Elecsys AMH system, consisting of the Elecsys AMH CalSet, PreciControl AMH, and AMH CalCheck 5, is intended for use in the in vitro quantitative determination of anti-Müllerian hormone (AMH) in human serum and lithium heparin plasma. The determination of AMH is used for the assessment of ovarian reserve in women presenting to fertility clinics. This system is intended to distinguish between women presenting with AFC (antral follicle count) values >15 (high ovarian reserve) and women with AFC values ≤15 (normal or diminished ovarian reserve). This system is intended to be used for assessing the ovarian reserve in conjunction with other clinical and laboratory findings before starting any fertility therapy. The Elecsys AMH system is not intended to be used for monitoring of women undergoing controlled ovarian stimulation in an Assisted Reproduction Technology program.

The Elecsys AMH system is intended for use on cobas e 411 analyzer.

AMH CalSet is used for calibrating the quantitative Elecsys AMH assay.

PreciControl AMH is used for quality control of the Elecsys AMH assay.

AMH CalCheck 5 is an assayed control for use in calibration verification and for use in the verification of the assay range established for the Elecsys AMH assay.

Device Description

The Elecsys AMH reagent working solutions are packed in Rack Pack (kit placed on analyzer), which include:

Streptavidin-coated microparticles (transparent cap). 1 bottle. 6.5 mL: Streptavidin-. coated microparticles 0.72 mg/mL; preservative.
. Reagent 1: Anti-AMH-Ab~biotin (gray cap), 1 bottle, 8 mL: Biotinylated monoclonal anti-AMH antibody (mouse) 1.0 mg/L, phosphate buffer 50 mmol/L, pH 7.5: preservative.
Reagent 2: Anti-AMH-Ab~Ru(bpy)32+ (black cap), 1 bottle, 8 mL: Monoclonal . anti-AMH antibody (mouse) labeled with ruthenium complex 1.0 mg/L, phosphate buffer 50 mmol/L, pH 7.5; preservative.

The AMH CalSet is a lyophilized equine serum matrix with endogenous AMH (Cal 1) and a lyophilized equine serum matrix with added bovine AMH (Cal 2). The CalSet includes:

AMH Cal 1: approximately 0.04 ng/mL endogenous AMH in an equine serum matrix, . preservative.
. AMH Cal 2: approximately 8 ng/mL bovine AMH in an equine serum matrix, preservative.

PreciControl AMH is a lyophilized equine serum matrix with added bovine AMH (male fetal bovine serum) in two concentration ranges. The controls are used for monitoring the accuracy and precision of the Elecsys AMH assay. PreciControl AMH includes:

. PC AMH 1: approximately 1 ng/mL bovine AMH in an equine serum matrix, preservative.
PC AMH 2: approximately 5 ng/mL bovine AMH in an equine serum matrix, ● preservative.

AMH CalCheck 5 is a (b) (4) (b) (4) (b) (4)

AI/ML Overview

Here's an analysis of the acceptance criteria and study details for the Elecsys AMH system, based on the provided text:

Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Criteria	Reported Device Performance
Precision	Defined by Repeatability (Within Run) and Intermediate Precision (%CV) for various AMH levels.	Internal Precision Study:- Control 1 (1.14 ng/mL): Repeatability 1.4% CV, Intermediate Precision 1.6% CV- Control 2 (5.61 ng/mL): Repeatability 1.6% CV, Intermediate Precision 1.8% CV- Human Serum 1 (0.055 ng/mL): Repeatability 1.6% CV, Intermediate Precision 2.3% CV- Human Serum 2 (1.05 ng/mL): Repeatability 1.3% CV, Intermediate Precision 1.8% CV- Human Serum 3 (3.56 ng/mL): Repeatability 1.5% CV, Intermediate Precision 1.6% CV- Human Serum 4 (11.7 ng/mL): Repeatability 1.0% CV, Intermediate Precision 1.2% CV- Human Serum 5 (19.0 ng/mL): Repeatability 1.4% CV, Intermediate Precision 1.5% CVReproducibility (External Sites):- Total %CV ranged from 3.45% (Serum 3, 3.55 ng/mL) to 5.24% (Control 1, 0.93 ng/mL)- Repeatability %CV ranged from 1.41% (Serum 3) to 1.89% (Control 2)
Linearity/Reportable Range	Evaluation according to CLSI EP6-A; linear regression with high correlation (r) to support claimed measuring range.	Three sample sets showed slopes close to 1 (1.0091, 1.0054, 1.0063) and correlation coefficients (r) of 0.999. Supports claimed measuring range of 0.03 ng/mL - 23 ng/mL.
Dilution	Demonstrated ability to dilute samples with AMH concentrations above the measuring range, both manually and automatically, with Diluent Universal 2 (1:2 ratio).	Data supports dilution with Diluent Universal 2 (1:2 ratio) for samples > 10 ng/mL, with automatic adjustment by cobas e software or manual multiplication.
Traceability	Adequate traceability plan to minimize the risk of drift; traceability to manufacturer's internal reference standards. Target values for Calibrators.	AMH CalSet traceable to manufacturer's internal reference standards (Master Calibrators). Target values for Calibrator 1 (<0.1 ng/mL) and Calibrator 2 (8.0 ng/mL, range 7.2-8.8 ng/mL) provided. Assessment found acceptable.
Stability (Shelf Life)	Assay reagents, calibrators, and controls stable for at least 15 months unopened at 2-8°C. Open Stability: 12 weeks for reagents (2-8°C), 8 weeks on board for reagents, single use for CalSet/PreciControl AMH, 3 hours on board for CalCheck 5.	Reagents, calibrators, and controls stable for 15 months unopened at 2-8°C. Opened AMH reagents stable for 12 weeks at 2-8°C, 8 weeks on board. Lyophilized AMH CalSet and PreciControl AMH are for single use only on board. Reconstituted AMH CalCheck 5 stable for 3 hours on board. Protocols and acceptance criteria reviewed and found adequate.
Stability (Sample)	Serum and Li-Heparin plasma stable for specified conditions (temperature, freeze/thaw).	Serum and Li-Heparin plasma stable for 3 days at 15-25°C, 5 days at 2-8°C, 6 months at -25°C to -15°C, freeze only once.
Detection Limits	Determined in accordance with CLSI EP17-A2 (LoB, LoD, LoQ).	LoB: 0.007 ng/mL, LoD: 0.01 ng/mL, LoQ: 0.03 ng/mL (with within-laboratory precision ≤ 20%).
Analytical Specificity (Endogenous Interference)	Interference considered significant if analyte recovery is outside of ± 10%. Highest concentrations of various endogenous substances tested with no significant interference.	No significant interference (recovery within ± 10%) observed for Hemoglobin (1000 mg/dL), Biotin* (30 ng/mL), Intralipid (1000 mg/dL), Bilirubin (66 mg/dL), Rheumatoid Factor (1000 IU/mL), HAMA (805 ug/L), Human IgG (2.5 g/dL), Human IgM (0.5 g/dL), Human IgA (1.8 g/dL). *Labeling includes a limitation for high biotin doses.
Analytical Specificity (Exogenous Interference)	Interference considered significant if analyte recovery is outside of ± 10%. Highest concentrations of various exogenous substances tested with no significant interference.	No significant interference observed for a range of pharmaceutical compounds at various concentrations (e.g., Acetylcysteine 150 mg/L, Ampicillin-Na 1000 mg/L, Ascorbic acid 300 mg/L, etc.). Labeling includes specific limitations for Cetrotide, Ovitrelle, Endometrin, and Follistatin.
Cross-reactivity	Cross-reactivity observed to be <0.1% at 0 ng/mL AMH for specified cross-reactants.	<0.1% cross-reactivity observed for Inhibin A (100 ng/mL), Activin A (100 ng/mL), LH (500 mIU/mL), FSH (500 mIU/mL).
Hook Effect	No hook effect observed up to 14000 ng/mL AMH.	No hook effect observed up to 14000 ng/mL AMH.
Clinical Performance (Prediction of AFC > 15)	Prospective clinical study demonstrating clinical performance; adequate clinical performance relative to a well-accepted comparator (AFC). AFC cutoff (15) correlated with AMH cutoff (1.77 ng/mL). PPV, NPV, Sensitivity, Specificity reported with 95% CI.	A multicenter, prospective, non-interventional study (N=856 women) correlated AMH values with AFC. Used an AMH cutoff of 1.77 ng/mL for predicting AFC > 15. Results: PPV 75.2% (71.3-78.8%), NPV 84.3% (80.0-88.1%), Sensitivity 88.3% (85.0-91.2%), Specificity 68.3% (63.6-72.8%).
Matrix Equivalence	Demonstration that Li-Heparin plasma samples perform equivalently to serum samples.	75 matched serum/Li-Heparin plasma samples tested. Passing/Bablok regression analysis yielded a slope of 1.017, intercept of -0.00186, and correlation coefficient (r) of 0.999, demonstrating equivalence.
Reference Intervals	Reference intervals generated by testing an adequate number of samples from apparently healthy normal individuals in the intended use population.	Age-dependent reference ranges established in 718 healthy females (20-44 years). Detailed percentile values (2.5%, 5%, Median, 95%, 97.5%) with 95% CIs provided for 5-year age groups.
Labeling	Sufficient and satisfies 21 CFR Parts 801 and 809 and special controls, including warning statement about use in conjunction with other clinical and laboratory findings and AFC.	Labeling deemed sufficient. Includes requirements for use in conjunction with other clinical/laboratory findings and AFC before fertility therapy.

Study Details for Clinical Performance (Prediction of AFC > 15)

Test Set Sample Size: N = 856 women
Data Provenance:
- Country of Origin: United States (samples collected at 13 geographically diverse sites).
- Retrospective or Prospective: Prospective, non-interventional study.
Number of Experts and Qualifications for Ground Truth: The document does not specify the number of experts or their qualifications for determining the Antral Follicle Count (AFC) which served as the ground truth. It states that "AFC was determined by transvaginal ultrasonography (TVUS)". It's implied that trained medical professionals (e.g., sonographers, gynecologists, reproductive endocrinologists) performed the TVUS, but specific numbers and experience levels are not provided.
Adjudication Method: Not specified. It only states that AFC was determined by TVUS.
Multi Reader Multi Case (MRMC) Comparative Effectiveness Study (AI vs. without AI assistance): Not applicable. This device is an immunoassay system, not an AI-assisted diagnostic imaging or interpretation tool for human readers. It provides a quantitative AMH value.
Standalone Performance (Algorithm only without human-in-the-loop): Yes, the study evaluates the standalone performance of the Elecsys AMH system. The AMH values determined by the system are correlated directly with the AFC values, operating without a human interpretation loop of the AMH value itself (though the AFC ground truth is human-derived). The reported Sensitivity, Specificity, PPV, and NPV are for the device's ability to predict AFC > 15 at a given cutoff.
Type of Ground Truth: "Antral Follicle Count (AFCS)" determined by transvaginal ultrasonography (TVUS).
Training Set Sample Size: The document does not explicitly mention a separate "training set" for the AMH assay itself in the context of predicting AFC. The N=856 women study is referred to as the "Clinical Studies" and the results from this study are presented as the device's clinical performance. Immunoassay development typically involves extensive analytical validation (precision, linearity, specificity, etc.) and calibration, which would use dedicated sample sets, but these are not explicitly labeled as "training sets" in the AI sense. The cut-off of 1.77 ng/mL for predicting AFC > 15 would have been established during the development and optimization phase of the assay, likely using a dataset from which this clinical study was drawn or informed.
How Ground Truth for Training Set was Established: Not explicitly detailed in the provided text for a specific "training set." For the purpose of establishing the AMH cutoff (1.77 ng/mL) which aligns with AFC > 15, it would have involved analyzing AMH levels and corresponding AFC values from a cohort of patients. The AFC ground truth would have been established via transvaginal ultrasonography, similar to the method used in the main clinical study, guided by a clinical definition of antral follicles (2-10 mm).

Summary

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EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR Elecsys AMH system

DECISION SUMMARY

A. DEN Number:

DEN150057

B. Purpose for Submission:

De Novo request for evaluation of automatic class III designation of the Elecsys AMH system

C. Measurand:

AMH (Anti-Müllerian [Mullerian] Hormone)

D. Type of Test:

Electrochemiluminescence immunoassay

E. Applicant:

Roche Diagnostics

F. Proprietary and Established Names:

Elecsys AMH system including the following: Elecsys AMH assay AMH CalSet PreciControl AMH AMH CalCheck 5

G. Regulatory Information:

1. Regulation Section:
  21 CFR 862.1092. Anti-mullerian hormone test system

2. Classification:

Class II (Special Controls)

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1. Product Code(s):
  POO JIT JJX
1. Panel:
  91 - Toxicology

H. Indications for use:

1. Indication(s) for use:
  Elecsys AMH system, consisting of the Elecsys AMH CalSet, PreciControl AMH, and AMH CalCheck 5, is intended for use in the in vitro quantitative determination of anti-Müllerian hormone (AMH) in human serum and lithium heparin plasma. The determination of AMH is used for the assessment of ovarian reserve in women presenting to fertility clinics. This system is intended to distinguish between women presenting with AFC (antral follicle count) values >15 (high ovarian reserve) and women with AFC values ≤15 (normal or diminished ovarian reserve). This system is intended to be used for assessing the ovarian reserve in conjunction with other clinical and laboratory findings before starting any fertility therapy. The Elecsys AMH system is not intended to be used for monitoring of women undergoing controlled ovarian stimulation in an Assisted Reproduction Technology program.

The Elecsys AMH system is intended for use on cobas e 411 analyzer.

AMH CalSet is used for calibrating the quantitative Elecsys AMH assay.

PreciControl AMH is used for quality control of the Elecsys AMH assay.

AMH CalCheck 5 is an assayed control for use in calibration verification and for use in the verification of the assay range established for the Elecsys AMH assay.

1. Special conditions for use statement(s):
  For Prescription Use Only

Samples for AMH levels should be drawn on days 2-4 of the menstrual cycle

The Elecsys AMH assay is intended to be used for assessing the ovarian reserve in conjunction with other clinical and laboratory findings before starting any fertility therapy (including pre-treatment such GnRH agonist down-regulation therapy) and should be used in conjunction with AFC. The Elecsys AMH assay is not intended to be used for monitoring of women undergoing controlled ovarian stimulation in an Assisted Reproduction Technology program.

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3. Special instrument requirements:

For use on the cobas e 411 analyzer

I. Device Description:

The Elecsys AMH reagent working solutions are packed in Rack Pack (kit placed on analyzer), which include:

Streptavidin-coated microparticles (transparent cap). 1 bottle. 6.5 mL: Streptavidin-. coated microparticles 0.72 mg/mL; preservative.
. Reagent 1: Anti-AMH-Ab~biotin (gray cap), 1 bottle, 8 mL: Biotinylated monoclonal anti-AMH antibody (mouse) 1.0 mg/L, phosphate buffer 50 mmol/L, pH 7.5: preservative.
Reagent 2: Anti-AMH-Ab~Ru(bpy)32+ (black cap), 1 bottle, 8 mL: Monoclonal . anti-AMH antibody (mouse) labeled with ruthenium complex 1.0 mg/L, phosphate buffer 50 mmol/L, pH 7.5; preservative.

The AMH CalSet is a lyophilized equine serum matrix with endogenous AMH (Cal 1) and a lyophilized equine serum matrix with added bovine AMH (Cal 2). The CalSet includes:

AMH Cal 1: approximately 0.04 ng/mL endogenous AMH in an equine serum matrix, . preservative.
. AMH Cal 2: approximately 8 ng/mL bovine AMH in an equine serum matrix, preservative.

. PC AMH 1: approximately 1 ng/mL bovine AMH in an equine serum matrix, preservative.
PC AMH 2: approximately 5 ng/mL bovine AMH in an equine serum matrix, ● preservative.

AMH CalCheck 5 is a	(b) (4)
	(b) (4)
	(b) (4)

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J. Standard/Guidance Document Referenced:

CLSI EP05-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition

CLSI EP6-A: Evaluation of Linearity of Quantitative Measurement Procedures; A Statistical Approach; Approved Guideline

CSLI EP17-A2: Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline- Second Edition

K. Test Principle:

The Elecsys AMH assay makes use of a sandwich test principle using monoclonal antibodies that are specifically directed against AMH. Endogenous AMH is bound by both a biotinylated monoclonal AMH-specific antibody and a monoclonal AMH-specific antibody labeled with a ruthenium complex to form a sandwich complex. Results are determined via a calibration curve which is instrument-specifically generated by a two-point calibration and a master curve provided via the reagent barcode.

L. Performance Characteristics:

1. Analytical performance:
- a. Precision/Reproducibility:

Precision:

An internal precision study was performed in accordance with CLSI EP05-A2, in which 5 human serum samples and 2 controls were tested in 2 replicates per run x 2 runs per day for 21 days (N = 84) on the cobas e 411 analyzer. The following results were obtained:

SampleMaterial	Mean(ng/mL)	Repeatability (Within Run)		Intermediate Precision
		SD	% CV	SD	% CV
Control 1	1.14	0.017	1.4	0.018	1.6
Control 2	5.61	0.088	1.6	0.101	1.8
Human Serum 1	0.055	0.001	1.6	0.001	2.3
Human Serum 2	1.05	0.014	1.3	0.019	1.8
Human Serum 3	3.56	0.055	1.5	0.058	1.6
Human Serum 4	11.7	0.113	1.0	0.144	1.2
Human Serum 5	19.0	0.265	1.4	0.281	1.5

Reproducibility:

At 3 external laboratory sites, 5 serum pools spiked with bovine AMH and 2 levels of PreciControl AMH were tested in triplicates per day for 5 days on the cobas e 411 analyzer. The results are summarized in the table below:

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Sample	PrecisionType	N	Mean	SD (95% CI)	%CV (95% CI)
Control 1	Total	90	0.93	0.049 (0.032, 0.099)	5.24 (3.46, 10.69)
	Repeatability			0.013 (0.011, 0.016)	1.42 (1.21, 1.73)
Control 2	Total	90	4.87	0.228 (0.155, 0.434)	4.70 (3.18, 8.91)
	Repeatability			0.092 (0.078, 0.112)	1.89 (1.60, 2.30)
Serum 1	Total	90	0.26	0.010 (0.007, 0.020)	3.99 (2.68, 7.77)
	Repeatability			0.004 (0.004, 0.005)	1.58 (1.34, 1.92)
Serum 2	Total	90	1.24	0.050 (0.034, 0.092)	4.05 (2.79, 7.42)
	Repeatability			0.022 (0.018, 0.026)	1.74 (1.48, 2.12)
Serum 3	Total	90	3.55	0.123 (0.083, 0.237)	3.45 (2.33, 6.66)
	Repeatability			0.050 (0.042, 0.061)	1.41 (1.19, 1.71)
Serum 4	Total	90	9.63	0.445 (0.290, 0.944)	4.62 (3.01, 9.80)
	Repeatability			0.163 (0.138, 0.198)	1.69 (1.44, 2.06)
Serum 5	Total	90	20.12	0.880 (0.592, 1.707)	4.38 (2.94, 8.48)
	Repeatability			0.340 (0.289, 0.414)	1.69 (1.43, 2.06)

b. Linearity/assay reportable range:

Linearity:

Linearity of the Elecsys AMH Assay were evaluated according to CLSI EP6-A. Three high level samples were diluted with postmenopausal female serum for a total of 15 concentration levels. Samples were assayed in triplicate on the cobas e 411 analyzer. The observed values were graphed against the calculated values and a linear regression was performed. Results are summarized in the table below:

Sample	Sample range (ng/mL)	Slope	Intercept	Correlation (r)
Set 1	0.004 – 27.5	1.0091	0.0105	0.999
Set 2	0.004 - 27.4	1.0054	0.0205	0.999
Set 3	0.004 - 25.8	1.0063	0.0013	0.999

The linear regression results support the Applicant's claimed measuring range (0.03

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ng/mL - 23 ng/mL).

Dilution:

A dilution study was performed by diluting six human samples with Diluent Universal in 1:2 ratio both manually and by the analyzer. The data support the following instruction for use:

Samples with AMH concentrations above the measuring range can be diluted automatically with Diluent Universal 2. Manual dilution can be performed with Diluent Universal 2. The recommended dilution is 1:2 (either automatically by the cobas e analyzer or manually). The concentration of the diluted sample must be > 10 ng/mL. After manual dilution, multiply the result by the dilution factor. After dilution by the analyzer, the cobas e software automatically takes the dilution into account when calculating the sample concentration.

Traceability, Stability, Expected values (controls, calibrators, or methods): C.

Traceability:

The AMH CalSet are traceable to manufacturer's internal reference standards (Master Calibrators), which consist of a panel of well characterized serum reference materials covering the entire measuring range. The Applicant submitted a detailed traceability assurance plan which was reviewed and found to be acceptable. The target values for AMH CalSet are shown below:

Level	Target Value(ng/mL)	Target Range(ng/mL)
Calibrator 1	<0.1	<0.1
Calibrator 2	8.0	7.2-8.8

Stability:

Shelf life stability studies were performed with assay reagents, calibrators and controls, and demonstrated that they are stable for at least 15 months when stored unopened at 2-8°C. Once opened, the AMH reagents are stable for 12 weeks at 2-8°C and for 8 weeks on board. The lyophilized AMH CalSet and lyophilized PreciControl AMH are for single use only on board. The reconstituted AMH CalCheck 5 is stable for 3 hours on board. The protocols for stability and acceptance criteria were reviewed and found to be adequate.

Sample Stability:

Sample stability studies were performed and demonstrated that both serum and Li-Heparin plasma are stable for 3 days at 15-25°C, 5 days at 2-8°C, 6 months at -25°C to -15℃, freeze only once.

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Value assignment

Concentrations of the AMH CalSet, PreciControl AMH and AMH CalCheck 5 are assigned through internal procedures that were reviewed and found to be acceptable.

d. Detection limit:

The Limit of Blank, Limit of Detection and Limit of Quantitation were determined in accordance with CLSI EP17-A2.

The Limit of Blank (LoB) was defined as the 95th percentile value from N ≥ 60 measurements of analyte-free samples over several independent series, and was determined to be 0.007 ng/mL.

The Limit of Detection (LoD) was calculated based on the LoB and the standard deviation of low concentration samples and was determined to be 0.01 ng/mL.

The Limit of Quantitation (LoQ) was defined as the lowest concentration of analyte that can be quantified with within-laboratory precision of ≤ 20% and was determined to be 0.03 ng/mL.

e. Analytical specificity:
Endogenous interference:

Endogenous interference was evaluated by testing three serum samples (with low, mid, and high AMH levels) with various concentrations of possible endogenous interferents. Each sample was tested in duplicate. The Applicant states in their submission that interference is considered to be significant if analyte recovery is outside of ± 10% of the initial value.

The highest concentrations of endogenous substances tested that show non-significant interference are summarized in the table below:

Substance	Highest concentration testedwith no significant interference
Hemoglobin	1000 mg/dL
Biotin*	30 ng/mL
Intralipid	1000 mg/dL
Bilirubin	66 mg/dL
Rheumatoid Factor	1000 IU/mL
HAMA	805 ug/L
Human IgG	2.5 g/dL
Human IgM	0.5 g/dL
Human IgA	1.8 g/dL

The labeling for this device states the following limitation:

Interference was observed at biotin concentrations above 30 ng/mL. Samples should not be taken from patients receiving therapy with high biotin doses (i.e. > 5 mg/day)

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until at least 8 hours following the last biotin administration.

Exogenous interference

Exogenous interference was evaluated by spiking pharmaceutical compounds (at 2 concentrations with the higher concentration corresponding to at least 3 times the maximum recommended daily dose) into two human serum sample pools with low and high AMH levels. Each sample was tested in triplicate. The Applicant states in their submission that interference is considered to be significant if analyte recovery is outside of ± 10% of the initial value.

The highest concentrations of exogenous substances tested that show non-signifficant interference are summarized in the table below:

Substance	Highest concentration tested withno significant interference (mg/L)
Acetylcysteine	150
Ampicillin-Na	1000
Ascorbic acid	300
Cyclosporine	5
Cefoxitin	2500
Heparin	5000 U
Levodopa	20
Methyldopa +1.5	20
Metronidazole	200
Phenylbutazone	400
Doxycycline	50
Acetylsalicylic Acid	1000
Rifampicin	60
Acetaminophen	200
Ibuprofen	500
Theophylline	100
Gonapeptyl	0.1
Metformin	2000
Folic Acid	0.4
Levothyroxine	0.2

The labeling for this device states the following limitation:

The following drugs may interfere with this test: Cetrotide, Ovitrelle, Endometrin and Follistatin; do not use this test to analyze samples from patients who have received one or more of these products within one to two weeks of testing.

Cross-reactivity:

The cross reactivity of the Elecsys AMH assay was evaluated using samples composed of Diluent Universal spiked with potential cross-reacting compounds. All

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Cross-reactant	Concentration tested
Inhibin A	100 ng/mL
Activin A	100 ng/mL
LH	500 mIU/mL
FSH	500 mIU/mL

samples were tested in duplicate and <0.1% Cross-reactivity at 0 ng/mL AMH was observed for the following cross reactants:

Hook effect:

Two serum samples spiked with high concentrations of AMH were serially diluted using Diluent Universal. No hook effect was observed up to 14000 ng/mL AMH.

f. Assay cut-off:
The AMH cutoff, intended to predict an antral follicle count (AFC) >15, is 1.77 ng/mL.
1. Comparison studies:
- a. Method comparison with predicate device:

Not applicable

b. Matrix comparaison:
The clinical study used to demonstrate clinical performance of the assay was performed in serum samples (see section L(3)(a) below). To demonstrate that Li-Heparin plasma samples perform equivalently to serum samples, 75 matched serum/Li-Heparin plasma samples with AMH concentrations covering the entire measuring range were tested on the cobas e 411 analyzer, and the results were assessed by Passing/Bablok regression analysis.

Slope	Intercept	Correlation coefficient (r)
1.017	-0.00186	0.999

1. Clinical studies:
- a. Clinical sensitivity and specificity:

Clinical Studies:

The use of AMH for the assessment of ovarian reserve was investigated in a multicenter, prospective, non-interventional study with N = 856 women presenting at fertility clinics for evaluation. Patient BMI included in the study ranged from 14.76 to 39.99, as shown below:

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BMI	N
<18.50	29
18.50-24.99	469
25.00-29.99	200
>30.00-39.99	158

AMH values were correlated to the antral follicle count (AFC) of the women. AFC was determined by transvaginal ultrasonography (TVUS), which measures antral follicles (2-10 mm) of the ovary. Both AFC and AMH were determined on days 2-4 of the same menstrual cycle. Clinical serum samples were collected at 13 geographically diverse sites in the United States, and then tested at 3 laboratory sites in the United States on cobas e 411 analyzers.

Based on the AFC, two groups are defined: AFC ≤ 15 and AFC > 15. Correlation of AMH (using the 1.77 ng/mL cutoff) and AFC is presented in the table below (relationship is shown in both absolute numbers and percentages per AMH group):

	AFC ≤ 15	AFC > 15	N
AMH ≤ 1.77 ng/mL	280(84.3 %)	52(15.7 %)	332
AMH > 1.77 ng/mL	130(24.8 %)	394(75.2 %)	524
N	410	446	856

The following figure illustrates the Validation Arm AMH results, presented by AFC group/class (AFC < 15 and AFC > 15).

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Image /page/10/Figure/0 description: The image shows a boxplot comparing AMH levels in ng/mL for two AFC classes, 0-15 and >15. The sample size for the 0-15 class is N=410, while the sample size for the >15 class is N=446. The AMH levels appear to be higher in the >15 AFC class compared to the 0-15 class, as indicated by the position of the boxes and the median values represented by the '+' symbols.

Positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity for predicting AFC > 15 (with 95% confidence intervals in parentheses) observed in the study using the 1.77 ng/mL cutoff are summarized in the following table:

	Result	95% CI
PPV	75.2%	(71.3-78.8%)
NPV	84.3%	(80.0-88.1%)
Sensitivity	88.3%	(85.0-91.2%)
Specificity	68.3%	(63.6-72.8%)

b. Other clinical supportive data (when a. is not applicable):
Not applicable.
1. Clinical cut-off:
  The AMH cutoff, intended to predict an antral follicle count (AFC) >15, is 1.77 ng/mL.
1. Expected values/Reference range:
  A reference range study was conducted to establish age-dependent reference ranges for AMH in 718 apparently healthy females of reproductive age between 20 and 44 years. Native serum samples were collected and testing was conducted at two sites. The reference range values for different age groups are summarized below:

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HealthyWomen(years)	N	2.5%-qng/mL(95% CI)	5%-qng/mL(95% CI)	Medianng/mL(95% CI)	95%-qng/mL(95% CI)	97.5%-qng/mL(95% CI)
20-24	150	1.22(0.478-1.67)	1.52(0.758-1.81)	4.00(3.60-4.44)	9.95(7.87-13.6)	11.7(9.11-15.7)
25-29	150	0.890(0.493-1.21)	1.20(0.797-1.75)	3.31(3.00-3.89)	9.05(7.59-10.3)	9.85(8.91-11.3)
30-34	138	0.576(0.256-0.958)	0.711(0.256-1.12)	2.81(2.35-3.47)	7.59(6.84-9.52)	8.13(7.27-9.72)
35-39	138	0.147(0.053-0.474)	0.405(0.053-0.496)	2.00(1.73-2.36)	6.96(5.31-9.37)	7.49(6.49-10.9)
40-44	142	0.030(0.030-0.063)	0.059(0.030-0.119)	0.882(0.726-1.13)	4.44(2.94-5.56)	5.47(3.92-6.76)

M. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809 and the special controls for this device type.

N. Identified Risks and Identified Mitigations:

Identified Risks to Health	Identified Mitigations
Inaccurate test results that provide false positive resultsmay lead to a modification, delay or cancellation before acontrolled ovarian stimulation procedure is initiated.	General controls and specialcontrols (1) and (2)
Inaccurate test results that provide false negative resultsmay lead to the development of ovarian hyperstimulationsyndrome in patients incorrectly thought to have normaland/or diminished ovarian reserve.	General controls and specialcontrols (1) and (2)

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O. Benefit/Risk Analysis:

Summary
Summary ofthe Benefit(s)	The primary benefit of the Elecsys AMH system is its use in the prediction (inconjunction with other clinical and laboratory findings) of high ovarianreserve. The assessment of ovarian reserve prior to performing controlledovarian stimulation (COS) can assist in the reduction of risk of patientsdeveloping ovarian hyperstimulation syndrome (OHSS) by identifying thosepatients with a higher OHSS risk (i.e., those with high ovarian reserve levels,which correspond to an antral follicle count (AFC) of >15).The AMH cut-off corresponding to an AFC > 15 was validated with asensitivity and specificity of 88.3% and 68.3%, respectively.
Summary ofthe Risk(s)	The primary risks to patients through the use of the device are related to theconsequences of clinical decisions based on false positive and the moreclinically significant false negative results.False positive results may lead to a modification, delay or cancellation beforea controlled ovarian stimulation procedure is initiated. Modifications to astimulation regimen may lead to less oocytes for fertilization. False positiveresults may result in the need for a repeat procedure and cancelled or delayedstimulation.False negative results may lead to the development of ovarianhyperstimulation syndrome, a potentially life-threatening condition, inpatients incorrectly thought to have normal and/or diminished ovarian reserve.However, this risk can be mitigated through appropriate labeling indicatingthat AMH assay is intended to be used for assessing the ovarian reserve inconjunction with other clinical and laboratory findings before starting anyfertility therapy, and should be used in conjunction with Antral Follicle Count.Additional risks to patients and laboratory workers include those that areassociated with routine phlebotomy performed as standard practice in aclinical setting.
Summary ofOther Factors	There are no additional factors to consider.
Summary
ConclusionsDo theprobablebenefitsoutweigh theprobable risks?	Given the performance characteristics, applicable general controls, includingdesign controls, and proposed special controls, including labelingmitigations, the probable benefits outweigh the probable risks for this device.

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Patient Perspectives:

This submission did not include specific information on patient perspectives for this device.

P. Conclusion:

Product Code:	PQO, JIT, JJX
Device Type:	Anti-mullerian hormone test system
Class:	II (special controls)
Regulation:	21 CFR 862.1092

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 antimullerian hormone test system is intended to be used as an aid for assessing ovarian reserve in women.
b) Classification. Class II (special controls). An anti-mullerian hormone test system must comply with the following special controls:
- 1. Premarket notification submissions must include the following information:
  - An adequate traceability plan to minimize the risk of drift in anti-1. 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:
    - Results must demonstrate adequate clinical performance relative to a. 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.

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1. Your 809.10(b) compliant labeling 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.

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.