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The NanoEnTek FREND™PSA Plus is designed for in vitro DIAGNOSTIC USE ONLY for the quantitative measurement of total Prostate Specific Antigen (PSA) in human serum, Li-heparinized plasma, and K3-EDTA plasma using the FREND™ System. This device is indicated for the serial measurement of total PSA to be used as an aid in the management of patients with prostate cancer.

The FREND™ PSA Plus is a rapid fluorescence immunoassay that measures prostate specific antigen (PSA) in human serum and in lithium heparin and K3-EDTA plasma using the FREND™ system. The FREND™ PSA Plus is intended for use as an aid for prostate cancer management.

The FREND™ PSA Plus Test is a single use fluorescence immunoassay designed to quantify the concentration of total PSA in serum and lithium heparin and K3-EDTA plasma samples. The specimen is added by the operator to the sample inlet with a transfer pipet, allowing the appropriate volume of sample (35 µL) to be delivered into the FREND™ PSA Plus Test Cartridge. The Cartridge is then placed into the FREND™ System, which is programmed to begin analysis once the sample has reacted with the reagents. The reaction and analysis time is approximately 4 minutes. The PSA quantification is based on the amount of fluorescence detected by the FREND™ System at the FREND™ PSA Plus Test Cartridge window. A higher level of fluorescence is indicative of a higher PSA concentration. In other words, the magnitude of the fluorescent signal is directly proportional to the amount of total PSA in the sample.

The total PSA detection range of the FREND™ PSA Plus Test System is 0.08 to 25 ng/mL. 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 five replicates at each level. The established curve is uploaded to the FREND™ via the PSA Plus Code-chip and is valid until the lot expiration date. The established curve is saved in the code-chip and valid until the expiration date of the test cartridge lot.

The FREND™ PSA Plus 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.

FREND™ System is a bench top fluorescence reader containing a touchscreen user interface. The System has a slot that accepts the sample loaded FREND™ PSA Plus Test Cartridge, 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 management 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™ PSA Plus includes the following in the kit:

• 25 FREND™ PSA Plus cartridges
• · 30 Disposable pipette tips
• 1 FREND™ PSA Plus Code Chip
• 1 FREND™ PSA Plus Package Insert

The FREND™ System (previously cleared in K124056, K131928, K152422, K153577, and K162754) is not provided with the kit but is required for the use of the FREND™ PSA Plus test cartridge.

Here's a breakdown of the requested information regarding the acceptance criteria and study for the NanoEnTek FREND™ PSA Plus device:

The provided text describes a 510(k) submission for a modified version of the FREND™ PSA Plus, comparing it to its predicate device (the previously cleared FREND™ PSA Plus assay, K124056). Therefore, the "acceptance criteria" are implicitly the performance of the predicate device, and the "study" aims to demonstrate that the modified device's performance is substantially equivalent to this predicate.

1. Table of Acceptance Criteria and Reported Device Performance

For the purpose of this analysis, the "acceptance criteria" are based on the performance of the predicate device (FREND™ PSA Plus, K124056), and the "reported device performance" refers to the modified FREND™ PSA Plus.

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The FREND™ Vitamin D test is a rapid indirect competitive fluorescent immunoassay designed for the quantitative measurement of 25-Hydroxy vitamin D and related hydroxylated metabolites in human serum and plasma (K;EDTA, lithium-heparin and citrate) specimens using the FREND™ System, and the FREND™ AP System. Measurements of total 25-hydroxy vitamin D and related hydroxylated metabolites are used to aid in the assessment of vitamin D sufficiency.

The FREND™ Vitamin D microfluidic flow cartridge is designed for use in the FREND™ System fluorescent immunoassay reader, and the FREND™ AP System. The FREND™ Vitamin D 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™ Vitamin D Test is a rapid fluorescence immunoassay designed to quantify the concentration of total 25-hydroxy (OH) vitamin D and related hydroxylated metabolites in human serum and plasma (K3 EDTA, lithium-heparin and citrate) samples using the FREND™ System.

The FREND™ Vitamin D Test System is a competitive immunoassay with gold microparticles labeled with Vitamin D-specific monoclonal anti-Vitamin D-antibody (mouse), Vitamin D-biotin labeled with fluorescence nanoparticles and fluorescence detection by the FREND™ System.

The FREND™ Vitamin D Cartridge is a single-use disposable rapid lateral flow fluorescence immunoassay designed to quantify the concentration of total 25-OH vitamin D and related hydroxylated metabolites in human serum and plasma (K3 EDTA, lithiumheparin and citrate) samples. Each test cartridge contains reagents to perform one test and bears a bar code with test type and lot information. Each FREND™ Vitamin D Cartridge contains a test zone and a reference zone (internal control). The fluorescence measured in the test and reference zones corresponds to the amount of fluorescent conjugates of Vitamin D-biotin that is bound to each zone. Cartridges are provided in individually sealed pouches and must be stored between 2 and 8 °C.

In addition to the QC Code Chip there is a Vitamin D Code Chip. Lot information and calibration data are loaded into the software via the Vitamin D Code Chip provided with each reagent kit. Up to three different Vitamin D Code Chip lots can be loaded and used at the same time. Each reagent cartridge bears a barcode that the FREND™ System uses to identify the test type and lot number and links it to the appropriate analytical program and calibration information. The FREND™ System will not output results if the Vitamin D Code Chip lot does not match the lot of the cartridge used.

The Vitamin D Pretreatment Tube is a small single-use disposable plastic tube that contains Vitamin D gold nano-particle coniugation antibody. The sample is diluted in the dilution tube containing perfluorohexanoic acid and transferred to the pretreatment tube prior to being inserted into the FREND™ AP System to be mixed and then added to the Vitamin D Test Cartridge. The test cartridge is then inserted into the FREND™ System to be analyzed.

The FREND™ AP System is an "Advanced Preparing" device that performs automated pre-analytical steps of mixing, timed heating, and pipetting of the sample from the Gold Antibody Pretreatment tube into the FREND Vitamin D test cartridge.

The FREND™ System utilizes microfluidic technology and detects immune-complexes bound to Vitamin D. The test cartridge is placed on the warming platform of the FREND™ AP System. A 35 µL patient sample is added to the dilution tube and 70 µL of diluted sample is pipetted into the pretreatment tube containing monoclonal anti-Vitamin D antibody conjugated with gold nanoparticles(Step 1). The tube is then loaded into the FREND™ AP System (Step 2). The tube is mixed and loaded into the test cartridge automatically. In the AP System (Step 3), mixing, reaction, sample addition, hydration of the Vitamin D-biotin fluorescent bead conjugate, and migration along the cartridge channel takes approximately 15 minutes, after which the cartridge is read on the FREND™ System. During migration, the bound Vitamin D in the sample and the fluorescent bead conjugates of Vitamin D-biotin compete to form antigen-antibody complex in the test zone. Unbound Vitamin D-biotin fluorescent conjugates flow through and bind to the anti-Vitamin D antibody that is fixed on the surface in the reference zone. The fluorescent signals in the test and reference zones are measured, typically within 4 minutes.

Vitamin D quantification is based upon the ratio of the intensity of the test and reference zones. A lower ratio of fluorescence is indicative of a higher Vitamin D concentration; in other words, the magnitude of the fluorescent ratio is inversely proportional to the amount of Vitamin D in the sample.

The measuring range of the FREND™ Vitamin D Test System is 13.0 to 96.0 ng/mL. Results are determined via a lot-specific calibration curve which is generated by the manufacturer using a four-point calibration determined from values averaged from 6 replicates at each level. The established curve is uploaded to the FREND™ System via the Vitamin D Code-chip and is valid until the lot expiration date.

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 test cartridge is a disposable plastic device that 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™ cartridge utilizes microfluidics 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™ Vitamin D 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 management 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™ Vitamin D Test System includes the following in the reagent kit:

• . 20 FREND™ Vitamin D Test Cartridges
• 20 FREND™ Sample Dilution Tubes .
• 20 FREND™ Vitamin D Gold Antibody Pretreatment Tubes .
• 30 Disposable pipette tips
• 1 FREND™ Vitamin D Code Chip .
• . 1 FREND™ Vitamin D Package Insert

One cartridge contains:

• . Monoclonal mouse anti- Vitamin D 1.6 ± 0.16 na
• . 25-hydroxyvitamin D 136 ± 13.6 ng
• . Fluorescence particles 2.4 ± 0.24 µg

One sample dilution tube contains:

• . Perfluorohexanoic acid 9.5 ± 0.95 µg
  One Gold antibody pretreatment tube contains:

• . Gold nano-particle conjugation antibody 7.0 ± 0.7 µg
  The FREND™ System (previously cleared in K124056 (FREND™ PSA), K131928 (FREND™ TSH), K152422 (FREND™ Free T4), and K153577 (FREND™ Testosterone) is not provided with the kit but it is required for the FREND™ Vitamin D Test cartridge.

Here's an analysis of the provided text to extract the requested information about acceptance criteria and the study that proves the device meets them:

1. A table of acceptance criteria and the reported device performance

The document doesn't explicitly state "acceptance criteria" in a codified format. However, based on the performance characteristics reported, we can infer the acceptance criteria implied by the study outcomes. For instance, the interference study specifies a recovery range of 90% to 110% for "no interference," which acts as an acceptance criterion. Similarly, the precision study reports specific CV% values, which are implicitly acceptable. For the method comparison, the slope, intercept, and correlation coefficient achieved are the performance metrics, implying that these values were considered acceptable for substantial equivalence.

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

• Precision/Reproducibility: Not explicitly stated as "test set," but 3 serum pools were used. Each pool was assayed in duplicate twice per day for 20 days, totaling 80 measurements per level.
• Linearity: 9 levels of serum samples tested in quadruplicate.
• Limit of Quantitation (LoQ): Not specified (CLSI EP17-A2 protocol was used).
• Interference Studies: Triplicate determinations for two concentrations of Vitamin D for each interferent tested.
• Cross-Reactivity Studies: Triplicate measurements for each cross-reactant at two Vitamin D concentrations.
• Method Comparison: 133 de-identified leftover samples. The provenance is implied to be from a CLIA-certified hospital laboratory (presumably in the US, given FDA submission). The samples were retrospective ("de-identified leftover samples").
• Matrix Comparison: 36 paired samples.
• Expected Values/Reference Range: 300 serum specimens from apparently healthy individuals residing in north, central, and southern regions of the US. Collected during summer and winter months. This is a prospective or cross-sectional study.

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) assay for measuring 25-hydroxy vitamin D. The "ground truth" for such devices is typically established by reference methods or gold-standard assays, not by expert human readers.

• For the method comparison study, the reference method was the Abbott ARCHITECT i 25-OH Vitamin D Assay (K110619) run on the Abbott ARCHITECT i System. This predicate device served as the "ground truth" for comparison.
• For traceability, calibrators were confirmed by measurement on the same predicate device (ARCHITECT i 25-OH Vitamin D assay).

Therefore, there were no human experts establishing ground truth in the way a medical imaging study might use radiologists. The ground truth was based on a previously cleared and accepted analytical method.

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

Not applicable. As this is an IVD assay where performance is compared against an established analytical method (predicate device), there is no human adjudication process involved in establishing ground truth for the test set as would be found in medical image analysis.

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

Not applicable. The FREND™ Vitamin D Test System is an automated in-vitro diagnostic device. It does not involve human readers interpreting results in a way that an MRMC study comparing human performance with and without AI assistance would be relevant. The device provides a quantitative measurement directly.

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

Yes, this entire submission focuses on the standalone performance of the FREND™ Vitamin D Test System. It is an automated system designed for use in clinical laboratories, which means it provides quantitative results directly from the sample without subjective human interpretation in the loop. The "FREND™ System" and "FREND™ AP System" are instrument-only components that analyze the cartridge.

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

The ground truth for the performance studies was predominantly based on comparison to a legally marketed predicate device, specifically the Abbott ARCHITECT i 25-OH Vitamin D Assay (K110619). For studies like linearity, precision, LoQ, interference, and cross-reactivity, the ground truth is defined by the known concentrations of analytes in the samples used (e.g., spiked samples, reference materials).

8. The sample size for the training set

The document does not explicitly mention a "training set" in the context of machine learning or AI models. This device is a fluorescent immunoassay, and its "training" or calibration is handled differently:

• The device uses a lot-specific calibration curve generated by the manufacturer.
• This curve is determined from values averaged from 6 replicates at each of four calibration levels.
• This calibration information is uploaded to the FREND™ System via a Vitamin D Code-chip for each reagent lot.

Therefore, the concept of a large "training set" of patient data as understood in AI/ML is not directly applicable here. The calibration is a much smaller, controlled process.

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

As noted above, "training set" in the AI/ML sense is not directly applicable. For the device's calibration (which serves a similar function to initial "training" for an assay):

• The calibrators are prepared gravimetrically. This means their concentrations are established by precisely weighing the components.
• These gravimetrically prepared calibrators are then confirmed by measurement on the ARCHITECT i 25-OH Vitamin D assay (K110619), the predicate device. This ensures they align with an established method.

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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 FREND™ Free T4 Test System is a rapid indirect competitive immunoassay for the quantitation of free thyroxine (FT4) in human serum and lithium heparinized plasma specimens using the FREND™ Free T4 system. Measurements of free thyroxine (FT4) are used in the diagnosis of thyroid disorders. The FREND™ Free T4 Test System is intended for use in clinical laboratories. For in vitro diagnostic use only. The test is not intended for point-of-care facilities.

The FREND™ Free T4 is a rapid fluorescence immunoassay that measures Free T4 in human serum and in lithium heparinized plasma using the FREND™ Free T4 Test System. The FREND™ Free T4 is a single use fluorescence immunoassay designed to quantify the concentration of free thyroxine in serum and lithium heparinized plasma samples, The FREND™ Free T4 test is a two-step competitive immunoassay with gold nanoparticles labeled with T4-specific monoclonal anti-T4- antibody (mouse), T3-BSA labeled with fluorescent nanoparticles, and fluorescence detection by the FREND™ System. The FREND™ Free T4 Test utilizes microfluidic technology and detects immunecomplexes bound to Free T4. A 70ul Sample is first incubated during Step 1 for five minutes at 37 degrees C in the Free T4 Gold AB Tube with monoclonal anti-T4 antibody conjugated with gold nanoparticles. In Step 2, 35 ul of the mixture from Step 1 is manually loaded into the inlet of the cartridge, where it hydrates a T3-BSA fluorescent bead conjugate and migrates along the test strip. During migration the bound Free T4 in the sample and the fluorescent bead conjugates of T3-BSA compete to form antigenantibody complex in the test zone. Unbound T3-BSA fluorescent conjugates flow through and bind to the anti-T4 antibody that is fixed on the surface in the reference zone. Step 2 takes approximately four minutes after which the fluorescent signals in the test and reference zones are measured. Free T4 quantification is based upon the ratio of the intensity of the test and reference zones. A lower ratio of fluorescence is indicative of a higher Free T4 concentration, in other words, the maqnitude of the fluorescence ratio is inversely proportional to the amount of Free T4 in the sample. The free T4 detection range of the FREND™ Free T4 Test System is 0.4 to 6.0 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 five replicates at each level. The established curve is uploaded to the FREND™ System via the Free T4 Code-chip and is valid until the lot expiration date. The established curve is saved in the code-chip and valid until the expiration date of the test cartridge lot. The FREND™ Free T4 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™ Free T4 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.

Here's a summary of the acceptance criteria and study details for the FREND™ Free T4 Test System, based on the provided 510(k) submission:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as pass/fail values in many sections, but rather implied by the statistical analyses meeting CLSI guidelines and demonstrating comparability to the predicate device. The performance data is presented against these implicit standards.

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

• Precision Study: 3 serum pools
• Linearity Study: 1 serum base pool diluted to 11 levels
• Interference Studies: Two levels of free T4 for various endogenous substances and pharmaceuticals.
• Cross-Reactivity Study: Two concentrations for various cross-reactants.
• Method Comparison: 358 samples
• Matrix Comparison: 48 paired serum and lithium heparin samples
• Expected Values/Reference Range: 196 normal, apparently healthy adult individuals

The specific country of origin for the test set data is not explicitly stated, but the precision, linearity, interference, and matrix comparison studies were performed at the NanoEnTek laboratory. The method comparison study was performed at a CLIA-certified laboratory testing facility. The clinical samples for the method comparison were evaluated at that CLIA laboratory. The reference range study used samples from 196 normal, apparently healthy adult individuals. The nature of "clinical samples" for the method comparison implies they would be patient samples, and "normal, apparently healthy adult individuals" for the reference range are also patient-like samples. The studies appear to be prospective in nature, as they involve testing the device with specific protocols (e.g., CLSI guidelines).

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

• None stated for the analytical performance studies. The ground truth for analytical studies (precision, linearity, LoD, LoQ, interference, cross-reactivity) is generally based on the inherent properties of the samples and the performance of established reference methods or spiked concentrations.
• For Method Comparison: The ground truth was established by a predicate device, the Abbott ARCHITECT Free T4 Assay. The number of human experts involved in interpreting results from either the predicate device or the FREND™ Free T4 Test System is not specified, as this is a quantitative immunoassay where results are read by a machine.

4. Adjudication Method for the Test Set

Not applicable for this type of quantitative immunoassay performance study. Ground truth is established by reference methods or defined concentrations, not human adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is a quantitative immunoassay, not an imaging device requiring human interpretation, so MRMC studies are not relevant.

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

Yes, the studies described are standalone performance studies for the FREND™ Free T4 Test System. The device is intended for use in clinical laboratories, and the results are quantitatively measured by the FREND™ System directly. There is no human-in-the-loop performance evaluation described beyond standard laboratory procedures for operating the instrument and handling samples.

7. The Type of Ground Truth Used

• Analytical Performance:
  • Precision, Linearity, LoD, LoQ, Interference, Cross-reactivity: Ground truth was established by prepared samples with known concentrations, spiking experiments, and measurements against established laboratory protocols and standards (CLSI guidelines).
• Method Comparison: Ground truth was established by the predicate device, the Abbott ARCHITECT Free T4 Assay (K123379). This is a comparison against an existing, legally marketed device.
• Matrix Comparison: Ground truth (or comparative standard) derived from measuring the same analyte in different matrices (serum vs. plasma), with the expectation of comparable results.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of an AI/machine learning algorithm. For this immunoassay, the system's "training" involves the manufacturer-generated lot-specific calibration curve (six-point calibration determined from values averaged from five replicates at each level), which is then uploaded to the FREND™ System via a Code-chip.

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

As described above, the "ground truth" for the device's operational curve (its calibration) is established by:

• Internal standards prepared according to CLSI C45-A Measurement of Free Thyroid Hormones.
• Gravimetric methods based on L-Thyroxine (Sigma T1775, Cell culture grade).
• Confirmation of calibrator Free T4 levels by measurement on the ARCHITECT i free T4 assay (K123379).

This process ensures that the device's internal calibration accurately reflects known Free T4 concentrations.

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