(376 days)
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
| 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% 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)
- 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).
§ 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.