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.

Device Description

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.

AI/ML Overview

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.

Summary

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June 10, 2022

Roche Diagnostics Edie Eads US Regulatory Affairs Program Manager 9115 Hague Road Indianapolis, Indiana 46250

Re: K203757

Trade/Device Name: Elecsys AMH Regulation Number: 21 CFR 862.1092 Regulation Name: Anti-Mullerian Hormone Test System Regulatory Class: Class II Product Code: PQO Dated: March 17, 2022 Received: March 21, 2022

Dear Edie Eads:

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.

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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 803) 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 medical devices and radiation-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.

Marianela Perez-Torres, Ph.D. 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) K203757

Device Name Elecsys AMH

Indications for Use (Describe)

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

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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Elecsys AMH 510(k) Summary

This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of 21 CFR 807.92.

In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).

Submitter Name	Roche Diagnostics
Address	9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457
Contact	Contact: Edie EadsPhone: (317) 734-8046Email: edie.eads@roche.comSecondary Contact: Todd DavisPhone: (317) 313-7112Email: todd.davis@roche.com
Date Prepared	June 9, 2022
Proprietary Name	Elecsys AMH
Common Name	Elecsys AMH
Classification Name	Clinical Chemistry
Product Codes,Regulation Numbers	PQO, 21 CFR 862.1092
Predicate Devices	DEN150057, Elecsys AMH System

The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Elecsys AMH.

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1. DEVICE DESCRIPTION

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.

INTENDED USE/INDICATIONS FOR USE 2.

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 assessment of 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.

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

INDICATIONS FOR USE COMPARISON 3.

The Elecsys AMH on the cobas e 601 (updated assay, Mat. No. 08819319160) is substantially equivalent to the Elecsys AMH system, granted under DEN150057.

The intended use was updated to remove additional components from the reagent intended use and to remove analyzers no longer supported for use with Roche assays. The indications for use was not changed for the Elecsys AMH from the predicate device.

Roche Diagnostics is updating the current Elecsys AMH to mitigate the potential interference of biotin. Roche implemented a technical solution consisting of a scavenger antibody to R2 allowing depletion of biotin in a patient sample by binding free biotin. There were no other technological changes to the current Elecsys AMH.

The submitted information in this premarket notification supports a substantial equivalence decision.

NON-CLINICAL AND/OR CLINICAL TESTS SUMMARY & CONCLUSIONS 4.

Precision of the updated Elecsys AMH assay was evaluated with native human serum pools. The protocol consisted of testing two replicates per run, 2 runs per day for 21 days. Repeatability and Intermediate imprecision were calculated according to EP05-A3. All samples met the predetermined acceptance criteria.

Reproducibility was performed using a modified protocol, incorporating CLSI guidelines, Assay Migration Guidance, and the study performed in the original De Novo (DEN150057). Reproducibility was performed at three sites with three reagent lots for five days using native human serum pools. Overall reproducibility, repeatability (within run) and intermediate (withinlab) precision (SD and/or CV values) were calculated for the updated Elecsys AMH. Data calculation was performed according to CLSI EP05-A3. All sites met the specifications for

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reproducibility testing. The results show that there is no influence of site variability on the performance of the assay.

The Limit of Blank (LoB) was determined according to CLSI EP17-A2. 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. The LoB claim in the labeling will be set to 0.007 ng/mL.

The Limit of Detection (LoD) was determined according to CLSI EP17-A2. Five native samples with low-analyte concentration were measured in 2-fold determination in 6 runs, distributed over 6 days, on one analyzer. The LoB claim in the labeling will be set to 0.01 ng/mL.

The Limit of Quantitation (LoO) was determined according to CLSI EP17-A2. Ten low-level human serum samples (HS) were measured in five-fold determinations with one run per day over 5 days. All lots met the predetermined acceptance criterion and the LoO claim in the labeling will be set to 0.030 ng/mL.

Linearity was assessed using one human serum sample with high analyte content above the measuring range diluted to the lower end of the measuring range with postmenopausal female serum (pmpFS), which can be considered to contain no AMH. The dilution series contained 15 steps (dilutions) throughout the measuring range. Labeling will reflect, "Linearity results confirm the measuring range claim of 0.03 - 23 ng/mL for the Elecsys AMH assay."

Accuracy and suitability of Diluent Universal for dilution of Elecsys AMH was assessed by diluting three high samples 1:2 with 2 different lots of Diluent Universal. The samples were manually diluted and multiplied by the dilution factor. Samples with AMH concentrations above the measuring range can be diluted with Diluent Universal 2 and the recommended dilution is 1:2 (either automatically by the analyzers or manually). The concentration of the diluted sample must be > 10 ng/mL.

The high-dose hook effect was assessed. Two high concentration samples were used to prepare a dilution series. For each sample, a dilution series was performed with postmenopausal female serum (pmpFS), which can be considered to contain no AMH. No hook effect up to > 1400 ng/mL.

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The effect of the presence of human anti-mouse antibodies (HAMA) was assessed in two-fold determination. A serum pool with a high-HAMA concentration and a serum pool without HAMA were each divided into three aliquots. Each set of three aliquots were spiked with different AMH concentrations. The serum pools spiked with AMH were diluted in 11 steps with the non-HAMA serum pool spiked with the same AMH concentration. The specification was fulfilled for the HAMA interference.

The effect on quantitation of AMH in the presence of biotin was tested with native human serum sample pools. Three human serum samples (containing low, mid, and high concentrations of AMH) were tested in duplicate with three reagent lots. The biotin interference claim will be set to 1200 ng/mL in labeling.

The effect on quantitation of AMH in the presence of seven endogenous interfering substances (Hemoglobin, Intralipid, Bilirubin, Rheumatoid Factor, Human IgG, Human IgM, and Human IgA) was tested using native human serum sample pools. For each potential interferent, three human serum samples (containing low, mid, and high concentrations of AMH) were tested in duplicate with one reagent lot. The results of endogenous interference testing met all specifications and there will be no changes from current AMH interference concentrations.

The specificity was determined using a native human serum pool without analyte content. The sample was spiked with potential cross-reactants. Samples were measured in the presence and absence of the potential cross-reactants and cross-reactivity was calculated with one lot of reagent.

Sixteen pharmaceutical compounds and four special pharmaceutical compounds were spiked into two human serum sample pools (low-AMH concentration and high-AMH concentration), and tested. The drug concentrations were chosen according to the recommendation (if available) given in the CLSI guideline EP07-A3. When concentrations were not available in the guideline, concentrations of at least three times of the maximum recommended daily dose were tested. All compounds met the acceptance criteria.

The effect on quantitation of AMH in the presence of lithium-heparin anticoagulant was determined by comparing values obtained from human samples drawn into Serum and Li

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Heparin plasma primary tubes. The specifications were fulfilled and thus the resulting data support the package-insert claim that Li-Heparin plasma is an acceptable sample type for use with the Elecsys AMH assay.

Roche performed method comparison studies in concordance with the "Assay Migration Studies for In Vitro Diagnostic Devices" guidance document and CLSI EP09-A3. Analyses were based on both quantitative and qualitative attributes of the assay. In total, all acceptance criteria were fulfilled for both quantitative and qualitative analyses; therefore, no clinically significant bias could be observed.

The stability studies were performed and the pre-specified acceptance criteria were met. The stability data supports the claims as reported in labeling.

The Elecsys AMH immunoassay (updated assay, Mat. No. 08819319160) is substantially equivalent to the Elecsys AMH system (current assay, Mat. No. 06331076160).

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.