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Elecsys AMH is intended for 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 ovarian reserve in women presenting to fertility clinics. This immunoassay 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 immunoassay is intended to be used for assessing the ovarian reserve in conjunction with other clinical and laboratory findings before starting any fertility therapy. Elecsys AMH is not intended to be used for monitoring of women undergoing controlled ovarian stimulation in an Assisted Reproduction Technology program.

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The Elecsys AMH immunoassay makes use of a sandwich test principle using a biotinylated monoclonal AMH-specific antibody and a monoclonal AMH-specific antibody labeled with a ruthenium complex. The Elecsys AMH immunoassay is intended for the quantitative determination of anti-Müllerian hormone (AMH) in human serum and lithium heparin plasma. It is intended for use on the cobas e immunoassay analyzers.

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.

The reagent working solutions include: Rack Pack (kit placed on the analyzer)

• M Streptavidin-coated microparticles (transparent cap), 1 bottle, 6.5 mL:

Streptavidin-coated microparticles 0.72 mg/mL; preservative.

• R1 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.

• Anti-AMH-Ab~Ru(bpy) (black cap), 1 bottle, 8 mL: Monoclonal anti-AMH antibody (mouse) labeled with ruthenium complex 1.0 mg/L, biotin scavenger antibody 1 mg/mL, phosphate buffer 50 mmol/L, pH 7.5; preservative.

The provided text describes the Elecsys AMH device, an immunoassay used for the quantitative determination of anti-Müllerian hormone (AMH) in human serum and lithium heparin plasma. It is intended to assess ovarian reserve in women presenting to fertility clinics by distinguishing between women with high ovarian reserve (AFC > 15) and those with normal or diminished ovarian reserve (AFC ≤ 15). The submission is a Traditional 510(k) Premarket Notification for an updated version of the Elecsys AMH assay designed to mitigate biotin interference.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document lists various performance criteria and states that "All samples met the predetermined acceptance criteria" or "All lots met the predetermined acceptance criterion" for each. Specific numerical acceptance criteria are generally not explicitly stated, but the reported performance values are provided for some.

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

The text provides some details on sample sizes for specific tests:

• Precision and Reproducibility: "two replicates per run, 2 runs per day for 21 days" for precision; "three sites with three reagent lots for five days using native human serum pools" for reproducibility.
• LoB: "Five analyte-free samples were measured in two-fold determinations in six runs, distributed over 6 days using native human serum samples and serum pools."
• LoD: "Five native samples with low-analyte concentration were measured in 2-fold determination in 6 runs, distributed over 6 days, on one analyzer."
• LoQ: "Ten low-level human serum samples (HS) were measured in five-fold determinations with one run per day over 5 days."
• Linearity: "one human serum sample with high analyte content... The dilution series contained 15 steps (dilutions)."
• HAMA: "two-fold determination... A serum pool with a high-HAMA concentration and a serum pool without HAMA... diluted in 11 steps."
• Biotin Interference: "Three human serum samples (containing low, mid, and high concentrations of AMH) were tested in duplicate with three reagent lots."
• Endogenous Interfering Substances: "For each potential interferent, three human serum samples (containing low, mid, and high concentrations of AMH) were tested in duplicate with one reagent lot."
• Specificity (Cross-reactants): "a native human serum pool without analyte content... Samples were measured in the presence and absence of the potential cross-reactants."
• Pharmaceutical Compounds: "Sixteen pharmaceutical compounds and four special pharmaceutical compounds were spiked into two human serum sample pools (low-AMH concentration and high-AMH concentration)."
• Sample Type Equivalence: "human samples drawn into Serum and Li Heparin plasma primary tubes."

Data Provenance: The data provenance (e.g., country of origin of the data, retrospective or prospective) is not explicitly stated in the provided text. The samples are described as "native human serum" or "human serum samples," but their origin is not specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

This device is an in vitro diagnostic (IVD) immunoassay, not an imaging device that would typically rely on expert human interpretation for ground truth. The "ground truth" here is based on analytical measurements against established laboratory standards and control materials. Therefore, the concept of "experts establishing ground truth for the test set" in the context of radiologists or similar clinical experts is not applicable to this type of device. The ground truth is inherent to the chemical and biological properties being measured and assessed through the analytical methods described (e.g., CLSI guidelines).

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

Adjudication methods like 2+1 or 3+1 typically refer to the process of resolving discrepancies among multiple expert readers in diagnostic imaging. As this is an in vitro diagnostic immunoassay, such adjudication methods are not applicable. Quality control and analytical performance are verified through statistical methods and adherence to CLSI guidelines.

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

An MRMC comparative effectiveness study is designed for evaluating the impact of AI on human readers, typically in imaging diagnostics. The Elecsys AMH is an automated immunoassay for quantitative measurement of a biomarker. It does not involve human readers interpreting images or otherwise making diagnostic decisions that would be augmented by AI. Therefore, an MRMC study and effect size of human improvement with AI assistance are not applicable to this device.

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

Yes, the studies described are essentially standalone performance evaluations of the algorithm (the immunoassay) without human-in-the-loop diagnostic performance being assessed. The device itself (on the cobas e immunoassay analyzers) performs the quantitative determination of AMH. The studies assess the analytical performance of this automated system, such as precision, accuracy, limits of detection, and interference, demonstrating its capability independent of human interpretation of the primary result.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for this type of IVD device is primarily based on analytical standards, reference materials, and established laboratory methods. For example:

• Known concentrations of AMH in spiked samples for linearity, accuracy, and interference studies.
• Analyte-free samples for LoB.
• Low-concentration samples with known, very low AMH levels for LoD and LoQ.
• Comparison to predicate device measurements in method comparison studies as an established "truth" for substantial equivalence.
• Verification against CLSI guidelines which represent standardized and accepted analytical performance criteria.

It's about the chemical and biological accuracy of the measurement, not a clinical ground truth like pathology or patient outcomes, although the results are used in a clinical context.

8. The sample size for the training set

The text does not provide information regarding a specific "training set" for the Elecsys AMH. As an immunoassay, its development would involve optimizing reagents and assay conditions, calibration curve generation, and extensive analytical validation. This is different from machine learning algorithms that typically have distinct training and test sets. The calibration curve is instrument-specifically generated by a two-point calibration and a master curve provided via the reagent barcode. This "master curve" could be considered analogous to some form of "training" for the instrument to interpret signals, but the raw data it was derived from is not detailed here.

9. How the ground truth for the training set was established

Since a "training set" in the context of machine learning is not explicitly mentioned or directly applicable to this immunoassay in the way it's described, the method for establishing its "ground truth" is not provided. Essentially, the assay is developed and optimized to accurately measure AMH concentrations, and its calibration (using known calibrators) serves a similar function to establishing a ground truth reference for its measurements. The master curve is provided with the reagent, implying it's based on extensive characterization with reference materials.

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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.

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)

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

• 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% CV

Reproducibility (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 ( 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)

1. Test Set Sample Size: N = 856 women
2. Data Provenance:
   • Country of Origin: United States (samples collected at 13 geographically diverse sites).
   • Retrospective or Prospective: Prospective, non-interventional study.
3. 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.
4. Adjudication Method: Not specified. It only states that AFC was determined by TVUS.
5. 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.
6. 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.
7. Type of Ground Truth: "Antral Follicle Count (AFCS)" determined by transvaginal ultrasonography (TVUS).
8. 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.
9. 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).

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