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The FREND™ Testosterone test is a fluorescent nanoparticle immunoassay designed for in vitro quantitative measurement of total testosterone in human serum and plasma (K3-EDTA and lithium heparin). Measurements of testosterone are used in the diagnosis and treatment of disorders involving the male sex hormones (androgens), including primary and secondary hypogonadism, impotence in males, hirsutisim (excessive hair) and virilization (masculinization) due to tumors, polycystic ovaries, and adrenogenital syndromes.

The FREND™ Testosterone microfluidic flow cartridge is designed for use in the FREND™ System fluorescent immunoassay reader. The FREND™ Testosterone Test System is intended for use in clinical laboratories. For in vitro diagnostic use only. The test is not intended for use in point-of-care settings.

The FREND™ Testosterone is a rapid fluorescence immunoassay that measures testosterone levels in human serum and plasma using the FREND™ system.

The FREND™ Testosterone test is a single-use rapid "competitive" immunoassay utilizing fluorescent nanoparticle in microfluidic flow to capture and quantify total testosterone levels in human serum and plasma (KgEDTA and lithium-heparin) specimens using the FREND™ system. The FREND™ Testosterone Test is a two-step competitive immunoassay with gold micro-particles labeled with mouse monoclonal antitestosterone antibody, testosterone-biotin labeled with fluorescence nanoparticles and fluorescence detection by the FREND™ System.

The FREND™ Testosterone test utilizes microfluidic technology and detects immunecomplexes bound to testosterone. In Step 1, a 70 µL patient sample is first incubated for 5 minutes at 98.6 °F (37 °C) in the Testosterone Gold Antibody pretreatment tube, where the sample interacts with a proprietary mix of a pretreatment solution. In Step 2, the Test Cartridge is placed on the warming platform of the heating block and 35 µL of the mixture from Step 1 is manually loaded into the inlet of the cartridge. The cartridge remains on the warming platform for 30 seconds, while the sample hydrates the testosterone-biotin fluorescent bead conjugate and migrates along the test strip. During migration the bound testosterone in the sample and the testosterone-biotin fluorescent bead conjugates compete to form antigen-antibody complexes in the test zone. Unbound testosterone-biotin fluorescent conjugates flow through and bind to the antitestosterone antibody that is immobilized on the surface in the reference zone. The cartridge is inserted into the FREND instrument for analysis where fluorescent signals in the test and reference zones are measured, typically within 4 minutes.

Testosterone quantification is based upon the ratio of the intensity of the test and reference zones. The magnitude of the fluorescent ratio is inversely proportional to the amount of testosterone in the sample.

The measuring range of the FREND™ Testosterone Test System is 20 to 1500 ng/dL. Results are determined via a lot-specific calibration curve which is generated by the manufacturer using a six-point calibration determined from values averaged from 5 replicates at each level. The established curve is uploaded to the FREND™ System via the Testosterone Code-chip and is valid until the lot expiration date.

The FREND™ Testosterone test cartridge is a disposable plastic device that houses the reagents and contains a port or opening (inlet) where the sample is applied. Once the sample is applied, it will mix with the reagents and travel towards the detection area via capillary action.

The FREND™ System is a portable, automated FREND™ cartridge reader. The FREND™ System is based on quantitative immunoassay technology capable of quantifying single or multiple analytes by measuring laser-induced fluorescence in a single-use disposable reagent cartridge. The FREND™ cartridge utilizes micro-fluidics lateral flow technology where the analyte of interest in the sample forms immune complexes while moving through the fluidics pathway in the cartridge. The concentration of the analyte of interest in an unknown sample is calculated using the ratio of the fluorescent intensity of the test zone and the reference zone.

The FREND™ System is a bench top fluorescence reader containing a touch screen user interface. The System has a slot that accepts the FREND™ Testosterone Test Cartridge (which contains the reagents and sample), and is programmed to analyze the Test when the sample has fully reacted with the on-board in-cartridge reagents. Results of the test are displayed on the screen and can be printed on an optional printer.

The FREND™ System software controls the graphical user interface, communication with hardware, database manaqement and data analysis. The software also controls the functions of the mechanical components including the motor, laser, printer control and acquisition of data from the sensor. The user can set the time and date and enter patient ID through the graphic user interface. The user cannot make any changes to the software.

The FREND™ Testosterone Test System includes the following in the kit:

• . 20 FREND™ Testosterone cartridges
• 20 Testosterone Gold Antibody Pretreatment Tubes .
• Disposable pipette tips .
• . 1 FREND™ Testosterone Code Chip
• 1 FREND™ Testosterone Package Insert ●

The FREND™ System (previously cleared in K124056 (FREND™ PSA Plus) K131928 (FREND™ TSH), and K152422 (FREND™ Free T4)) is not provided with the kit but is required for the use of the FREND™ Testosterone test cartridge.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for each performance characteristic as clear pass/fail thresholds. Instead, it provides the results of various analytical performance studies. However, the implicit acceptance criterion for most of these studies is typically that the device performs within expected and acceptable analytical limits for a diagnostic test of its type, and that its performance is comparable to the predicate device.

For the purpose of this table, I will infer the performance goals based on industry standards and the presented data.

• 39.723 ng/dL: 11.2% CV
• 202.965 ng/dL: 8.2% CV
• 1012.208 ng/dL: 5.4% CV
  Within-laboratory (Inter-assay):
• 39.723 ng/dL: 11.8% CV
• 202.965 ng/dL: 8.5% CV
• 1012.208 ng/dL: 5.7% CV |
  | Linearity/Reportable Range | The device should demonstrate linearity across its claimed measuring range, meaning results accurately reflect the concentration of the analyte over that range. | Linearity demonstrated across 17 ~ 1650 ng/dL, supporting a reportable range of 20 ng/dL ~ 1500 ng/dL. |
  | Detection Limit (LoD) | The device should be able to reliably detect testosterone at its claimed analytical sensitivity. | LoD established at 14.3 ng/dL. Functional sensitivity established at 19.66 ng/dL. Analytical sensitivity claimed at 20 ng/dL. |
  | Analytical Specificity (Interference) | Key endogenous substances and common pharmaceuticals should not significantly interfere with the test results (e.g., recoveries within 90-110% of expected values). | All tested endogenous substances (Hemoglobin, Bilirubin, Triglyceride, Total protein, Biotin, SHBG) and pharmaceuticals (e.g., Acetylcysteine, Ampicillin-Na, Ascorbic acid, Cyclosporine, Cefoxitin, Heparin, Levodopa, Methyldopa, Metronidazole, Doxycycline, Acetylsalicylic Acid, Rifampin, Acetaminophen, Ibuprofen, Theophylline) showed %Recovery of Testosterone between 90% and 110%. Heterophilic Antibodies (RF, HAMA) also showed recoveries within this range. |
  | Analytical Specificity (Cross-Reactivity) | Structurally similar compounds or other hormones should not lead to significant false-positive readings or inaccurate quantification of testosterone. | No significant cross-reactivity was found for all tested substances (e.g., Androstenedione, Androsterone, Cortisone, Danazol, Estradiol, Estrone, 17a-Ethinyl estradiol, Progesterone, Dexamethasone, Ethisterone, D(-) Norgestrel, Prednisolone, Prednisone, Spironolactone, Cortisol, DHEA, DHEAS, Dihydrotestosterone, Epitestosterone, Ethynodiol diacetate). The % Cross-reactivity was generally very low, with the highest at 0.5160% for Estradiol and 1.0463% for DHEA, and 0.4134% for Dihydrotestosterone. |
  | Method Comparison with Predicate Device | The device's results should correlate well with a legally marketed predicate device (Abbott ARCHITECT 2nd Generation Testosterone), demonstrated by a slope close to 1 and an intercept close to 0 in Passing-Bablok regression analysis. | Passing-Bablok regression analysis comparing FREND™ Testosterone (y) with Abbott ARCHITECT 2nd Generation Testosterone (x) yielded a slope of 0.983 and an intercept of -2.353. This indicates good agreement with the predicate. |
  | Matrix Comparison | The device should produce equivalent results across different sample matrices (serum, K3EDTA plasma, lithium heparin plasma) as specified in its intended use, indicating that the anticoagulant used does not interfere with the test. | Testosterone concentrations measured in serum, lithium heparin, and K3EDTA plasma from 40 individuals using the FREND™ Testosterone Test System gave equivalent results. |
  | Stability | The reagent kit should maintain its performance characteristics for a specified period when stored appropriately. | Reagent stability studies showed the cartridges will meet performance acceptance criteria for one year from the date of manufacture if stored refrigerated as directed. |

2. Sample Sizes and Data Provenance (for test set/comparison studies)

• Precision/Reproducibility: Three serum pools were assayed, each in duplicate, twice per day for 20 days (80 total measurements per level).
• Linearity/Assay Reportable Range: Seven levels of serum testosterone were tested in quadruplicate using three reagent lots.
• Detection Limit (LoD): Not specified in terms of sample number, but established according to CLSI EP17-A2 protocol.
• Analytical Specificity (Interference): Not explicitly stated how many samples were used, but testing involved samples spiked with various interferents.
• Analytical Specificity (Cross-Reactivity): Not explicitly stated how many samples were used, but testing involved samples spiked with various cross-reactants.
• Method Comparison with Predicate Device: 157 de-identified leftover samples were used. An additional 2 samples were outside the range of both methods.
  • Data Provenance: The method comparison study was performed in a CLIA-certified laboratory testing facility. The document does not specify the country of origin for the samples directly, but the applicant company is located in Korea, and the US FDA is reviewing the device for the US market. The samples were "de-identified leftover samples," indicating they were retrospective.
• Matrix Comparison: 40 individuals' samples (serum, lithium heparin, and K3EDTA plasma) were used.
• Expected Values/Reference Range: 488 normal, apparently healthy adult male and female individuals.

3. Number of Experts and Qualifications for Ground Truth

This document describes a diagnostic in vitro medical device (an assay for testosterone levels) and does not involve image interpretation or clinical diagnosis by human experts for establishing ground truth as typically seen in AI/CADe devices.

Instead, the "ground truth" for the comparison studies is established by:

• Reference methods/predicate devices (e.g., Abbott ARCHITECT 2nd Generation Testosterone assay).
• Gravimetric preparation for standards/calibrators.
• Protocols and standards like CLSI guidelines for analytical performance.

Therefore, the concept of "number of experts" and "qualifications of those experts" in the context of clinical interpretation of a test set is not directly applicable here. The experts involved would be laboratory scientists and method developers ensuring adherence to CLSI guidelines and proper validation of the reference method.

4. Adjudication Method for the Test Set

Not applicable. For an in vitro diagnostic device measuring a quantitative analyte, adjudication methods like 2+1 or 3+1 consensus are not generally used. The ground truth for method comparison is the result obtained from the predicate device or a recognized reference method.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This type of study is relevant for imaging devices or AI tools that assist human readers in making diagnoses or interpretations. The FREND™ Testosterone Test System is a laboratory assay that provides a quantitative value, not an assistive AI tool for human interpretation.

6. Standalone Performance

Yes, a standalone performance was done for the device itself. All the analytical performance studies (Precision, Linearity, LoD, Analytical Specificity, Stability) and matrix comparison were conducted to assess the performance of the FREND™ Testosterone Test System independently. The method comparison study also shows the device's standalone performance compared to another established device. The device generates a quantitative result directly, rather than assisting a human in an interpretative task.

7. Type of Ground Truth Used

The ground truth used for various performance evaluations includes:

• Reference Method: For method comparison, the Abbott ARCHITECT 2nd Generation Testosterone assay (K120009) was used as the reference method.
• Gravimetric Preparation: For standards/calibrators, the ground truth is established through gravimetric preparation and confirmed by the reference method.
• Expected Values/Spiked Samples: For interference and cross-reactivity studies, known concentrations of analytes and interferents are spiked into samples, creating a known "ground truth" to measure recovery and specificity.
• CLSI Protocols: Adherence to CLSI (Clinical and Laboratory Standards Institute) protocols for various analytical studies (e.g., EP5-A3 for precision, EP6-A for linearity, EP17-A2 for LoD, EP07-A2 for interference/cross-reactivity, EP14-A3 for matrix comparison, C28-A3 for reference intervals) implies that the ground truth is established based on recognized industry standards and best practices for in vitro diagnostic device validation.

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning or AI algorithm development because the FREND™ Testosterone Test System is a fluorescent nanoparticle immunoassay. While it uses the "FREND™ System" which includes software and data analysis, it's a fixed algorithm for quantifying a chemical analyte based on fluorescent ratio, not a learning algorithm that requires a traditional training set like a deep learning model.

The "calibration curve" is "generated by the manufacturer using a six-point calibration determined from values averaged from 5 replicates at each level." This is a form of calibration rather than algorithm training.

9. How the Ground Truth for the Training Set Was Established

As there is no traditional "training set" in the AI/ML sense, the concept of establishing ground truth for it is not applicable. The device's operational parameters (like the calibration curve) are established by the manufacturer through rigorous calibration using control materials with known testosterone concentrations derived from a six-point calibration curve, averaged from 5 replicates at each level. The standards/calibrators themselves are prepared gravimetrically and confirmed by measurement on the predicate device.

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The ARCHITECT SHBG assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of sex hormone binding globulin (SHBG) in human serum and plasma on the ARCHITECT i System. The ARCHITECT SHBG assay is used as an aid in the diagnosis of androgen disorders.

The ARCHITECT SHBG assay is a two-step immunoassay to determine the presence of SHBG in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology with flexible assay protocols, referred to as Chemiflex. In the first step, sample, assay diluent, and anti-SHBG coated paramagnetic microparticles are combined. SHBG present in the sample binds to anti-SHBG coated microparticles. After washing, the SHBG binds to the anti-SHBG acridinium-labeled conjugate that is added in the second step. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs). A direct relationship exists between the amount of SHBG in the sample and the RLUs detected by the ARCHITECT i System optics. The concentration of SHBG in the sample is determined by comparing the chemiluminescent signal in the reaction to the ARCHITECT SHBG calibration.

This document is primarily a 510(k) summary for a labeling change to the ARCHITECT SHBG assay. It is not about a new device or an AI/ML device, but rather an update to the "Free Testosterone Index (FTI) / Free Androgen Index (FAI)" expected values section of the existing device's labeling. Therefore, many of the requested categories for acceptance criteria and study details for AI/ML devices are not applicable.

Here's an interpretation based on the provided text, focusing on the available information:

1. Table of Acceptance Criteria and Reported Device Performance

The device itself (ARCHITECT SHBG assay) was previously cleared. The current submission is for a labeling change to update expected values for the Free Testosterone Index (FTI) or Free Androgen Index (FAI). Therefore, there are no new performance acceptance criteria for the device itself as part of this submission. The performance of the underlying assay remains as established in K060818.

However, the "study" described in the document is the generation of new FTI/FAI expected values. The implicit acceptance criterion for this study is that the calculated FTI/FAI values are representative of the studied populations and are suitable for inclusion in the device labeling. The "reported device performance" in this context refers to the generated expected value ranges.

SHBG Expected Values (nmol/L)

Testosterone Expected Values

% FTI or % FAI Expected Values

2. Sample Size Used for the Test Set and Data Provenance

• Sample sizes:
  • Males (21-49 years of age): 163 samples
  • Males (≥ 50 years of age): 144 samples
  • Females (Premenopausal, 21-49 years of age): 174 samples
  • Females (Postmenopausal, ≥ 50 years of age): 175 samples
  • Total samples: 163 + 144 + 174 + 175 = 656 samples
• Data Provenance: The document states "A new study was conducted in 2014 to calculate FTI or FAI..." It specifies "individuals in the following categories: normal males... normal females..." without explicitly stating the country of origin. The study appears to be prospective in nature, as it was specifically conducted to establish these new expected values.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

• This is not applicable as the study involves quantitative measurements using an immunoassay device, not subjective expert assessment of images or clinical findings that would require ground truth established by experts.

4. Adjudication Method for the Test Set

• Not applicable for a quantitative in vitro diagnostic assay. The results are raw numerical measurements from the ARCHITECT i System.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

• Not applicable. This is an immunoassay, not an imaging device or an AI/ML algorithm requiring human reader performance evaluation.

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

• Not applicable as this is not an AI/ML algorithm. The "standalone" performance here refers to the ARCHITECT SHBG and ARCHITECT 2nd Generation Testosterone assays themselves, which provide quantitative results directly from the instrument.

7. The Type of Ground Truth Used

• The "ground truth" in this context is the quantitative determination of SHBG and Testosterone concentrations in human serum/plasma samples using the respective ARCHITECT assays. These are measured values, not a 'ground truth' in the sense of a consensus diagnosis or pathology result. For FTI/FAI, the ground truth is derived calculation based on these assay results.

8. The Sample Size for the Training Set

• Not applicable as this is not an AI/ML device that undergoes a training phase. The study involved collecting new data to establish expected values for FTI/FAI, effectively acting as a validation/reference range study, not a training set for an algorithm.

9. How the Ground Truth for the Training Set Was Established

• Not applicable.

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