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cobas pure integrated solutions is an automated analyzer, intended for running qualitative, semiguantitative and quantitative clinical chemistry and immunochemistry assays as well as ion selective measurements.

Glucose HK Gen.3 is an in vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoqlycemia, idiopathic hypoglycemia and pancreatic islet cell tumors.

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of large amounts of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Methadone II (MDN2) is an in vitro diagnostic test for the qualitative and semiquantitative detection of methadone in human urine on Roche/Hitachi cobas c systems at a cutoff concentration of 300 ng/mL. Semiquantitative test results may be obtained that permit laboratories to assess assay performance as part of a quality control program. Semiquantitative assays are intended to determine an appropriate dilution of the specimen for confirmation by a confirmatory method such as gas chromatography/mass spectrometry (GC-MS).

Elecsys TSH is an immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The cobas pure integrated solutions is a fully automated, random-access, software controlled system intended for in vitro quantitative and qualitative analysis of analytes in body fluids. It will typically be used in low to mid throughput clinical laboratories. The system consolidates clinical chemistry, homogenous immunoassays as well as electrolyte testing within one workplace. The cobas pure integrated solutions consists of a clinical chemistry analytical unit (cobas c 303) with an integrated ISE analytical unit, an immunoassay analytical unit (cobas e 402) and a core unit.

Glucose is phosphorylated by hexokinase (HK) in the presence of adenosine triphosphate (ATP) and magnesium ions to produce glucose-6-phosphate (G-6-P) and adenosine diphosphate (ADP). Glucose-6-phosphate dehydrogenase (G-6-PDH) specifically oxidizes G-6-P to 6-phosphogluconate with the concurrent reduction of nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide reduced (NADH). One micromole of NADH is produced for each micromole of glucose consumed. The NADH produced absorbs light at 340 nm and can be detected spectrophotometrically as an increased absorbance.

The ISE analytical unit for Na+ employs ion-selective membrane to develop an electrical potential (electromotive force, EMF) for the measurements of ions in solution. Selective membrane is in contact with both the test solution and an internal filling solution. Due to the selectivity of the membrane, only the ions to be EMF. The membrane EMF is determined by the difference in concentration of the test ion in the test solution and the internal filling solution.

The ISE analytical unit of the Roche/Hitachi cobas c systems is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium is the major extracellular cation and functions to maintain fluid distribution and osmotic pressure. Some causes of decreased levels of sodium include prolonged vomiting or diarrhed reabsorption in the kidney and excessive fluid retention. Common causes of include excessive fluid loss, high salt intake and increased kidney reabsorption.

The Methadone assay is based on the kinetic interaction of microparticles in a solution (KIMS) as measured by changes in light transmission. In the absence of sample drug conjugates bind to antibody-bound microparticles, causing the formation of particle aggregates. As the aggregation reaction proceeds in the absence of sample drug, the absorbance increases.

When a urine sample contains the drug in question, this drug derivative conjugate for microparticle-bound antibody. Antibody bound to sample drug is no longer available to promote particle aggregation, and subsequent particle lattice formation is inhibited. The presence of sample drug diminishes the increasing absorbance in proportion to the concentration of drug in the sample. Sample drug content is determined relative to the value obtained for a known cutoff concentration of drug.

The Elecsys TSH immunoassay makes use of a sandwich test principle using monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex) construct from human and mouse specific components. Elecsys TSH immunoassay is intended for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. It is intended for use on the cobas e immunoassay analyzers.

The provided text describes several in vitro diagnostic (IVD) devices and their performance characteristics. It outlines how Roche Diagnostics established the substantial equivalence of these devices (Glucose HK Gen.3, ISE indirect Na for Gen.2, ONLINE DAT Methadone II, Elecsys TSH, and the cobas pure integrated solutions analyzer) to their predicate devices through various non-clinical tests.

However, the document does not provide a table of acceptance criteria and reported device performance in a format that easily allows for direct comparison against specific numeric targets. Instead, it describes general study types and states that the "analytical performance data for all representative assays meet specifications and support the substantial equivalence."

Furthermore, it does not explicitly detail the following requested information:

• Sample sizes used for the test set and data provenance: The document mentions "human serum, plasma, urine and CSF" as sample types but not explicit test set sample numbers or their country of origin for most tests. It generally refers to "human samples" or "pooled human plasma and serum samples."
• Number of experts used to establish the ground truth for the test set and their qualifications: This information is not present for any of the described tests. The ground truth for these IVDs is typically established through reference methods or established control materials, not expert consensus on individual cases.
• Adjudication method: Not applicable/provided as the tests are analytical and do not involve human interpretation requiring adjudication.
• Multi Reader Multi Case (MRMC) comparative effectiveness study: Not applicable, as these are IVD assays, not AI-assisted reader studies.
• Standalone performance: The entire document describes the standalone performance of the algorithms/assays.
• Type of ground truth used: For quantitative assays (Glucose, Sodium, TSH), the ground truth is implicitly based on established reference methods or known concentrations in control materials. For qualitative/semi-quantitative assays like Methadone, it's based on known concentrations relative to a cutoff or confirmed by methods like GC-MS.
• Sample size for the training set: Not explicitly stated, as these are typically not machine learning models in the sense of needing a distinct "training set" for classification, but rather reagents and analytical systems whose performance is validated. The mentioned "study" refers to validation studies, not AI model training.
• How the ground truth for the training set was established: Not applicable, as explained above.

Given the nature of the document, which focuses on device-specific analytical performance claims rather than AI model validation, several of the requested categories are not directly addressed or are not relevant.

Below is an attempt to structure the available information, noting the limitations.

1. Table of Acceptance Criteria and Reported Device Performance

As specific numerical acceptance criteria (e.g., "sensitivity ≥ 95%") are not explicitly provided in the text, this table will summarize what types of performance were evaluated and that they met specifications as stated in the document.

Overall Conclusion for all devices: "The analytical performance data for all representative assays meet specifications and support the substantial equivalence...to the predicate devices."

2. Sample sizes used for the test set and the data provenance

• Glucose HK Gen.3:
  • Precision studies: "Two aliquots per run, two runs per day for ≥ 21 days". Types of samples (e.g., patient, control) not specified, but typically human-derived.
  • Linearity, LoB, LoD, LoQ, Interference, Matrix Comparison, Post Dilution Check, Recovery in Controls: Sample numbers or types of samples for these specific studies are not detailed.
  • Method Comparison: "all sample types" (e.g., human serum, plasma, urine, CSF) tested between cobas c 303 and cobas c 503.
  • Data Provenance: Not specified (e.g., country of origin, retrospective/prospective).
• ISE indirect Na for Gen.2:
  • Precision studies: "One run per day for ≥ 21 days with two parts, two aliquots per part". Typically human-derived samples.
  • Endogenous Interference: "pooled human plasma and serum samples spiked with varying levels of interferent."
  • Linearity, LoB, LoD, LoQ, Drug Interference, Calibration Frequency, Post Dilution Check, Recovery in Controls: Sample numbers or specific types of samples not detailed.
  • Method Comparison: "all sample types" (e.g., human serum, plasma, urine) tested.
  • Data Provenance: Not specified.
• ONLINE DAT Methadone II:
  • Precision: "human samples and controls" (n=84 for repeatability, with 2 aliquots per run, 2 runs per day, 21 days for intermediate precision).
  • Endogenous Interference: "urine containing methadone" and "pooled human urine".
  • Drug Interference: "human urine containing methadone".
  • Cross Reactivity: Details not given, but likely spiked drug solutions into human urine.
  • Method Comparison: Urine samples compared against GC-MS and cobas c 503.
  • Data Provenance: Not specified.
• Elecsys TSH:
  • Precision: Likely control materials and potentially patient samples.
  • Endogenous Interfering Substances: "human serum samples (native serum pools)".
  • Cross-reacting Compounds: "native human serum sample pool".
  • Anticoagulants Effect: "native human serum samples, single donors as well as pools" drawn into various tubes.
  • Linearity, LoB, LoD, LoQ, Drug Interference, On-board Reagent Stability, High-dose Hook Effect: Sample numbers or types not specified.
  • Method Comparison: Human serum and plasma samples compared between cobas e 402 and cobas e 801.
  • Data Provenance: Not specified.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Not applicable. For in vitro diagnostic assays, "ground truth" is established through analytical reference methods, defined concentrations of calibrators/standards, or confirmed by other laboratory methods (e.g., GC-MS for Methadone) rather than expert human interpretation of results.

4. Adjudication method

Not applicable. These are analytical tests performed by automated systems; there is no human interpretation or adjudication involved in generating the primary test result.

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 is for in vitro diagnostic assays on automated analyzers, not AI-assisted human reader studies. The "AI" would refer to the algorithms within the analytical unit, not a system designed to assist human readers.

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

Yes, the entire document focuses on the standalone performance of the analytical systems and assays. The results are generated directly by the device/analyzer without human intervention for interpretation beyond loading samples and performing quality control.

7. The type of ground truth used

• For Glucose, Sodium, TSH (Quantitative assays): The ground truth for these quantitative measurements is based on reference methods, known concentrations in calibrators and controls, or comparative methods (e.g., flame photometry for sodium, or existing cleared assays on predicate devices).
• For Methadone (Qualitative/Semi-quantitative assay): Ground truth is established by known concentrations relative to a cutoff (e.g., 225 ng/mL for negative control, 375 ng/mL for positive control) and confirmed by a "confirmatory method such as gas chromatography/mass spectrometry (GC-MS)".

8. The sample size for the training set

Not explicitly specified. These are not AI/ML models in the typical sense that require a distinct "training set." The development of reagents and analytical platforms involves extensive R&D and optimization, but the validation studies described here are for demonstrating performance and equivalence, not for "training" an algorithm in a machine learning context.

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

Not applicable, as a distinct "training set" with established ground truth in the context of machine learning model development is not typically associated with the development and validation of these types of in vitro diagnostic reagents and analyzers. The principles are generally based on established biochemical reactions, electrochemical measurements, or immunoassays.

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The cobas pro integrated solutions is an IVD device used for the quantitation of clinical chemistry and Ion Selective Electrolyte parameters from various biological fluids.

Glucose HK Gen.3 is an in vitro test for the quantitative determination of glucose in human serum, plasma, urine and CSF on Roche/Hitachi cobas c systems. Glucose measurements are used in the diagnosis and treatment of carbohydrate metabolism disorders including diabetes mellitus, neonatal hypoglycemia and pancreatic islet cell tumors.

The ISE indirect Na for Gen. 2 is intended for the quantitative determination of sodium in serum, plasma or urine using ion-selective electrodes. Sodium measurements are used in the diagnosis and treatment of aldosteronism (excessive secretion of the hormone aldosterone), diabetes insipidus (chronic excretion of dilute urine, accompanied by extreme thirst), adrenal hypertension, Addison's disease (caused by destruction of the adrenal glands), dehydration, inappropriate antidiuretic hormone secretion, or other diseases involving electrolyte imbalance.

Elecsys TSH immunoassay is intended for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders. The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

The cobas pro integrated solutions (cobas pro) is a fully automated, random-access, software controlled system intended for in vitro quantitative analysis of analytes in body fluids. It will typically be used in clinical laboratories with large workload. The system consolidates clinical chemistry, homogenous and heterogeneous immunoassays as well as electrolyte testing within one workplace. It consists of a high throughput sample distribution unit (core unit) and different analytical units for ISE (cobas pro ISE analytical unit), clinical chemistry (c 503 analytical unit) and immunoassay (e 801 analytical) testing. The system hardware is comprised of new or previously cleared members of the Roche/Hitachi cobas c or Elecsys families of analyzers. The instrument software is unique to the cobas pro and was developed from previous generations of Roche/Hitachi instrument systems.

Here's a breakdown of the acceptance criteria and study information for the cobas pro integrated solutions device, specifically focusing on the Glucose HK Gen.3, ISE indirect Na for Gen.2, and Elecsys TSH assays.

Preamble: This document describes a Traditional 510(k) Premarket Notification for the cobas pro integrated solutions. The core purpose is to show that previously cleared Glucose, Sodium, and TSH assays, when run on the new cobas pro integrated solutions system, are substantially equivalent to their predicate devices. Therefore, the acceptance criteria and studies presented are largely comparative or validation studies demonstrating consistent performance with previously cleared devices and established analytical standards.

1. Table of Acceptance Criteria and Reported Device Performance

Given that this is a 510(k) submission demonstrating substantial equivalence to pre-existing predicate devices for assays and a new integrated system, the acceptance criteria are generally focused on meeting established performance claims or showing equivalence within acceptable statistical limits. The summary provided focuses on the reported device performance which is then implicitly compared to internal acceptance criteria (often relative to the predicate device or CLSI guidelines).

Note on Acceptance Criteria: The document explicitly states "All samples met the predetermined acceptance criterion" for precision studies. For LoQ, it states "LoQ determined at maximum allowable %TE (total error) of no more than 20% (Glucose and TSH) and 30% (Sodium)." For endogenous interference, it was "recovery of 100±10%". For exogenous interference (common drugs for Elecsys TSH), it was "± 10% of the reference value". For method comparisons, the slope, intercept, and correlation coefficients approaching 1 or 0 respectively, indicate strong agreement, satisfying the intent of substantial equivalence. Specific numerical acceptance criteria are not always stated outright but are implied by the study design and conclusion of meeting criteria.

• Serum Repeatability CV: 0.4%-9.2%
• Serum Intermediate Precision CV: 0.5%-10.0%
• Urine Repeatability CV: 0.4%-8.3%
• Urine Intermediate Precision CV: 0.7%-8.5%
• CSF Repeatability CV: 0.4%-3.0%
• CSF Intermediate Precision CV: 0.5%-3.5%
  ISE indirect Na (N=84 per application):
• Plasma Repeatability CV: 0.3%-0.6%
• Plasma Intermediate Precision CV: 0.5%-1.5%
• Serum Repeatability CV: 0.3%-0.5%
• Serum Intermediate Precision CV: 0.5%-1.7%
• Urine Repeatability CV: 0.3%-0.5%
• Urine Intermediate Precision CV: 0.6%-4.8%
  Elecsys TSH (N=84):
• Repeatability CV: 1.6%-6.3%
• Intermediate Precision CV: 2.4%-11.7% |
  | Analytical Sensitivity | LoQ: Total error not more than 20% (Glucose, TSH), 30% (Na). | Glucose HK Gen.3: LoB: 0.2 mg/dL, LoD: 0.4 mg/dL, LoQ: 1.4 mg/dL.
  Claimed: LoB: 2 mg/dL, LoD: 2 mg/dL, LoQ: 2 mg/dL.
  ISE indirect Na: LoB: 3.50 mmol/L, LoD: 4.42-4.51 mmol/L, LoQ: 11.8-12.2 mmol/L.
  Claimed: LoB: 3.5 mmol/L, LoD: 4.5 mmol/L, LoQ: 12.2 mmol/L.
  Elecsys TSH: LoB: 0.0013-0.0015 µIU/mL, LoD: 0.00282-0.00348 µIU/mL, LoQ: 0.00386-0.00495 µIU/mL.
  Claimed: LoB: 0.0025 µIU/mL, LoD: 0.005 µIU/mL, LoQ: 0.005 µIU/mL. |
  | Linearity/Reportable Range | Deviations within predetermined acceptance criteria. | Glucose HK Gen.3: Serum (R2=0.9999), Urine (R2=0.9997), CSF (R2=0.9992) linear in claimed range (2.0-750 mg/dL).
  ISE indirect Na: Plasma (R2=0.9998), Serum (R2=0.9998), Urine (R2=0.9999) linear in claimed range (80-180 mmol/L for S/P, 20-250 mmol/L for U).
  Elecsys TSH: Serum (R2=0.9972) linear in range 0.004-118 uIU/mL. |
  | High Dose Hook Effect | No hook effect observed up to a specified concentration. | Elecsys TSH: No hook effect up to 1466 uIU/mL TSH. |
  | Endogenous Interference | Recovery of 100 ± 10%. | Glucose HK Gen.3: No interference from albumin, bilirubin, hemolysis, IgG, lipemia, etc. at specified high concentrations.
  ISE indirect Na: No interference from bilirubin, hemolysis, lipemia at specified high concentrations.
  Elecsys TSH: No interference from biotin, lipemia, hemoglobin, bilirubin, rheumatoid factor, immunoglobulins at specified high concentrations. |
  | Exogenous Interference (Drugs) | ± 10% of the reference value in comparison to unspiked samples. | ISE indirect Na: No interference from various common and special drugs at specified concentrations.
  Elecsys TSH: No interference from common and special drugs at specified concentrations. |
  | Analytical Specificity/Cross-Reactivity | % cross-reactivity near zero. | Elecsys TSH: hGH, hCG, LH, FSH showed 0.000% cross-reactivity at high tested concentrations. |
  | Method Comparison to Predicate | Strong correlation (slope ≈ 1, intercept ≈ 0, high R/tau values) indicating substantial equivalence to predicate device/reference method. | Glucose HK Gen.3: Slope close to 1.0, intercept close to 0, strong correlation (Pearson r/Kendall tau close to 1) comparing to cobas c 501.
  ISE indirect Na: Slope close to 1.0, intercept close to 0, strong correlation (Pearson r close to 1) comparing to cobas c 501 ISE and Flame Photometer.
  Elecsys TSH: Slope = 1.018 (LCL/UCL: 1.004/1.025), Intercept = -0.0018 µIU/mL (LCL/UCL: -0.0040/-0.0001), Pearson r = 0.999, Kendall tau = 0.977 when compared to predicate Elecsys TSH on cobas 8000. |
  | Sample Matrix Comparison | Acceptable recovery of analyte values and strong correlation between different sample types (e.g., serum vs. various plasma anticoagulants). | Glucose HK Gen.3: Strong correlation (slope near 1, intercept near 0, r near 1) comparing serum to serum tube with separation gel, and various plasma anticoagulants (K2EDTA, Li-Heparin, NaF/K-Oxalate, NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA, KF/Na2-EDTA).
  ISE indirect Na: Strong correlation (Slope = 1.015, Intercept = -2.69, r = 0.998) between Serum and Li-Heparin Plasma.
  Elecsys TSH: Strong correlation (slope near 1, intercept near 0, r near 1) comparing serum to Li-Heparin, K2-EDTA, and K3-EDTA plasma. |
  | Stability | Stability data supports Roche Diagnostic's claims as reported in the package inserts. (Implied: device maintains performance over its claimed shelf life and in-use stability.) | Stability data for Glucose HK Gen.3, ISE indirect Na, and Elecsys TSH was provided in prior 510(k)s (K061048, K060373, and K190773 respectively) and supports the claims. |

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

• Glucose HK Gen.3 (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2) and 5 human serum samples per application (serum, urine, CSF). So, for repeatability and intermediate precision, 84 measurements for 2 controls + 5 samples, across serum, urine, and CSF applications.
  • Data Provenance: Human serum, plasma, urine, and CSF samples. These were "native, single donors as well as pools." The study was conducted in-house by Roche Diagnostics (implied by the submission).
• ISE indirect Na (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl ClinChem Multi 1 and 2, Liquichek 1 and 2) and 5 human plasma, serum, and urine samples per application. So, for repeatability and intermediate precision, 84 measurements for controls + 5 samples, across Li-Heparin Plasma, Serum, and Urine.
  • Data Provenance: Human Li-Heparin plasma, serum, and urine samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
• Elecsys TSH (Precision):
  • Sample Size: 84 measurements for each control level (PreciControl Universal, PC Thyro Sensitive) and 5 human serum samples.
  • Data Provenance: Human serum samples. These were "native, single donors as well as pools." Conducted in-house by Roche Diagnostics.
• Analytical Sensitivity (LoB, LoD, LoQ) for all assays:
  • Sample Size:
    • LoB: ≥ 60 measurements of analyte-free samples.
    • LoD: 60 measurements (5 low-analyte concentration samples, measured in duplicate over 6 runs, 3 days).
    • LoQ: ≥ 60 measurements per sample type (samples with low analyte concentration measured over 3 to 5 days).
  • Data Provenance: Not explicitly stated for specific blanks or low-concentration samples beyond "analyte-free" or "low-analyte concentration". Conducted in-house by Roche Diagnostics.
• Linearity/Assay Reportable Range:
  • Glucose HK Gen.3: Three high analyte human serum, urine, and CSF samples diluted to 12 levels.
  • ISE indirect Na: Three high analyte human serum, urine, and CSF samples diluted to multiple aliquot concentrations.
  • Elecsys TSH: Three high analyte human serum samples diluted to concentrations covering the measuring range.
  • Data Provenance: Human serum, urine, CSF samples. Conducted in-house by Roche Diagnostics.
• Endogenous Interference:
  • Glucose HK Gen.3: Plasma and urine samples, glucose levels ~79.5 mg/dL and ~116.3 mg/dL.
  • ISE indirect Na: Human plasma, serum, and urine samples. Low (~124 mmol/L) and high (~151 mmol/L) for S/P; low (26.3 mmol/L) and high (188 mmol/L) for urine.
  • Elecsys TSH: Human serum samples with TSH concentrations ~0.462 uIU/mL, ~3.95 µIU/mL, and ~7.54 µIU/mL.
  • Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
• Exogenous Interference (Drugs):
  • ISE indirect Na: Two sample pools (low and high concentration ISE indirect Na).
  • Elecsys TSH: Two human serum samples (~0.5 uIU/mL and ~8 uIU/mL TSH).
  • Data Provenance: Human samples. Conducted in-house by Roche Diagnostics.
• Analytical Specificity/Cross-Reactivity (Elecsys TSH):
  • Sample Size: Native human serum sample pool.
  • Data Provenance: Human serum samples. Conducted in-house by Roche Diagnostics.
• Method Comparison to Predicate:
  • Glucose HK Gen.3: 74 native human serum samples, 67 native human urine samples, 75 native CSF samples.
  • ISE indirect Na: 120 human Lithium heparin plasma samples (vs cobas c 501 ISE), 118 human Lithium heparin plasma (vs Flame Photometer), 120 human serum (vs cobas c 501 ISE), 120 human serum (vs Flame Photometer), 120 human urine (vs cobas c 501 ISE/Flame Photometer).
  • Elecsys TSH: 138 samples (129 native human serum, 9 diluted human serum samples; single donors and pools).
  • Data Provenance: Native human samples (serum, plasma, urine, CSF), some diluted. Conducted in-house by Roche Diagnostics.
• Sample Matrix Comparison:
  • Glucose HK Gen.3: At least 39 serum/plasma pairs for each anticoagulant type (K2-EDTA, Li-Heparin, NaF/K-Oxalate, NaF/Na2-EDTA, NaF/Citrate/Na2-EDTA, KF/Na2-EDTA plasma tubes) + serum vs. serum tube with separation gel.
  • ISE indirect Na: 50 serum/Li-Heparin plasma pairs.
  • Elecsys TSH: Minimum of 56 serum/plasma pairs for Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. Serum separation tubes from 3 manufacturers, blood from five donors were used.
  • Data Provenance: Native human samples. Conducted in-house by Roche Diagnostics.

3. Number of Experts and Qualifications for Ground Truth

This submission concerns in vitro diagnostic (IVD) devices for quantitative measurements of analytes. For such devices, "ground truth" is typically established by:

• Reference methods (e.g., flame photometry for Sodium reference),

• Previously cleared and validated predicate devices,

• Known concentrations in control materials or spiked samples, or

• The inherent chemical/physical measurement by the device itself (for analytical performance criteria like precision, linearity).

• No human "experts" (like radiologists interpreting images) were used to establish ground truth in the context of these analytical performance studies. The "ground truth" is analytical, derived from established chemical/instrumental methods and reference standards.

4. Adjudication Method for the Test Set

Since this is an IVD device for quantitative measurements and the studies are analytical performance evaluations based on instrumental precision, accuracy, and comparison to established methods or predicate devices, there is no adjudication method (e.g., 2+1, 3+1) involving human experts as would be seen in diagnostic imaging studies. The data points are quantitative measurements from the instruments themselves or reference methods. Statistical analysis (e.g., regression, CVs, SDs) is used to assess performance against pre-defined criteria.

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

No MRMC comparative effectiveness study was done. This type of study, involving multiple human readers interpreting cases with and without AI assistance, is relevant for diagnostic imaging AI algorithms where human interpretation is part of the clinical pathway. This submission is for an in vitro diagnostic (IVD) measurement system, not an AI-powered diagnostic imaging tool that assists human readers. The comparative studies involved comparing the new system's analytical performance against predicate IVD systems or reference methods, not human readers.

6. Standalone Performance Study (Algorithm Only)

The entire non-clinical performance evaluation could be considered analogous to a "standalone" performance study, as it describes the analytical performance of the device itself (the integrated system with its assays) without human intervention in the measurement process. The device provides quantitative results, and these results are directly evaluated for precision, linearity, sensitivity, interference, and agreement with predicate devices or reference methods. There is no "human-in-the-loop" aspect to the core measurement and output of these IVD assays.

7. Type of Ground Truth Used

The ground truth used for these analytical studies consists of:

• Known concentrations: For studies like linearity, analytical sensitivity (LoB, LoD, LoQ), and interference, samples prepared with known concentrations of analytes or interferents serve as the ground truth.
• Reference methods: For method comparison studies, well-established and often independently validated reference methods (e.g., flame photometry for sodium measurement) serve as the ground truth or gold standard for comparison.
• Predicate device results: For demonstrating substantial equivalence, the results obtained from a legally marketed predicate device (which itself has established ground truth capabilities) serve as the comparative ground truth.
• Internal statistical controls: For precision studies, consistent and stable control materials are used, where the expected range or value is the "ground truth" against which repeatability and intermediate precision are measured.

8. Sample Size for the Training Set

This document describes the non-clinical performance evaluation for a 510(k) submission, primarily for demonstrating analytical performance and substantial equivalence. It does not describe the development or training of an AI algorithm based on machine learning, so there is no specific "training set" in the context of AI/ML models. The data presented here are validation data for the analytical performance of the assay and integrated system.

For a traditional IVD device, method development involves internal studies and optimization, but this is distinct from "training data" for a machine learning model. The various studies (precision, linearity, etc.) use samples/replicates as described in point 2.

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

As noted in point 8, there isn't a "training set" in the machine learning sense described in this document. If this were to refer to the developmental studies for the underlying assays (Glucose HK Gen.3, ISE indirect Na, Elecsys TSH, which are previously cleared), their ground truth would have been established during their initial development and validation process using:

• Reference materials: Certified reference materials (CRMs) with known analyte concentrations.
• Clinical samples: Patients samples characterized by confirmed diagnoses or clinical outcomes for intended use populations.
• Comparison to established methods: Correlation with existing, approved methods, often considered the "gold standard."
• Spiking and dilution experiments: Preparing samples with known added amounts of analyte.

These are standard practices in IVD assay development, ensuring the analytical and clinical performance of the individual assays before they are integrated into a new system like the cobas pro integrated solutions.

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Immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid and pituitary disorders.

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

The Elecsys TSH immunoassay makes use of a sandwich test principle using monoclonal antibodies specifically directed against human TSH. The antibodies labeled with ruthenium complex) consist of a chimeric construct from human and mouse specific components. The Elecsys TSH immunoassay is used for the in vitro quantitative determination of thyroid stimulating hormone in human serum and plasma. It is intended for use on the cobas e immunoassay analyzers.

The Elecsys TSH device is an immunoassay for the in vitro quantitative determination of thyrotropin in human serum and plasma, used in the diagnosis of thyroid and pituitary disorders. It is an electrochemiluminescence immunoassay (ECLIA) intended for use on cobas e immunoassay analyzers. The key change in the updated device is a two-step approach to block biotin interference by adding an antibody to bind free biotin in the sample and changing the linker on the biotinylated capture antibody.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

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

The document provides performance data across various non-clinical studies. The acceptance criteria are generally implied by "All samples met the predetermined acceptance criterion" or "All lots met the predetermined acceptance criterion" for studies like precision, LoB, LoD, LoQ, and linearity. For interference studies, the "No interference seen up to" values represent the performance vs. a defined limit. For lot-to-lot reproducibility, the comparability of SDs and CVs implicitly confirms acceptance. For method comparison, the statistical results (slope, intercept, correlation coefficient, bias) are compared against internal acceptance criteria.

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

• Precision (Repeatability & Intermediate Precision): The test set involved 2 replicates per run for 21 days, across 2 runs per day, for PreciControl Universal, PC Thyro Sensitive, and 5 human serum samples. This is a prospective study design for precision. Sample types were native, single human donors as well as pools.
• Lot-to-Lot Reproducibility: 2 replicates of each of 5 human serum samples per run, 2 runs per day, for 21 days (7 days per lot, n=28 determinations per lot). Prospective design. Sample types were native, single human donors as well as pools.
• Limit of Blank (LoB): Five blank samples with two replicates each per run, for 6 runs on ≥ 3 days (total 60 determinations for analyte free samples). Prospective design.
• Limit of Detection (LoD): Five low analyte samples with two replicates each per run, for 6 runs on ≥ 3 days (total 60 replicates per sample per reagent lot). Prospective design.
• Limit of Quantitation (LoQ): 25 replicates per sample per reagent lot, over 5 days (1 run per day). Prospective design.
• Linearity/Assay Reportable Range: Three high analyte human serum samples were diluted and measured in 3-fold determination within a single run. Prospective design.
• High Dose Hook Effect: Three human serum samples spiked with analyte, dilution series performed, measured in one-fold determination. Prospective design.
• Endogenous Interference: Varied by interferent. For Biotin, Lipemia, Hemoglobin, Bilirubin, RF, IgG, IgM, samples were spiked with interfering substances and diluted into a dilution pool in 10% increments. The number of individual samples/pools is not explicitly stated but implies multiple. Prospective design.
• Analytical Specificity/Cross-Reactivity: A native human serum sample pool was used for each potential cross-reacting compound. Prospective design.
• Exogenous Interferences (Drugs): Two human serum samples (native serum pools) were used. Prospective design.
• Sample Matrix Comparison: A minimum of 56 serum/plasma pairs per sample material (Li-heparin, K2-EDTA, K3-EDTA plasma) were tested in singleton. For PST/SST, blood from five donors was used, measured in duplicate. Prospective design.
• Method Comparison to Predicate: 138 samples (129 native human serum samples and 9 diluted human serum samples, single donors as well as pools diluted) were measured in singleton. Prospective design.

Data Provenance: The document does not explicitly state the country of origin for the human serum and plasma samples. However, the manufacturer, Roche Diagnostics, operates globally with establishments in Mannheim and Penzberg, Germany, and Indianapolis, USA. The studies typically indicate the use of "human serum" or "human serum samples" without further geographic specification. All described studies appear to be prospective experimental designs conducted in a laboratory setting for device validation.

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 immunoassay testing for a quantifiable biomarker (TSH), not an imaging device or a device requiring expert interpretation of complex clinical data to establish ground truth for its performance characteristics. The ground truth for such assays is established through analytical methods and reference standards (e.g., spectrophotometry for linearity, spiked samples for interference, reference materials for precision, comparison to a predicate device). No human experts are used to "establish primary ground truth" in the sense of clinical diagnosis for these analytical performance studies. The ground truth is the actual concentration of the analyte, or the known characteristics of the samples (e.g., spiked amount of interferent).

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

Not applicable. As described above, this is an in vitro diagnostic analytical performance study, not a clinical study requiring adjudication of diagnoses or interpretations by experts.

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 automated immunoassay, an in vitro diagnostic (IVD) test, not an imaging device or AI-driven diagnostic tool that would involve human "readers" or AI assistance.

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

Yes, the studies described are all standalone performance studies of the Elecsys TSH immunoassay system. It's an automated device (cobas e immunoassay analyzer) that provides quantitative results without human intervention in the measurement process itself, beyond sample loading and general operation/maintenance.

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

The ground truth used for these analytical studies includes:

• Known concentrations: For LoB, LoD, LoQ, and linearity, the samples are either analyte-free, at known low concentrations, or dilutions from known high concentrations.
• Spiked samples: For interference studies (endogenous and exogenous), known amounts of interfering substances are added to samples.
• Reference materials/standards: For precision, controls with defined concentrations are used. Traceability is to the 2nd IRP WHO Reference Standard 80/558.
• Comparison to a legally marketed predicate device: For method comparison, the results of the new device are compared quantitatively to those of the predicate device.
• Clinical samples (native human serum/plasma): These are used to assess the device's performance across a range of physiological concentrations and in real-world matrices for studies like precision, linearity, and matrix comparison.

8. The sample size for the training set

This document describes a 510(k) submission for a revised immunoassay, not a machine learning or AI-based device. Therefore, there is no "training set" in the context of algorithm development. The development of the assay itself would have involved extensive R&D and analytical testing to optimize reagents and protocols, but this is distinct from training an AI model on a dataset.

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

Not applicable, as there is no "training set" in the AI/ML context for this device. The assay's performance characteristics are established through the non-clinical studies detailed in the summary.

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cobas e 801 immunoassay analyzer is intended for the in-vitro determination of analytes in body fluids.

Elecsys TSH immunoasay is intended for the in vitro quantitative determination of thyrotropin in human serum and plasma. Measurements of TSH are used in the diagnosis of thyroid or pituitary disorders. The Elecsys TSH immunoassay is an electrochemiluminescence immunoasay 'ECLIA', which is intended for use on the cobas e immunoassay analyzers.

The cobas e 801 immunoassay analyzer is a fully automated, software controlled analyzer system for in vitro determination of analytes in human body fluids. It is part of the cobas 8000 modular analyzer series cleared under K100853. It uses electrochemiluminescent technology for signal generation and measurement.

Here's a breakdown of the acceptance criteria and study information for the Elecsys TSH assay on the Cobas e 801 immunoassay Analyzer, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" for each performance characteristic as pass/fail thresholds. Instead, it presents the results of various validation studies. I will present the reported performance, and where applicable, infer the implied acceptance based on the presentation of the results as successful.

2. Sample Size and Data Provenance for Test Set

• Repeatability and Intermediate Precision:
  • Sample Size:
    • 7 human serum samples (5 pooled, 5 pooled spiked) and 2 control samples (PC Universal, PreciControl TS).
    • Each sample tested in 2 replicates per run, 2 runs per day for 21 days (total of 84 replicate measurements per sample type).
• Linearity:
  • Sample Size: 3 high analyte serum samples diluted to 12 concentrations. Each concentration assayed in 3-fold determination within a single run.
• Analytical Sensitivity (LoB, LoD, LoQ):
  • LoB: Blank sample tested with 60 replicates (10 replicates per run, 6 days).
  • LoD: 5 low-level human serum samples tested with 60 replicates (2 replicates per sample per run, 6 days).
  • LoQ: 10 low-level TSH samples tested over 5 days, 5 replicates per sample per day.
• Endogenous Interferences:
  • Human serum samples. Specific number not provided, but the outcome is qualitative ("No interference observed").
• Exogenous Interferences (Anticoagulants):
  • A minimum of 40 serum/plasma pairs per sample material (presumably 40 serum, 40 Li-Heparin plasma, 40 K2-EDTA plasma, 40 K3-EDTA plasma). Tested in singleton for each type.
• Exogenous Interferences (Drugs):
  • 16 commonly used drugs and 13 special drugs. Specific number of samples not provided, but the outcome is qualitative ("No interference").
• Method Comparison:
  • Sample Size: 130 human serum samples (single donors and serum pools; native, spiked as well as diluted).
• Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). However, the use of "human serum samples" and "human serum/plasma pairs" indicates biological samples. The studies are prospective in nature, conducted specifically to validate the device.

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

This device is an immunoassay for quantitative determination of TSH. The "ground truth" for the test set is established by the reference measurement method or the quantitative value itself. No human experts are used to establish ground truth in the same way they would be for image interpretation. The accuracy of the quantitative measurements is assessed against known concentrations (e.g., in linearity, LoB/LoD studies) or against a predicate device (method comparison).

4. Adjudication Method

Not applicable for an immunoassay. Adjudication is typically used when human interpretation of results contributes to the ground truth, which is not the case here.

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

No. This type of study is relevant for diagnostic imaging or other interpretations where human readers are involved. This document describes the performance of an in-vitro diagnostic device (IVD) for quantitative measurement, which operates without direct human interpretive input being part of the core measurement.

6. Standalone Performance

Yes, these studies describe the standalone (algorithm only, in this context meaning the device's automated performance without human intervention after sample loading) performance of the Elecsys TSH assay on the cobas e 801 immunoassay analyzer. The results presented are directly from the instrument's measurements.

7. Type of Ground Truth Used

• Reference Materials/Known Concentrations: For precision, linearity, LoB, LoD, LoQ, endogenous and exogenous interference studies, ground truth implicitly refers to the expected concentration/value based on the preparation of known samples or the absence of an analyte (for blanks).
• Predicate Device Measurements: For the method comparison study, the "ground truth" for comparison is the measurement obtained from the predicate device (Elecsys TSH on Elecsys 2010 analyzer).
• Expected Values: The "Expected Values" section establishes a reference range (0.27-4.20 µIU/mL) based on healthy test subjects. This is a clinical reference range, not a direct ground truth for individual measurements, but rather a benchmark for interpretation.

8. Sample Size for the Training Set

The document describes validation studies for an in vitro diagnostic device (IVD), specifically an immunoassay analyzer and assay. IVDs like this do not typically have a "training set" in the machine learning sense. The device's operational parameters, calibration curves, and algorithms are developed during the product development phase by the manufacturer, which might involve internal data, but generally, the submission focuses on external validation. The document does not provide details on the development data used.

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

As there is no "training set" described in the context of machine learning, this question about establishing ground truth for it is not applicable here. The device output is a quantitative value based on chemical reactions and detection, not a learned prediction from a ground-truthed dataset in the AI sense.

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The Elecsys TSH CalCheck 5 is an assayed control for use in calibration verification and for use in the verification of the assay range established by the Elecsys TSH reagent on the indicated Elecsys cobas e immunoassay analyzers.

The Elecsys TSH CalCheck 5 is a lyophilized product consisting of TSH in equine serum matrix. During manufacture, the analyte is spiked into the matrix at the desired concentration levels.

The provided 510(k) summary for the device, "Elecsys TSH CalCheck 5," is for an in-vitro diagnostic control material. As such, it does not involve clinical studies with human patients, image analysis, or expert-based ground truth establishment in the same way a diagnostic imaging device would. Instead, its "performance" is assessed based on its chemical and physical characteristics and how accurately it can verify instrument calibration and assay ranges.

Therefore, many of the requested categories in the prompt are not applicable to this type of device submission.

Here is an analysis based on the information provided in the K093836 document:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state formal "acceptance criteria" in a quantitative, pass/fail table as would be expected for a diagnostic device. Instead, it states that the device was evaluated for "value assignment and stability." The implication is that the performance characteristics (e.g., how well the assigned values match expectations, and the stability over time) were deemed acceptable for substantial equivalence to the predicate device.

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

• Test set: Not applicable in the traditional sense of patient data. The "test set" would be samples of the manufactured control material itself, used for evaluation. The document does not specify the number of batches or individual vials tested.
• Data Provenance: The exact location or nature of the testing is not specified, but it would have been conducted by Roche Diagnostics as part of their product development and validation process. This would be considered prospective manufacturing and testing data.

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

• Not Applicable. For an in-vitro diagnostic control, the "ground truth" is established through highly controlled analytical methods and established reference materials/methods, not through expert human interpretation. The concentrations of TSH in the control material are assigned through a rigorous internal process, not "established by experts."

4. Adjudication Method for the Test Set

• Not Applicable. No human adjudication is involved for this type of chemical control material. The "adjudication" is metrological, relating to the accuracy and precision of the analytical measurements used to assign values and assess stability.

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

• No. An MRMC study is relevant for diagnostic devices that involve human interpretation of medical images or data. This device is a quality control material for an automated immunoassay analyzer.

6. If a Standalone (Algorithm only without human-in-the-loop performance) was done

• Not Applicable / Inherent. This device itself is not an algorithm or a diagnostic tool; it's a calibrator/control. Its performance is entirely "standalone" in the sense that it is a physical product with defined chemical characteristics. Its interaction is with the immunoassay analyzer, not a human interpreter directly.

7. The Type of Ground Truth Used

• Assigned Values based on Analytical Methods and Reference Materials: The "ground truth" for the Elecsys TSH CalCheck 5 is the assigned TSH concentration values for each of its five levels. These values are determined by the manufacturer (Roche Diagnostics) using highly precise and accurate analytical methods, typically traceable to international reference standards and/or internal established reference methods. This ensures that the control material has known concentrations to verify the performance of the Elecsys TSH reagent and analyzer.

8. The Sample Size for the Training Set

• Not Applicable. This device is a chemical control product, not a machine learning algorithm that requires a "training set" of data.

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

• Not Applicable. See point 8.

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The Elecsys TSH CalSet is used for calibrating the quantitative Elecsys TSH assay on the Elecsys immunoassay analyzers.

The Elecsys TSH CalSet consists of equine serum matrix (Cal 1) and a human serum matrix with human TSH (Cal 2) in two concentration ranges. The Elecsys TSH CalSet is supplied in ready for use liquid format.

This 510(k) summary (K060754) for the Elecsys TSH CalSet provides limited information regarding specific performance studies and acceptance criteria typically found for diagnostic devices. The submission primarily focuses on demonstrating substantial equivalence to a predicate device (Elecsys TSH CalSet K961491) rather than presenting detailed performance data from a new clinical study.

Here's an analysis based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state acceptance criteria or report specific device performance metrics in the format of a table with numerical values for sensitivity, specificity, accuracy, etc. This type of information is generally expected for diagnostic devices that analyze patient samples.

The comparison table in the 510(k) summary focuses on device features of the modified Elecsys TSH CalSet versus the predicate, such as intended use, traceability, levels, storage form, matrix, stability, and target concentrations. These are design and manufacturing specifications, not performance metrics against clinical outcomes or a ground truth.

For example, it states "Stability: Unopened... at 2-8°C up to the stated expiration date," and "Opened... after opening in aliquots at 2-8°C for 12 weeks." While these are important characteristics, they are not performance metrics like accuracy or precision.

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

The document does not mention any specific sample size for a test set or provide details on data provenance (e.g., country of origin, retrospective or prospective data). The submission is for a calibrator, which is used to standardize an assay, not to directly diagnose patients from a test set of patient samples. Therefore, a "test set" in the traditional sense of patient samples for diagnostic performance evaluation is not detailed here.

3. Number of Experts Used to Establish Ground Truth and Qualifications

This information is not applicable or provided in the context of this 510(k) submission. A calibrator's "ground truth" relates to its traceable concentration values, not to interpretations by medical experts. The document states "Assay standardized against the 2nd IRP WHO reference standard 80/558," which indicates traceability to an international reference standard, not ground truth established by medical experts for diagnostic outcomes.

4. Adjudication Method

This information is not applicable or provided. Adjudication methods are used to resolve discrepancies among experts when establishing ground truth for diagnostic studies using patient data. Since this submission is for a calibrator and does not involve patient diagnoses or expert interpretation, adjudication is not relevant.

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

A MRMC comparative effectiveness study was not conducted and is not mentioned. This type of study is relevant for diagnostic devices that involve human interpretation (e.g., imaging devices) to assess the impact of AI assistance on human reader performance. As the Elecsys TSH CalSet is a chemical calibrator for an automated immunoassay, human readers are not directly involved in its function or interpretation in a way that would necessitate an MRMC study.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

A standalone performance study, as typically understood for diagnostic algorithms, was not conducted and is not mentioned. The Elecsys TSH CalSet itself is a physical calibrator used within an automated immunoassay system. Its performance relates to its ability to correctly set the assay's measurement scale, which is typically evaluated through analytical studies (e.g., precision, accuracy, linearity) of the overall assay system when calibrated. The document implies that the performance of the assay itself (when calibrated with the device) is acceptable, but does not detail studies specifically for the calibrator's standalone performance in isolation.

7. Type of Ground Truth Used

The ground truth used for the Elecsys TSH CalSet is based on international reference standards and defined concentrations. The document explicitly states: "Assay standardized against the 2nd IRP WHO reference standard 80/558." This refers to a recognized international reference for TSH measurements, which provides the basis for establishing the "true" concentration values of the calibrator.

8. Sample Size for the Training Set

The document does not mention a training set sample size. This is because the Elecsys TSH CalSet is a chemical reagent (calibrator), not an AI algorithm or a diagnostic model that requires a training set in the machine learning sense.

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

Since there is no training set for an AI algorithm or diagnostic model, the method for establishing its ground truth is not applicable or provided. The "ground truth" for the calibrator's stated concentrations is established through reference to the 2nd IRP WHO reference standard 80/558, as mentioned above.

In summary:

This 510(k) submission for the Elecsys TSH CalSet focuses on demonstrating substantial equivalence to a predicate calibrator by comparing manufacturing specifications and intended use. It does not contain detailed performance studies or acceptance criteria typical for diagnostic devices that interpret patient data. The "studies" implied are likely internal analytical validations of the calibrator's characteristics (e.g., stability, concentration accuracy) and its impact on the overall TSH assay, rather than clinical trials with patient cohorts.

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Immunoassay for the in vitro quantitative determination of Thyroid Stimulating Hormone in human serum and plasma.

Sandwich principle: Total duration of assay: 18 minutes (37°C).
• 1st Incubation (9 minutes): Sample (50µL), a biotinylated monoclonal TSH-specific antibody (60 µL), and a monoclonal TSH-specific antibody labeled with a ruthenium complex (50 µL) react to form a sandwich complex.
• 2nd Incubation (9 minutes): After addition of streptavidin-coated microparticles (40 µL) the complex becomes bound to the solid phase via interaction of biotin and streptavidin.
• The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell.
• Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier (0.4 second read frame).
• Results are determined via a calibration curve which is instrument-specifically generated by a 2-point calibration curve and a master curve provided via the reagent bar code.

This document describes the Elecsys® TSH Assay, an electrochemiluminescence assay for the quantitative determination of Thyroid Stimulating Hormone (TSH) in human serum and plasma. The K961491 submission claims substantial equivalence to the Enzymun-Test® TSH (K915195).

Here's an analysis of the acceptance criteria and study information provided:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied by the comparison to the predicate device, Enzymun-Test® TSH, and general scientific principles for immunoassay performance. The document presents performance characteristics for both the Elecsys® TSH and the predicate device, demonstrating that the new device meets or exceeds the predicate's performance in key areas.

• Sample Control 1 (0.914 µU/ml): 2.08%
• Control 2 (2.451 µU/ml): 1.88%
• Control 3 (10.670 µU/ml): 1.47%
  Total %CV:
• Sample Control 1 (0.914 µU/ml): 3.28%
• Control 2 (2.451 µU/ml): 2.20%
• Control 3 (10.670 µU/ml): 1.76% |
  | Sensitivity | Should have a lower detection limit and functional sensitivity suitable for clinical applications, ideally comparable to or better than the predicate's 0.03 µU/ml. | Functional Sensitivity: 0.01 µU/ml
  Lower Detection Limit: 0.005 µU/mL |
  | Assay Range / Linearity | Reportable range should cover clinically relevant TSH levels, and values within this range should be linear (e.g., within ±10% deviation from the linear line). Predicate range: 0.03 µU/ml - 40.00 µU/ml. | Reportable Range: 0.01 µU/ml - 100 µU/ml
  (within ±10% deviation from the linear line) |
  | Method Comparison (Correlation with Predicate) | Should demonstrate good correlation with the predicate device (e.g., r > 0.95, slope near 1, intercept near 0). | Vs Enzymun-Test® TSH:
• Least Squares: y = 1.09x + 0.14, r = 0.991, SEE = 0.798 (N=132)
• Passing/Bablok: y = 1.12X - 0.05, r = 0.991, SEE = 0.798 (N=132)
  Vs Nichols 3rd Generation:
• Least Squares: y = 1.02x - 0.24, r = 0.985, SEE = 1.12 (N=142) |
  | Interfering Substances | Should show no significant interference from common biological substances at clinically relevant concentrations. | No interference at:
• Bilirubin 25 mg/dL
• Hemoglobin 1 g/dL
• Lipemia 1500 mg/dL
• Biotin 30 ng/mL
• RF 339 IU/mL |
  | Specificity (Cross-Reactivity) | Should demonstrate minimal or no cross-reactivity with other related hormones to avoid false positives/negatives. | Conc % Cross-Reactivity:
• HCG 200: 0
• LH 400: 0.038
• FSH 400: 0.008
• HGH 400: 0.00004 |

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

• Precision: For "Within-Run" and "Total" precision, N = 60 was used for each of the three control levels for the Elecsys® TSH. (The predicate used N=120 for each of its three levels.)
• Method Comparison:
  • N = 132 samples were used for comparison between Elecsys® TSH and Enzymun-Test® TSH.
  • N = 142 samples were used for comparison between Elecsys® TSH and Nichols 3rd Generation.
• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given the context of a 510(k) summary for a diagnostic assay, it is highly probable that these studies involved prospective collection of human serum and plasma samples according to standard clinical laboratory practices.

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

For an in vitro diagnostic (IVD) immunoassay like the Elecsys® TSH, the "ground truth" is typically established by the reference method (the predicate device, in this case, Enzymun-Test® TSH, and an additional comparator, Nichols 3rd Generation TSH assay) or by expert consensus on the clinical state of the patient using standard clinical diagnostic criteria for thyroid function, rather than by human interpretation of images by experts. Therefore, the concept of "experts" as in radiologists, for example, is not applicable in this context. The "ground truth" values for TSH concentration are derived directly from the laboratory measurements by the reference assays.

4. Adjudication Method for the Test Set

Not applicable for this type of IVD device. The "ground truth" is the quantitative measurement from the reference methods, not subjective interpretation requiring adjudication among human experts.

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 is an immunoassay for TSH, not an imaging device requiring human readers or AI assistance.

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

This device is a standalone algorithm/instrument system. The Elecsys® TSH Assay on the Elecsys® 2010 instrument performs the measurement and provides a quantitative TSH value without human interpretation in the loop impacting the result generation directly. The reported "Performance Characteristics" (precision, sensitivity, linearity, method comparison, interference, specificity) represent the standalone performance of the assay and instrument system.

7. The Type of Ground Truth Used

The ground truth used for establishing the performance of the Elecsys® TSH Assay was:

• Reference Method Comparison: TSH values obtained from samples analyzed by the predicate device (Enzymun-Test® TSH) and another established method (Nichols 3rd Generation TSH). These assays provide quantitative measurements that serve as the "true" or reference values for TSH concentration.
• Known Concentrations/Spiked Samples: For studies like linearity, sensitivity, and interfering substances, samples with known TSH concentrations or spiked with interfering substances would be used as the ground truth.
• Clinical Samples: Samples from patients with various TSH levels (e.g., hyperthyroid, euthyroid, hypothyroid) would be used for method comparison studies to ensure broad clinical utility.

8. The Sample Size for the Training Set

The document does not explicitly mention a "training set" in the context of machine learning. For an immunoassay, the "training" analogous to adjusting an algorithm would be the development and optimization of the assay reagents, protocols, and calibration procedures. The calibration curve for the Elecsys® TSH is generated by a 2-point calibration curve and a master curve provided via the reagent bar code. This essentially "calibrates" the system, allowing it to accurately quantitate unknown samples. The details of the samples used to establish the master curve are not provided but would typically involve highly characterized standard materials.

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

As discussed above, the concept of a training set as understood in AI/ML is not directly applicable. However, the "ground truth" for the development and calibration of the assay would be established through:

• WHO Standardization: The assay standardization is stated to be via the World Health Organization (WHO), indicating that the assay's measurements are traceable to international reference standards for TSH. These standards are rigorously characterized and assigned specific TSH values by expert international committees.
• Internal Validation and Reference Materials: Boehringer Mannheim would have used a series of internal reference materials and standards, carefully characterized for their TSH concentrations, during the assay development and for establishing the master curve. These internal standards would be assigned values based on comparisons to WHO international standards and/or highly accurate internal reference methods.

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