Count (AFC) values, as measured by transvaginal ultrasound. This is a clinical measure widely accepted in fertility assessment.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" in the context of a machine learning or AI algorithm development. This is an in vitro diagnostic assay, where performance is typically established through analytical validation and clinical correlation studies, not through AI model training. The data used for most performance characteristics are considered validation data.

The "Expected Values" data set (totaling 209+122+123+126+152+121+139 = 992 samples) could be seen as reference data used to establish norms, but not a "training set" for an algorithm in the AI sense.
The "Clinical Sensitivity and Specificity" study of 533 women served as a clinical validation dataset.

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

As no "training set" in the AI sense is explicitly mentioned for algorithm development, there's no described method for establishing ground truth for such a set. For the validation data described:

Clinical Study Ground Truth: The ground truth was Antral Follicle Count (AFC) values, determined by transvaginal ultrasound by unspecified qualified personnel at 11 sites across the US.
Expected Values Ground Truth: These are based on AMH measurements from "apparently healthy subjects," where their health status (absence of relevant pathologies) constitutes the ground truth for establishing normal ranges.

Summary

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June 2, 2023

Siemens Healthcare Diagnostics Inc. Mey Vasquez Regulatory Affairs Professional 511 Benedict Avenue Tarrytown, NY 10591

Re: K221801

Trade/Device Name: ADVIA Centaur® Anti-Müllerian Hormone (AMH) Regulation Number: 21 CFR 862.1092 Regulation Name: Anti-Müllerian Hormone Test System Regulatory Class: Class II Product Code: PQO Dated: March 4, 2023 Received: March 7, 2023

Dear Mey Vasquez:

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. 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 located 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.

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 of medical device-related adverse events) (21 CFR

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for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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 https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/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-device-advice-comprehensive-regulatoryassistance/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.

Paula V. Caposino -S

Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K221801

Device Name

ADVIA Centaur® Anti-Müllerian Hormone (AMH)

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

510(k) Summary of Safety and Effectiveness

Introduction: According to the requirements of SMDA 1990 and 21 CFR 807.92, the following information provides sufficient details to understand the basis for determination of substantial equivalence.

The assigned 510(k) Number:

1. Date Prepared

June 1, 2023

2. Applicant Information

Siemens Healthcare Diagnostics Inc. 511 Benedict Avenue, Tarrytown, NY 10591 USA

Contact:	Mey VasquezRegulatory Affairs Professional
Phone :	(862) 213-8409
E-mail :	mey.vasquez@siemens-healthineers.com

3. Regulatory Information

Assay

Full Product Name	ADVIA Centaur Anti-Müllerian Hormone (AMH)
Abbreviated Product Name	ADVIA Centaur AMH
Trade Name	ADVIA Centaur® Anti-Müllerian Hormone (AMH)
Common Name	Anti-Müllerian Hormone Test System
Classification Name	Anti-Müllerian Hormone Test System
Definition	An Anti-Müllerian hormone test system is an in vitro diagnosticdevice intended to measure anti-Müllerian hormone in humanserum and plasma. The test is intended to be used as an aid ofassessing ovarian reserve in women.
FDA Classification	Class II

Siemens Healthcare Diagnostics, Inc. Unrestricted

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510(k) Summary

Review Panel	Toxicology
Product Code	PQO
Regulation Number	21 CFR 862.1092

PREDICATE DEVICE 4.

Name of Device: Access AMH

510(k): K170524

5. ASSAY PRINCIPLE

DEVICE DESCRIPTION 6.

Material Description
ADVIA Centaur AMH ReadyPack® primary reagent packSolid Phase22.0 mL/reagent packStreptavidin-coated paramagnetic microparticles (~0.15 mg/mL) with biotinylatedmouse monoclonalanti-human AMH antibody (~2 µg/mL) in buffer; sodium azide (< 0.1%); blocker (bovine);surfactant; preservatives
ADVIA Centaur AMH ReadyPack® ancillary reagent packAncillary Reagent10.0 mL/reagent packMouse monoclonal anti-human AMH antibody labeled with acridinium ester in buffer(~0.6 µg/mL); sodium azide (<0.1%); blocker (bovine, murine); stabilizers; surfactant;preservatives

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510(k) Summary

AMH CAL

2.0 mL/vial (1 vial of Low and High AMH CAL) After reconstitution, low and high levels of AMH antigen (bovine) in defibrinated human plasma; sodium azide (< 0.1%); preservatives

INTENDED USE/ INDICATIONS FOR USE 7.

This assay is intended to be used in coniunction with other clinical and laboratory findings. such as AFC, before starting fertility therapy. This assay is not intended to be used for monitoring women undergoing controlled ovarian stimulation in an Assisted Reproduction Technology program.

Special Conditions for Use Statement 8.

For Prescription Use

COMPARISION OF TECHNOLOGICAL CHARACTERISTICS WITH THE 9. PREDICATE DEVICE

Item	Candidate DeviceADVIA Centaur® Anti-MüllerianHormone (AMH)	PredicateBeckman Coulter AccessAMH (K170524)
Intended Use	The ADVIA Centaur®Anti-Müllerian Hormone (AMH)assay is for in vitro diagnostic usein the quantitative determination ofanti-Müllerian hormone (AMH) inhuman serum and plasma (lithium)	The Access AMH assay is aparamagnetic particlechemiluminescent immunoassayfor the quantitativedetermination of anti-Müllerianhormone (AMH) levels in humanserum and lithium heparin
Item	Candidate Device	Predicate
	ADVIA Centaur® Anti-MüllerianHormone (AMH)	Beckman Coulter AccessAMH (K170524)
	heparin) using the ADVIACentaur® XP system.The measurement of AMH is usedas an aid in the assessment of theovarian reserve in womenpresenting to fertility clinics. Thisassay is intended to distinguishbetween women with AFC (antralfollicle count) values > 15 (highovarian reserve) and women withAFC values ≤ 15 (normal ordiminished ovarian reserve).This assay is intended to be usedin conjunction with other clinicaland laboratory findings,such as AFC, before startingfertility therapy. This assay is notintended to be used formonitoring women undergoingcontrolled ovarian stimulation in anAssisted ReproductionTechnology program.	plasma using the AccessImmunoassay Systems as anaid in the assessment of ovarianreserve in women presenting tofertility clinics.This system is intended todistinguish between womenpresenting with AFC (antralfollicle count) values > 15 (highovarian reserve) and womenwith AFC values ≤ 15 (normal ordiminished ovarian reserve).The Access AMH is intended tobe used in conjunction withother clinical and laboratoryfindings such as antral folliclecount, before starting fertilitytherapy. The Access AMH is notintended to be used formonitoring of womenundergoing controlled ovarianstimulation in an AssistedReproduction Technologyprogram.
Indications forUse	Same as Intended Use (Candidate)	Same (for Predicate)
	Similarities
LoB	0.010 ng/mL	≤ 0.01 ng/mL
LoD	0.020 ng/mL	≤ 0.02 ng/mL
Item	Candidate Device	Predicate
	ADVIA Centaur® Anti-MüllerianHormone (AMH)	Beckman Coulter AccessAMH (K170524)
LoQ	0.043 ng/mL	≤ 0.08 ng/mL
Measurement	Quantitative	Same
Technology	Chemiluminescence	Same
OperatingPrinciple	1-Step Sandwich immunoassay	Same
Sample type	Plasma (lithium heparin) andSerum	Same
Standardization	Traceable to an internal standardmanufactured using highly purifiedmaterial	Same
Clinical Cut-Off	1.77 ng/mL to distinguish womenwith an antral follicle count (AFC)>15 or ≤ 15.	Same
Intended UsePopulation(s)	Women presenting to fertility clinics	Same
	Differences
Calibration	2 levels	6 levels
Assay Range	0.043–24.0 ng/mL	0.08 – 24 ng/mL
Hook Effect	No hook effect up to 1151 ng/mL	No hook effect up to 1000 ng/mL
Sample Volume	100 µL	20 µL
DetectionAntibody	Mouse monoclonal anti-humanAMH antibody labeled withacridinium ester in buffer	Mouse monoclonal anti-AMHantibody conjugated to alkalinephosphatase in MES buffer
Item	Candidate Device	Predicate
	ADVIA Centaur® Anti-MüllerianHormone (AMH)	Beckman Coulter AccessAMH (K170524)
CaptureAntibody	Monoclonal mouse anti-humanAMH antibody (~2 µg/mL)labeled with biotin bound tostreptavidin magnetic particles(~0.15 mg/mL) in buffer	Mouse monoclonal anti-AMHantibody bound to paramagnetic particles in buffer
Precision (TotalCV)	≤ 10% CV for concentration ≥0.100ng/mL	≤ 10% CV for concentration ≥0.16 ng/mL

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510(k) Summary

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510(k) Summary

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510(k) Summary

PERFORMANCE CHARACTERISTICS DATA 10.

10.1. Detection Capability

The limit of blank (LoB), limit of detection (LoD), and the limit of quantitation (LoQ) were determined as described in CLSI protocol EP17-A2.

The ADVIA Centaur AMH assay has an LoB of 0.010 ng/mL (0.071 pmol/L), an LoD of 0.020 ng/mL (0.143 pmol/L), and an LoQ of 0.043 ng/mL (0.307 pmol/L).

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510(k) Summary

10.2. Precision

Precision was determined in accordance with CLSI Document EP05-A3.22 Testing was performed using 2 instruments and 3 reagent lots. Samples were assayed in replicates of 2 with 2 runs per day using a 20-day protocol.

The following results are representative of the performance of the assay:

			Repeatability		Within-Laboratory Precision		Reproducibility(Total Imprecision)
Sample	Na	Mean(ng/mL)	SDb(ng/mL)	CVc(%)	SD(ng/mL)	CV(%)	SD(ng/mL)	CV(%)
Serum A	480	0.112	0.0032	2.9	0.0036	3.2	0.0049	4.4
Serum B	480	0.193	0.0046	2.4	0.0053	2.7	0.0066	3.4
Serum C	480	0.969	0.0205	2.1	0.0236	2.4	0.0240	2.5
Serum D	480	3.60	0.092	2.6	0.107	3.0	0.115	3.2
Serum E	480	6.71	0.156	2.3	0.198	3.0	0.224	3.3
Serum F	480	6.93	0.158	2.3	0.177	2.6	0.206	3.0
Serum G	480	16.2	0.34	2.1	0.40	2.5	0.52	3.2
Serum H	480	16.4	0.37	2.3	0.42	2.6	0.47	2.9
Control 1	480	0.955	0.0252	2.6	0.0284	3.0	0.0312	3.3
Control 2	480	4.75	0.120	2.5	0.135	2.8	0.140	2.9
Control 3	480	14.1	0.33	2.3	0.37	2.6	0.41	2.9

a Number of measurements.

b Standard deviation.

Coefficient of variation.

Siemens Healthcare Diagnostics, Inc. Unrestricted

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510(k) Summary

10.3. Reproducibility

Reproducibility was determined in accordance with CLSI Document EP05-A3. Samples were assayed in triplicate in 2 runs per day for 5 days using 3 sites and 1 reagent lot. The following results are representative of the performance of the assay:

			Repeatability			Between-Run		Between-Day		Between-Site		Reproducibility
		Mean	SD	%CV	SD	%CV	SD	%CV	SD	%CV	SD	%CV
Sample	Na	(ng/mL)	(ng/mL)		(ng/mL)		(ng/mL)		(ng/mL)		(ng/mL)
Serum A	90	0.199	0.0041	2.1	0.0027	1.4	0.0000	0.0	0.0025	1.3	0.0055	2.8
Serum B	90	1.01	0.025	2.5	0.000	0.0	0.016	1.6	0.007	0.7	0.031	3.1
Serum C	90	3.73	0.058	1.6	0.039	1.0	0.000	0.0	0.033	0.9	0.077	2.1
Serum D	90	6.96	0.105	1.5	0.158	2.3	0.000	0.0	0.071	1.0	0.203	2.9
Serum E	90	17.0	0.31	1.8	0.31	1.8	0.00	0.0	0.06	0.4	0.44	2.6
Control 1	90	1.01	0.022	2.2	0.017	1.7	0.005	0.5	0.008	0.8	0.029	2.9
Control 2	90	4.87	0.080	1.6	0.046	0.9	0.090	1.8	0.034	0.7	0.134	2.8
Control 3	90	14.4	0.30	2.1	0.17	1.2	0.17	1.2	0.00	0.0	0.38	2.6

a Number of measurements.

10.4. Linearity

Linearity testing was performed in accordance with CLSI Document EP06-A. The ADVIA Centaur AMH assay is linear for the measuring interval of 0.043-24.0 ng/mL (0.307-171 pmol/L).

Assay Comparison 10.5.

Assay comparison was determined with the Passing-Bablok regression model in accordance with CLSI Document EP09c-ed3.

The assay is designed to have a correlation coefficient of ≥ 0.950, a slope of 1.00 ± 0.10, and an intercept of ± 0.035 ng/mL

Specimen Type	Comparative Assay (x)	Regression Equation	Sample Interval	Na	rb
Serum	commercial AMH assay	$y = 1.04x - 0.032 ng/mL$( $y = 1.04x - 0.228 pmol/L$ )	0.080–22.0 ng/mL(0.571–157 pmol/L)	120	0.994

a Number of samples tested.

b Correlation coefficient.

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510(k) Summary

10.6. Specimen Equivalence

Specimen equivalency was determined with the weighted Deming regression model in accordance with CLSI Document EP09c-ed3.

The assay is designed to have a correlation coefficient of ≥ 0.950, a slope of 0.90-1.10, and an intercept of ± 0.035 ng/mL.

Tube (y) vs. Serum (x)	Regression Equation	Sample Interval	Na	rb
Gel-barrier tube (serum)	$y = 1.00x + 0.003$ ng/mL( $y = 1.00x + 0.021$ pmol/L)	0.110–19.7 ng/mL(0.785-141 pmol/L)	88	0.997
Plasma, lithium heparin	$y = 1.08x - 0.004$ ng/mL( $y = 1.08x - 0.029$ pmol/L)	0.110–19.7 ng/mL(0.785-141 pmol/L)	88	0.997

Number of samples tested.

b Correlation coefficient.

10.7. Interferences

Hemolysis, Icterus, Lipemia (HIL)

Interference testing was performed in accordance with CLSI Document EP07-ed3. The following substances do not interfere with the assay when present in serum at the concentrations indicated.

Bias due to these substances does not exceed 10% at an AMH concentration of 0.719-0.944 ng/mL (5.13-6.74 pmol/L) and 6.13-6.68 ng/mL (43.8-47.7 pmol/L).

Substance	Substance Test Concentration
Hemoglobin	1000 mg/dL (10.0 g/L)
Bilirubin, conjugated	66.0 mg/dL (783 µmol/L)
Bilirubin, unconjugated	39.0 mg/dL (667 µmol/L) a
Lipemia (Intralipid)	2000 mg/dL (20.0 g/L)

a At concentrations ≥ 40 mg/dL, there is statistically significant (>10% bias) interference for unconjugated bilirubin. At 40 mg/dL, the following bias was observed: 10.6% bias at 6.79 ng/mL AMH and 11.4% bias at 0.936 ng/mL AMH.

Other Substances

Interference testing was performed in accordance with CLSI Document EP07-ed3 and EP37-ed1. The following substances do not interfere with the assay when present in serum at the concentrations indicated.

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510(k) Summary

Bias due to these substances does not exceed 10% at an AMH concentration of 0.782–1.38 ng/mL (5.58-9.85 pmol/L) and 5.86-7.49 ng/mL (41.8-53.5 pmol/L).

Substance	Substance Test Concentration	Substance	Substance Test Concentration
Acetaminophen	20 mg/dL (1324 µmol/L)	Human IgG	2500 mg/dL (25.0 g/L)
Acetylcysteine	15.0 mg/dL (920 µmol/L)	Human IgM	500 mg/dL (5.0 g/L)
AcetylsalicylicAcid (Aspirin)	65.0 mg/dL(3608 µmol/L)	Ibuprofen	50.0 mg/dL (2425 µmol/L)
Ampicillin sodium	100 mg/dL (2693 µmol/L)	Levodopa	2.00 mg/dL (101 µmol/L)
L-Ascorbic acid	3.00 mg/dL (170 µmol/L)	Levothyroxine	0.020 mg/dL(0.258 µmol/L)
Biotin	0.350 mg/dL(14.3 µmol/L)	Metforminhydrochloride	200 mg/dL(12,076 µmol/L)
Cefoxitin sodium salt	250 mg/dL (5563 µmol/L)	Methyldopa	2.00 mg/dL (83.9 µmol/L)
Cholesterol	500 mg/dL (13.0 mmol/L)	Metronidazole	20.0 mg/dL (1168 µmol/L)
Cyclosporine	0.500 mg/dL(4.16 µmol/L)	Phenylbutazone	40.0 mg/dL (1296 µmol/L)
Doxycycline hyclate	5.00 mg/dL (48.7 µmol/L)	Rheumatoid Factor	1000 IU/mL
Folic acid	0.040 mg/dL(0.906 µmol/L)	Rifampicin	6.00 mg/dL (73.2 µmol/L)
Gonapeptyl(Triptorelin acetate)	0.010 mg/dL(0.073 µmol/L)	Theophylline	10.0 mg/dL (555 µmol/L)
Heparin	500 U/dL	Total Protein	12.0 g/dL (120 g/L)
Human IgA	1800 mg/dL (18.0 g/L)	Uric acid	25.0 mg/dL (1487 µmol/L)

10.8. Cross-Reactivity

Cross-reactivity was determined in accordance with CLSI Document EP07-ed3. Crossreactants were tested at anti-Müllerian hormone concentrations of 0 ng/mL (0 pmol/L) and 0.924–1.05 ng/mL (6.60–7.50 pmol/L).

Cross-reactant	Cross-reactant Concentration	Cross-reactivity (%)
Activin A	100 ng/mL (7.69 nmol/L)	≤0.1
		≤0.1

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510(k) Summary

Cross-reactant	Cross-reactant Concentration	Cross-reactivity (%)
Activin B	50.0 ng/mL (3.91 nmol/L)	≤ 0.1
		≤ 0.1
Activin AB	50.0 ng/mL (1.94 nmol/L)	≤ 0.1
		≤ 0.1
Follicle stimulating hormone	500 mlU/mL	Not Detectable a
		0.2
Inhibin A	100 ng/mL (3.57 nmol/L)	≤ 0.1
		≤ 0.1
Inhibin B	100 ng/mL (3.08 nmol/L)	≤ 0.1
		≤ 0.1
Luteinizing hormone	500 mlU/mL	Not Detectable a
		2.9
TGF b-1	65.0 ng/mL (5.08 nmol/L)	≤ 0.1
		≤ 0.1

a FSH and LH were expressed in biological activity units (mIU/mL). The observed analyte dose change was reported as percent dose bias to control sample. Bias does not exceed 10%, and is therefore considered insignificant.

10.9. Stability

The on-board stability of the ADVIA Centaur AMH reagents was determined to be 70 days with a calibration interval of 28 days.

The ADVIA Centaur AMH calibrators when reconstituted were determined to be stable at 2-8°C and ≤ -20°C for 90 days.

10.10. High Dose Hook

High AMH concentrations can cause a paradoxical decrease in the RLUs (high-dose hook effect). In this assay, no hook effect was observed up to 1151 ng/mL (8218 pmo//L).

10.11. Expected Values

Samples were collected prospectively from apparently healthy subjects. The 90th reference interval was determined by calculating the 5th and 95th percentiles of the distribution of values.

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510(k) Summary

The 95th reference interval was determined by calculating the 2.5th and 97.5th percentiles of the distribution of values.

Group	Na	Medianng/mL(pmol/L)	90% Reference Intervalng/mL (pmol/L)	95% Reference Interval ng/mL(pmol/L)
Females(18–25years)	209	4.70(33.6)	1.28–11.8 (9.14–84.3)	1.02–15.6 (7.28–111)
Females(26–30years)	122	3.80(27.1)	0.843–8.81 (6.02–62.9)	0.520–10.0 (3.71–71.4)
Females(31–35years)	123	2.70(19.3)	0.772–8.07 (5.51–57.6)	0.676–10.2 (4.83–72.8)
Females(36–40years)	126	1.59(11.4)	0.156–6.13 (1.11–43.8)	0.079–8.66 (0.564–61.8)
Females(41–45years)	152	0.493(3.52)	< 0.043–3.47 (< 0.307–24.8)	< 0.043–4.46 (< 0.307–31.8)
Females(46–50years)	121	0.083(0.593)	< 0.043–1.33 (< 0.307–9.50)	< 0.043–1.89 (< 0.307–13.5)
Females(51 years andolder)	139	< 0.043(< 0.307)	< 0.043–0.134(< 0.307–0.957)	< 0.043–0.277(< 0.307–1.98)

a Number of samples tested.

As with all in vitro diagnostic assays, each laboratory should determine its own reference interval for the diagnostic evaluation of patient results. Consider these values as guidance only.

10.12. Clinical Sensitivity and Specificity

A multi-center clinical study consisting of women who presented to fertility clinics for evaluation was used to correlate AMH serum concentration to antral follicle count (AFC). Data were analyzed from 533 women at 11 sites across the United States using the ADVIA Centaur XP systems. The participants ranged in age from 22–45 years, with a mean age of 34.4 years. The Body Mass Index (BMI) ranged from 16.0-39.9 kg/m², with a mean BMI of 26.84 kg/m². The AFC result was determined by transvaginal ultrasound and included follicles 2-10 millimeters in diameter. The AFC and AMH data were collected between day 2 and day 4 of the same menstrual cycle.

Clinical sensitivity and specificity were determined in accordance with CLSI Document EP12-A2. The sensitivity, specificity, Positive Predictive Value (PPV), and Negative Predicative Value (NPV) were calculated and are shown below.

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510(k) Summary

Parameter	Na	Estimate	95% Confidence
Sensitivity	283	90.5% (256/283)	(86.47, 93.36)
Specificity	250	52.0% (130/250)	(45.82, 58.12)
PPV	376	68.1% (256/376)	(63.21, 72.59)
NPV	157	82.8% (130/157)	(76.13, 87.90)

a Number of measurements.

A subgroup analysis by subject age (< 35 years of age vs. > 35 years of age) using results of the clinical data (n=533) was performed. The clinical study had 270 subjects evaluated who were < 35 years of age and 263 subjects who were ≥ 35 years of age. Differences in clinical performance were observed between subjects < 35 years of age and > 35 years of age. The likelihood of a subject with a result > 1.77 ng/mL having high ovarian reserve was higher in subjects < 35 years of age and the likelihood of a subject with a result ≤ 1.77 ng/mL having normal/diminished ovarian reserve was higher in subjects > 35 years of age.

	Females <35 yearsof age	Females ≥ 35 yearsof age
Prevalence by Age(AFC > 15)	67.4%	38.4%
PPV	73.6% (67.47, 78.88)	59.7% (51.71, 67.27)
NPV	65.1% (50.17, 77.58)	89.5% (82.50, 93.88)

*PPV and NPV are dependent on prevalence

11. CONCLUSION

Comparative testing of the ADVIA Centaur® Anti-Müllerian Hormone (AMH) assay is substantially equivalent in principle and performance to the Predicate Device - Access AMH assay cleared under 510(k) K170524.

Regulation Number and Section

§ 862.1092 Anti-mullerian hormone test system.

(a)
Identification. An anti-mullerian hormone test system is an in vitro diagnostic device intended to measure anti-mullerian hormone in human serum and plasma. An anti-mullerian hormone test system is intended to be used for assessing ovarian reserve in women.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include:
(i) An adequate traceability plan to minimize the risk of drift in anti-mullerian hormone test system results over time.
(ii) Detailed documentation of a prospective clinical study to demonstrate clinical performance or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:
(A) Results must demonstrate adequate clinical performance relative to a well-accepted comparator.
(B) Clinical sample results must demonstrate consistency of device output throughout the device measuring range that is appropriate for the intended use population.
(C) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the proposed indications for use(s), and results of all statistical analyses.
(iii) Reference intervals generated by testing an adequate number of samples from apparently healthy normal individuals in the intended use population.
(2) The labeling required under § 809.10(b) of this chapter must include a warning statement that the device is intended to be used for assessing the ovarian reserve in conjunction with other clinical and laboratory findings before starting any fertility therapy, and that the device should be used in conjunction with the antral follicle count.