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510(k) Data Aggregation
(105 days)
The ARK™ Methotrexate Assay is a homogeneous enzyme immunoassay intended for the quantitative determination of Methotrexate in human serum or automated clinical chemistry analyzers. The measurements obtained are used in monitoring levels of methotrexate to help ensure appropriate therapy.
The ARK™ Methotrexate Calibrator is intended for use in calibration of the ARK Methotrexate Assay.
The ARKTM Methotrexate Control is intended for use in quality control of the ARK Methotrexate Assay.
Specimens from patients who have received glucarpidase (carboxypeptidase G2) as a high dose methotrexate rescue therapy should not be tested with the ARK Methotrexate Assay.
The ARK Methotrexate Assay is a homogeneous immunoassay based on competition between drug in the specimen and Methotrexate labeled with the enzyme glucose-6-phosphate dehydrogenase (G6PDH) for binding to the antibody reagent. As the latter binds antibody, enzyme activity decreases. In the presence of drug from the specimen, enzyme activity increases and is directly proportional to the drug concentration. Active enzyme converts the coenzyme nicotinamide adenine dinucleotide (NAD) to NADH that is measured spectrophotometrically as a rate of change in absorbance. Endogenous serum G6PDH does not interfere with the results because the coenyzme NAD functions only with the bacterial enzyme used in the assay.
The ARK Methotrexate Assay consists of reagents R1 anti-Methotrexate polyclonal antibody with substrate and R2 Methotrexate labeled with bacterial G6PDH enzyme. The ARK Methotrexate Calibrator consists of a six-level set to calibrate the assay, and the ARK Methotrexate Control consists of a six-level set used for quality control of the assay (tri-level calibration range set and tri-level high range set). The ARK Methotrexate Dilution Buffer is equivalent to zero calibrator (Calibrator A).
Here's a breakdown of the acceptance criteria and the studies that prove the device meets them, based on the provided text:
Acceptance Criteria and Reported Device Performance
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Limit of Quantitation (LoQ) | LoB < Result < LoQ: report "analyte detected; concentration < LoQ" Result ≥ LoQ: report the result as measured | LoB: 0.01 µmol/L LoD: 0.02 µmol/L LoQ: 0.04 µmol/L (LoQ-2 SD > LoD met) |
| Accuracy (Analytical Recovery) | Not explicitly stated as a numerical criterion in the "Acceptance Criteria" section for each data point, but typically implied to be close to 100% recovery. | Mean percentage recovery: 102.1% (Individual recoveries ranged from 98.3% to 111.1%) |
| Linearity | Percent difference was ±10% between the predicted 1st and 2nd order regressed values for concentrations >0.10 µmol/L or ±0.01 µmol/L at concentrations ≤ 0.10 µmol/L. | All observed differences for concentrations >0.10 µmol/L were within ±10% (-2.3% to 4.8%).All observed differences for concentrations ≤ 0.10 µmol/L were within ±0.01 µmol/L (-0.010 µmol/L to -0.004 µmol/L). The highest theoretical concentration tested was 1.30 µmol/L. Regression of assayed methotrexate concentrations was linear throughout the range of 2 to 1200 µmol/L when proportionally diluted. |
| Assay Range | Not explicitly stated as an acceptance criterion, but the functional range. | Measurement range: 0.04 - 1.20 µmol/L |
| Method Comparison | Not explicitly stated as a numerical acceptance criterion (e.g., minimum correlation coefficient or confidence intervals for slope/intercept), but comparison to a predicate device is expected. | Range 0.04 to 1.19 µM (102 samples): Slope: 1.00 (95% CI: 1.00 to 1.02) y-intercept: 0.01 (95% CI: 0.00 to 0.01) Correlation Coefficient (r²): 0.978 (95% CI: 0.968 to 0.985)Range 0.04 to 1440 µM (147 samples, including diluted): Slope: 0.99 (95% CI: 0.96 to 1.00) y-intercept: 0.01 (95% CI: 0.01 to 0.01) Correlation Coefficient (r²): 0.998 (95% CI: 0.997 to 0.998) |
| Precision | <10% total CV at >0.10 µmol/L SD ≤0.01 at ≤0.10 µmol/L | All control and patient pool samples met the criteria: - ARK Methotrexate Control (MID, HIGH, 5, 50, 500 µmol/L): Total CVs ranged from 3.8% to 7.0%. - ARK Methotrexate Control (LOW, 0.06 µmol/L): Total SD was 0.007, which is ≤0.01. - Patient Pool (MID, HIGH, 5, 50, 500 µmol/L): Total CVs ranged from 5.3% to 7.2%. - Patient Pool (LOW, 0.07 µmol/L): Total SD was 0.008, which is ≤0.01. |
| Interfering Substances | Not substantially affected by tested endogenous substances. | Measurement of methotrexate was not substantially affected by clinically high concentrations of Albumin, Bilirubin (conjugated & unconjugated), Cholesterol, Gamma-Globulin, Hemoglobin, Intralipid®, Rheumatoid Factor, Triglycerides, and Uric Acid. |
| Specificity - Crossreactivity | < 0.07% crossreactivity with 7-Hydroxymethotrexate. | 7-Hydroxymethotrexate: ≤ 0.07% crossreactivity. DAMPA: 64.3% to 100% crossreactivity (significant). Triamterene: Crossreactivity ranged from 1.85% to 3.32%. Trimethoprim: Crossreactivity ranged from 0.12% to 0.54%. Folate analogs and other compounds (e.g., Adriamycin, Cyclophosphamide): ≤ 0.01% crossreactivity at ≥ 1000 µmol/L. |
| Anticoagulants | No significant difference in recovery between serum and plasma. | No significant difference found in methotrexate recovery between serum and plasma samples. |
| Sample Stability | Acceptable stability under various storage conditions. | Stable frozen (at least 15 months), 48 hours at room temperature, refrigerated (at least 21 days), and after three (3) successive freeze/thaw cycles. |
| On-Board Stability | Acceptable stability of calibration curve and reagents on the analyzer. | Calibration curve effective up to at least 19 days. Reagents effective for up to at least 25 days in analyzer-specific containers. In-use stability of calibrator and controls also demonstrated. |
Study Details
2. Sample sizes used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective):
- Limit of Quantitation (LoQ):
- LoB, LoD: N = 60
- LoQ: N = 40
- Data provenance: Not specified, but generally analytical studies like this are conducted with prepared samples in a laboratory setting (prospective).
- Accuracy: Concentrated methotrexate drug added into human serum negative for methotrexate. Six replicates of each sample were assayed.
- Sample size: 5 target concentrations, each with 6 replicates (30 assays).
- Data provenance: Not specified, but likely prospective, prepared samples in a lab.
- Linearity: Dilutions of a 1.30 µmol/L serum sample and proportional dilutions of samples between 2 and 1200 µmol/L in pooled human serum.
- Sample size: 13 different concentrations were tested for the initial linearity study. The second linearity study for higher concentrations (2-1200 µmol/L) stated "samples containing methotrexate... were prepared proportionally," implying multiple samples across this range.
- Data provenance: Not specified, but likely prospective, prepared samples in a lab.
- Method Comparison:
- Sample size: 102 specimens within the measurement range (0.04 to 1.19 µM) and 147 specimens including those above the measurement range requiring dilution (total range 0.04 to 1440 µM).
- Data provenance: Not specified, but these are likely clinical samples (human serum/plasma), which could be retrospective or prospective. The document does not specify country of origin.
- Precision:
- Sample size: Each of the 6 control levels and 6 patient pool levels were assayed in quadruplicate, twice a day for 20 days. This means 4 * 2 * 20 = 160 measurements per level.
- Data provenance: Not specified, but likely prospective, prepared controls and pooled patient samples in a lab.
- Interfering Substances: Multiple substances tested, each with samples at ~0.05 and ~0.50 µmol/L methotrexate.
- Sample size: Each interfering substance was tested at two methotrexate levels, likely with duplicates or triplicates, plus control samples. The specific number of individual assays is not given but implies a significant number of tests.
- Data provenance: Not specified, but likely prospective, prepared samples in a lab setting.
- Specificity (Crossreactivity):
- Sample size: Two concentrations of methotrexate (0.05 and 0.50 µmol/L) were tested with triamterene and trimethoprim. Various other compounds and folate analogs were tested at high concentrations (e.g., ≥ 1000 µmol/L), presumably just once for cross-reactivity.
- Data provenance: Not specified, but likely prospective, prepared samples in a lab setting.
- Anticoagulants:
- Sample size: "Studies were conducted," implying multiple samples, but no specific number is given.
- Data provenance: Not specified, but likely prospective, prepared samples in a lab setting.
- Sample Stability:
- Sample size: Not specified, but involved human specimens.
- Data provenance: Not specified, but likely prospective.
- On-Board Stability:
- Sample size: Not specified, but utilized a calibration curve and reagents over time.
- Data provenance: Not specified, but likely prospective, lab-based testing.
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 assay for quantitative determination of methotrexate. The "ground truth" for such assays is typically established by:
- Reference materials: Certified reference standards for methotrexate concentration (used in Accuracy, LoQ, Linearity, Crossreactivity).
- Predicate device comparison: The "gold standard" or accepted method (Fluorescence Polarization Immunoassay - FPIA in this case, specifically the Abbott TDx®/TDxFLx® Methotrexate II assay) for method comparison.
Therefore, the concept of "experts" establishing ground truth as it applies to image interpretation (like radiologists) or pathological diagnosis is not directly relevant here. The ground truth is analytical and based on established methodology and certified materials.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:
Not applicable. Adjudication methods like 2+1 or 3+1 are typically used in clinical studies where subjective human interpretation (e.g., reading medical images) is involved and discrepancies between readers need to be resolved to establish a consensus ground truth. For in vitro diagnostic device performance studies, the results are quantitative and compared against analytical or predicate methods, not subjective expert consensus.
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. This device is an in vitro diagnostic assay, not an AI-powered image analysis tool or a device requiring human "readers" in the context of an MRMC study. Its performance is evaluated analytically, not by assessing human performance improvement with or without AI.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
Yes, all the performance studies described (analytical recovery, linearity, method comparison, precision, interference, specificity, stability) represent the standalone performance of the ARK Methotrexate Assay. There is no human-in-the-loop aspect described in these tests; the assay directly provides quantitative results.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):
The ground truth used for this in vitro diagnostic assay consists of:
- Reference Standards: For accuracy, LoQ, linearity, and specificity, the ground truth was based on precisely known concentrations of methotrexate prepared using certified stock concentrates.
- Predicate Device (Monoclonal FPIA): For method comparison, the ground truth was the results obtained from the legally marketed predicate device (Abbott TDx®/TDxFLx® Methotrexate II), which is an established method for methotrexate measurement.
- Pre-defined Parameters/Conditions: For interference, specificity, and stability studies, the ground truth was the expectation of what the device should measure under specific well-defined conditions (e.g., no cross-reactivity with certain compounds, stability over a given period).
8. The sample size for the training set:
Not applicable. This document describes the validation of an immunoassay kit, not a machine learning or AI algorithm that requires a "training set." Immunoassays are based on biochemical reactions with antibodies, not pattern recognition learned from data.
9. How the ground truth for the training set was established:
Not applicable, as there is no "training set" in the context of this immunoassay device.
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