(534 days)
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.
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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.
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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.
| Performance Metric | Acceptance Criteria (Implicit) | Reported Device Performance |
|---|---|---|
| Precision (Repeatability & Intermediate Imprecision) | Met predetermined criteria (according to EP05-A3) | All samples met criteria. |
| Reproducibility (Overall, Within-run, Within-lab) | Met specifications at all sites (according to CLSI EP05-A3, Assay Migration Guidance, and original De Novo study) | No influence of site variability. |
| Limit of Blank (LoB) | Determined according to CLSI EP17-A2 | Labelling claim: 0.007 ng/mL |
| Limit of Detection (LoD) | Determined according to CLSI EP17-A2 | Labelling claim: 0.01 ng/mL |
| Limit of Quantitation (LoQ) | Met predetermined criteria (according to CLSI EP17-A2) | Labelling claim: 0.030 ng/mL |
| Linearity | Demonstrated across measuring range | Measuring range claim: 0.03 - 23 ng/mL |
| Accuracy (Diluent Universal) | Diluted samples accurate | Recommended 1:2 dilution for samples > 10 ng/mL. |
| High-Dose Hook Effect | No hook effect observed up to a certain concentration | No hook effect up to > 1400 ng/mL. |
| HAMA Interference | Specification fulfilled | Specification fulfilled. |
| Biotin Interference | Biotin interference mitigated | Biotin interference claim: 1200 ng/mL. |
| Endogenous Interfering Substances (Hemoglobin, Intralipid, Bilirubin, Rheumatoid Factor, Human IgG, Human IgM, Human IgA) | Met all specifications | No changes from current AMH interference concentrations. |
| Specificity (Cross-reactants) | Acceptable cross-reactivity | Calculated with one lot of reagent. |
| Pharmaceutical Compounds (16 general, 4 special) | Met acceptance criteria (according to CLSI guideline EP07-A3) | All compounds met acceptance criteria. |
| Sample Type Equivalence (Serum vs. Lithium Heparin Plasma) | Specifications fulfilled | Li-Heparin plasma is an acceptable sample type. |
| Method Comparison (Quantitative & Qualitative) | All acceptance criteria fulfilled (according to "Assay Migration Studies" guidance and CLSI EP09-A3) | No clinically significant bias observed. |
| Stability | Met pre-specified acceptance criteria | Stability data supports claims in labeling. |
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.
§ 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.