(143 days)
The IDS SHBG assay is an in vitro diagnostic device intended for the quantitative determination of SHBG in human serum or plasma on the IDS System. Results are to be used as an aid in the diagnosis of androgen disorders
The IDS SHBG assay is an in vitro diagnostic device intended for the quantitative determination of sex hormone binding globulin (SHBG) in human serum and plasma on the IDS-iSYS Multi-Discipline Automated System. Results are to be used in conjunction with other clinical and laboratory data to assist the clinician in the diagnosis of androgen disorders.
The assay is based on chemiluminescence technology. 5 uL of patient sample or calibrators are incubated with biotinylated monoclonal anti-SHBG antibody, an acridinium labelled monoclonal anti-SHBG conjugate and streptavidin labelled magnetic particles. The magnetic particles are captured using a magnet and a wash step performed to remove any unbound analyte. Trigger reagents are added; the resulting light emitted by the acridinium label is directly proportional to the concentration of analyte in the original sample.
The IDS SHBG assay is an in vitro diagnostic device consisting of ready to use reagents provided in individual compartments within the reagent cartridge.
The reagent cartridge contains:
- Magnetic particles magnetic particles coated with streptavidin in a phosphate buffer containing preservatives
- -Biotin antibody - monoclonal anti-SHBG labelled with biotin in a buffer containing proteins and preservatives
- Conjugate monoclonal anti-SHBG labelled with an acridinium ester derivative in a buffer containing proteins and preservatives The calibrators consist of:
- Calibrators A and B are included in the assay kit. The calibrators consist of a human serum matrix with defined concentrations of SHBG and preservatives. Together with a lot specific master calibration curve, the calibrators will be used to perform adjustment of the master calibration curve.
The provided document is a 510(k) summary for the IDS SHBG assay, an in vitro diagnostic device for the quantitative determination of Sex Hormone Binding Globulin (SHBG). The document details the device's performance characteristics and compares it to a predicate device to demonstrate substantial equivalence.
Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:
Key Takeaway: This document describes the validation of an in vitro diagnostic (IVD) assay, not an AI/ML-based diagnostic device that typically involves human readers or image analysis. Therefore, many of the requested categories (e.g., number of experts, adjudication method, MRMC studies, human reader improvement with AI, standalone AI performance) are not applicable to this type of device and study. The ground truth in this context is established by reference methods or validated reference materials, typical for IVD assays.
1. Table of Acceptance Criteria and Reported Device Performance
The document describes several analytical performance characteristics that serve as "acceptance criteria" for the IDS SHBG assay. These are primarily related to the accuracy, precision, limits of detection, and specificity of the assay.
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance |
|---|---|---|
| Precision (Reproducibility) | Within-run and total precision (CV%) to be within acceptable limits for a quantitative assay. | Within Run CV: 1.7% to 3.7% across various SHBG concentration levels (e.g., IQC 1: 1.7% at 5.57 nmol/L; CV 3: 3.7% at 201.67 nmol/L). |
| Total CV: 3.2% to 5.0% across various SHBG concentration levels (e.g., IQC 3: 3.2% at 96.82 nmol/L; CTL3: 5.0% at 93.43 nmol/L). | ||
| (Compared favorably to predicate which reported 2.5-3.8% within run and 3.1-6.5% total precision.) | ||
| Linearity/Reportable Range | Assay to be linear over its claimed measuring range; accuracy demonstrated for automated dilution. | Measuring Range: Linear from 1.60 to 180.00 nmol/L for serum and K2 EDTA plasma (R2 values of 0.999 and 0.998 respectively). |
| Reportable Range: 0.30 to 720.00 nmol/L with automated 1:4 dilution for samples >180 nmol/L. | ||
| Recovery (Automated Dilution): 87% to 100% when compared to predicate for samples in the 180-720 nmol/L range (Mean recovery: 93%). | ||
| Detection Limits (LoB, LoD, LoQ) | Limits should be sufficiently low to meet diagnostic needs. | LoB: 0.01 nmol/L |
| LoD: 0.15 nmol/L | ||
| LoQ: 0.30 nmol/L | ||
| Traceability of Calibrator | Calibrator values must fall within specified acceptable ranges and internal quality controls within their respective ranges with defined precision. | Calibrator A: 0.10 to 0.30 nmol/L, precision CV ≤ 11%. Verified through internal QC procedures. |
| Calibrator B: 110.00 to 130.00 nmol/L, precision CV ≤ 8%. Verified through internal QC procedures. | ||
| Internal QC controls: CV ≤ 11% for IQC1, ≤ 8% for IQC2 and IQC3. Results from Table 11 show these were met (e.g., IQC1 Total CV 4.1%, IQC2 Total CV 3.4%, IQC3 Total CV 3.2%). | ||
| Analytical Specificity (Interference) | No significant interference from common biological substances and exogenous compounds up to tested concentrations. | No significant interference found for: |
- Triglycerides: up to 3000 mg/dL
- Haemoglobin: up to 500 mg/dL
- Bilirubin (conjugated/unconjugated): up to 40 mg/dL
- Total Protein: up to 12 g/dL
- Biotin: up to 6000 ng/mL (and 1500 ng/mL)
- Rheumatoid Factor: up to 7000 IU/mL
- HAMA: up to 3000 ng/mL
- Cholesterol: up to 456 mg/dL
- Various common drugs (e.g., Acetaminophen, Ibuprofen, Ascorbic acid, Creatinine, Dopamine, Tetracycline, Tolbutamide, Tolazamide, Uric Acid). |
| Analytical Specificity (Cross-Reactivity) | No significant cross-reactivity with structurally similar compounds or other biological substances up to tested concentrations. | Low/No significant cross-reactivity observed (50y:** 14.85 – 65.21 nmol/L (n=180)
Premenopausal Females: 20.30 – 140.18 nmol/L (n=206)
Postmenopausal Females: 11.30 – 127.31 nmol/L (n=120)
(Based on 671 apparently healthy adults from the United States). |
2. Sample Size Used for the Test Set and Data Provenance
- Precision/Reproducibility: 14 serum-based samples at different SHBG concentration levels covering the assay range. Tested across 21 days for one kit lot. (Table 11 shows individual sample IDs, CTLs, CALBs, IQCs)
- Linearity/Assay Reportable Range:
- Linearity: A high human serum sample and a low human serum sample, plus 14 evenly spaced dilutions created by mixing high and low samples.
- Automated Post-dilution Accuracy: 9 native samples with known SHBG concentrations obtained from the predicate device.
- Traceability of Calibrator:
- Value assignment of Internal Reference Standards (IRs): At least 24 runs using three iSYS instruments, 2 kit lots, 3 replicates for each run. Serial dilutions of WHO 2nd international standard 08/266 used.
- Value assignment of kit calibrators: At least 20 runs (14 runs using previous IR lot, 6 runs using international standard) using one iSYS instrument, 2 replicates for each run.
- Value assignment verification: Internal quality controls at 3 SHBG levels tested in five replicates in one run and on each of three different iSYS instruments.
- Correlation study (2-point calibration vs. IS 08/266 curve): 189 samples (139 serum, 50 K2 EDTA plasmas). Tested in two replicates using three lots (MB1, MB2, MB3) on one iSYS instrument.
- Detection Limit (LoB, LoD, LoQ):
- LoB: LoB sample run in 12 replicates for each of 5 runs over 3 days, by one operator, on one different instrument for each of 3 manufacture batches (MB1, MB2B, MB3) = total 60 replicates per lot.
- LoD: 7 LoD samples measured in duplicate. For each of 3 kit lots, 5 assays over 3 days by one operator on a different instrument = total 70 replicates per lot.
- LoQ: Panel of 9 samples measured in singlicate two times per day. For each of 3 kit lots, 10 assays over 5 days by one operator on a different instrument = total 90 replicates per lot.
- Analytical Specificity (Interference): Two serum samples (low and high SHBG conc.) spiked with potential interferents. Control samples were also run. Number of replicates for each specific test not detailed but implied to be sufficient for statistical comparison.
- Analytical Specificity (Cross-Reactivity): Low and high SHBG samples spiked with various cross-reactants. Number of replicates for each specific test not detailed.
- Method Comparison: 136 samples, selected to represent a wide range of SHBG concentrations (2.54 - 172.12 nmol/L).
- Matrix Comparison: 69 samples (68 native, 1 diluted) covering a range of 0.51 to 238.45 nmol/L.
- Expected Values/Reference Range: 671 serum samples from apparently healthy adults (21-77 years old). Data Provenance: From the United States. Retrospective/Prospective: Not explicitly stated, but typically such studies for establishing reference ranges are retrospective collections of banked samples or a prospective study designed to collect samples from a healthy population.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
Not Applicable (N/A).
This is an in vitro diagnostic (IVD) assay quantifying a biomarker (SHBG). "Ground truth" for an IVD assay is established through:
- Reference Methods: Such as the WHO 2nd international standard 08/266 for SHBG, against which the calibrators are standardized.
- Known Concentrations: Use of accurately prepared standards, spiked samples, or samples extensively characterized by reference methods.
- Clinical Data: For expected values, SHBG concentrations are measured in samples from defined healthy populations.
Therefore, the concept of "experts establishing ground truth" in the way it applies to image interpretation or AI-assisted diagnostics (e.g., radiologists labeling images) is not relevant here. The ground truth is analytical and based on metrological traceability to international standards.
4. Adjudication Method for the Test Set
N/A.
Adjudication methods (like 2+1, 3+1) are relevant for subjective interpretations (e.g., radiology reads) where discrepancies between readers need to be resolved to establish a definitive ground truth. For a quantitative IVD assay like IDS SHBG, the "reading" is a numerical output from the instrument based on chemical reactions. Accuracy is determined by comparison to reference materials or established methods, not by human adjudication of interpretations.
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
N/A.
This is an IVD assay, not an AI/ML diagnostic for human interpretation. No MRMC study or human reader improvement with AI assistance is applicable.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
N/A.
This is not an AI/ML algorithm. The "device" is a fully automated immunoassay system (IDS-iSYS Multi-Discipline Automated System) that performs the biochemical analysis and reports a quantitative result without human "interpretation" of a signal beyond reading the numerical output. Its performance is evaluated as a standalone analytical system.
7. The Type of Ground Truth Used
The ground truth for the analytical performance studies (precision, linearity, detection limits, specificity, method comparison) is based on:
- International Reference Standards: Specifically, the WHO 2nd international standard for SHBG (IS 08/266) for traceability and calibration. This is the primary reference.
- Known Concentrations/Spiked Samples: Samples with defined, known concentrations of SHBG or interferents, prepared in a laboratory setting.
- Comparison to a Legally Marketed Predicate Device: The Siemens ADVIA Centaur SHBG assay (K151986) was used as a comparative method to assess agreement and accuracy (e.g., for method comparison and automated dilution accuracy).
- Healthy Population Data: For expected values/reference ranges, a large cohort of apparently healthy individuals were tested to establish population-specific normal ranges.
8. The Sample Size for the Training Set
N/A (for AI/ML 'training set' in the traditional sense).
For an IVD assay, the equivalent of a "training set" would be the samples and calibrators used during the assay's development and optimization phases to set parameters, establish reagent formulations, and fine-tune the system. This information is typically proprietary development data and is not explicitly detailed as a 'training set' in 510(k) summaries, which focus on the final validation/test data.
The closest analogous "training" or "calibration" process mentioned is the traceability and value assignment of calibrators:
- Value assignment of secondary standards (IRs) involves at least 24 runs (using 3 instruments, 2 kit lots, 3 replicates) comparing to the WHO international standard.
- Value assignment of IDS SHBG kit calibrators A and B involves at least 20 runs (1 instrument, 2 replicates) using the secondary standards and IS-08/266.
These processes are used to establish the calibration curve for the assay.
9. How the Ground Truth for the Training Set Was Established
N/A (for AI/ML 'training set').
As explained in point 8, the concept of a "training set" for an IVD assay is different from that for AI/ML. The "ground truth" for establishing the calibration and parameters of the assay is based on:
- Metrological traceability to the WHO 2nd international standard for SHBG (IS 08/266). This involved serial dilutions of the international standard in SHBG-depleted human serum to create reference points.
- Use of internal reference calibrators (IRs) that were themselves value-assigned against the WHO standard.
The goal is that the assay's measurements accurately reflect the true concentration of SHBG as defined by an international reference.
§ 862.1680 Testosterone test system.
(a)
Identification. A testosterone test system is a device intended to measure testosterone (a male sex hormone) in serum, plasma, and urine. Measurement of testosterone are used in the diagnosis and treatment of disorders involving the male sex hormones (androgens), including primary and secondary hypogonadism, delayed or precocious puberty, impotence in males and, in females hirsutism (excessive hair) and virilization (masculinization) due to tumors, polycystic ovaries, and adrenogenital syndromes.(b)
Classification. Class I.