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COBAS INTEGRA Ceruloplasmin: Ceruloplasmin
Indications For Use:
COBAS INTEGRA:
In vitro test for the quantitative immunological determination of ceruloplasmin in human serum and plasma on COBAS INTEGRA systems.
Measurements of Ceruloplasmin aid in the diagnosis of copper metabolism disorders.
Roche/Hitachi cobas c systems:
In vitro test for the quantitative determination of ceruloplasmin in human serum and plasma on Roche/Hitachi cobas c systems.
Measurements of Ceruloplasmin aid in the diagnosis of copper metabolism disorders.

The COBAS INTEGRA Ceruloplasmin cassette (CERU) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA SYSTEMS for the quantitative immunological determination of human ceruloplasmin in serum and plasma. The calibrator and control were cleared via K954992.
Measurements of ceruloplasmin aid in the diagnosis of copper metabolism disorders.
The test principle is an immunoturbidimetric assay. The calibrator is Serumproteins T Standard and the recommended control material is the Serumproteins T Control.

Here's a breakdown of the acceptance criteria and study information for the COBAS INTEGRA Ceruloplasmin device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

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

The document does not explicitly state the sample sizes used for validating each performance characteristic (e.g., precision, linearity, interference studies, or method comparison). The data provenance is not specified regarding country of origin or an explicit retrospective/prospective design. However, the context of a 510(k) submission for a new in vitro diagnostic (IVD) device typically implies prospective testing conducted by the manufacturer, likely at their facilities.

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

Not applicable. This device is an in vitro diagnostic (IVD) assay for a quantitative biomarker (ceruloplasmin). The "ground truth" for such devices is established by analytical methods and comparison to a predicate device or reference material, not by expert interpretation of images or clinical cases.

4. Adjudication Method for the Test Set

Not applicable, as this is an IVD assay, not a device requiring human interpretation and adjudication of results. The method comparison refers to the statistical comparison of results from the new device against the predicate device.

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 in vitro diagnostic device, not an AI-assisted diagnostic tool that involves human readers interpreting cases.

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

Yes, this is an algorithm-only (standalone) performance. The device is a fully automated immunoturbidimetric assay system that quantitatively determines ceruloplasmin levels. There is no human intervention in the result generation process; the result is directly reported by the instrument.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

The ground truth for this device's performance is established through:

• Reference materials: The device "Standardized against IFCC/BCR/CAP reference preparation CRM 470 (RPPHS 91/0619) for 14 serum proteins." This reference material serves as a "ground truth" for calibrating the assay.
• Comparison to a legally marketed predicate device: The method comparison data shows results against the DakoCytomation Polyclonal Rabbit Anti-Human Ceruloplasmin (K812486), which serves as a clinical benchmark (or "ground truth" in terms of clinical performance equivalence).

8. The Sample Size for the Training Set

Not explicitly stated. For IVD devices, a "training set" in the context of machine learning is not directly applicable. The "training" here refers to the development and optimization of the reagent formulation and assay parameters. The document doesn't provide specific sample sizes for these development phases.

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

Not explicitly stated in the document. For IVD assays, the "ground truth" for development and optimization (analogous to training) would typically involve:

• Using known concentrations of ceruloplasmin (e.g., from purified human ceruloplasmin or spiked samples).
• Testing against established reference methods or highly characterized samples.
• Performing extensive analytical verification during the development phase to ensure the assay performs as intended across its measuring range and with various interference challenges.

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The cassette COBAS INTEGRA LDL Direct (LDL-D) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative determination of LDL-cholesterol direct concentration in serum and plasma. Low density lipoprotein cholesterol measurement, in conjunction with other lipid determinations, has been shown to be useful in assessing the risk of coronary heart disease.

The Roche Calibrator LDL Direct is intended for use as calibrator in quantitative Low Density Lipoprotein cholesterol assays. It is recommended for use with LDL Direct reagents on COBAS® chemistry systems. A calibrator is a device intended for medical purposes for use in a test system to establish points of reference that are used in the determination of values in the measurement of substances in human specimens.

The COBAS INTEGRA test applications contained in this submission are intended for use with the COBAS INTEGRA Analyzer, which is also known as the COBAS INTEGRA 700. The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents.

The cassette COBAS INTEGRA LDL Direct (LDL-D) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative determination of LDL-cholesterol direct concentration in serum and plasma.

The Roche Calibrator LDL Direct is intended for use as calibrator in quantitative Low Density Lipoprotein cholesterol assays. It is recommended for use with LDL Direct reagents on COBAS® chemistry systems.

Here's a breakdown of the acceptance criteria and study information for the Roche COBAS® INTEGRA LDL Direct and Roche Calibrator LDL Direct, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" as a separate, pre-defined set of thresholds. Instead, it presents performance characteristics of the new device and compares them to those of predicate devices to demonstrate substantial equivalence. The implication is that if the new device's performance aligns with or is comparable to the predicate devices, it meets the "acceptance criteria" for substantial equivalence.

Note: For accuracy, the new device is compared to COBAS MIRA, Beta-quantification, and Friedewald formula. The predicate device's accuracy is provided against Beta-quantification. The document implies that a strong correlation (e.g., r > 0.95) and a linear regression close to y=x would be acceptable for accuracy.

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

The document refers to "clinical and nonclinical studies."

• Test Set Sample Size for Accuracy:

  • Against COBAS MIRA: n = 276
  • Against Beta-quantification: n = 150
  • Against Friedewald formula: n = 276

• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective.

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

This type of information is not provided in the document. For an in vitro diagnostic device like this, ground truth is typically established through reference methods or established laboratory procedures, not by human experts in the way it would be for an imaging AI.

4. Adjudication Method for the Test Set

This information is not applicable and therefore not provided. Adjudication methods (like 2+1, 3+1) are common in clinical trials involving subjective interpretations (e.g., imaging reads) to resolve discrepancies. For a quantitative diagnostic test like LDL-cholesterol, discrepancies would typically be resolved by retesting, using a definitive reference method, or investigating pre-analytical/analytical errors.

5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Readers Improvement with AI vs. Without AI Assistance

This information is not applicable and therefore not provided. MRMC studies are relevant for imaging devices or AI tools where human readers are interpreting data, and the AI's role is to assist or augment their performance. The Roche COBAS INTEGRA LDL Direct is a laboratory diagnostic assay, not one that involves human interpretation of "cases" in an MRMC context.

6. If a Standalone Study (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, this is essentially a standalone study. The document describes the performance of the COBAS INTEGRA LDL Direct system itself (the reagent cassette + analyzer) in measuring LDL-cholesterol directly. There isn't a human-in-the-loop component described for the function of this diagnostic device.

7. The Type of Ground Truth Used

The ground truth for the accuracy studies was established by comparing the COBAS INTEGRA LDL Direct results against:

• COBAS MIRA: Another automated chemistry analyzer, likely acting as a comparative reference method.
• Beta-quantification: A established reference method for lipoprotein analysis, considered highly accurate for LDL-cholesterol.
• Friedewald formula: A calculated estimate of LDL-cholesterol based on other lipid measurements (total cholesterol, HDL-cholesterol, triglycerides).

8. The Sample Size for the Training Set

The document does not mention a "training set". This is an in vitro diagnostic device, not an AI/machine learning algorithm in the typical sense that would require a distinct training set for model development. The development process for an IVD involves formulation, optimization, and verification, rather than "training" with a dataset for an algorithm.

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

Since there is no "training set" mentioned or implied for this type of device, this information is not applicable.

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The cassette COBAS INTEGRA x-1-Antitrypsin (AAT) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative immunological determination of human x-1-antitrypsin in serum and plasma. The measurements aid in the diagnosis of several conditions including juvenile and adult cirrhosis of the liver. In addition, a-1-antitrypsin deficiency has been associated with pulmonary emphysema.

The cassette COBAS INTEGRA Immunoglobulin A (IGA/IGAP) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative immunological determination of human immunoglobulin A in serum and plasma. addition to the standard application (IGA), the sensitive application (IGAP) is designed for the quantitative determination of low IgA concentrations in e.g. pediatric samples. Measurement of this immunoglobulin aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

The cassette COBAS INTEGRA Immunoglobulin M (IGM/IGMP) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative immunological determination of human immunoglobulin M in serum and plasma. In addition to the standard application (IGM), the sensitive application (IGMP) is designed for the quantitative determination of low IgM concentrations in e.g. pediatric samples. Measurement of this immunoglobulin aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

The cassette COBAS INTEGRA Immunoglobulin G (Turbidimetric) (IGGT/IGGTC) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA 700 for the quantitative immunological determination of human immunoglobulin G in serum, plasma (IGGT) and cerebrospinal fluid (IGGTC). Measurement of this immunoglobulin aids in the diagnosis of abnormal protein metabolism and the body's lack of ability to resist infectious agents.

The COBAS INTEGRA test applications contained in this submission are intended for use with the COBAS INTEGRA Analyzer, which is also known as the COBAS INTEGRA 700. The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents.

Here's a breakdown of the acceptance criteria and study information for the Roche COBAS® INTEGRA Reagent Cassettes for α-1-Antitrypsin (AAT), Immunoglobulin A (IGA/IGAP), and Immunoglobulin M (IGM/IGMP), based on the provided text:

Important Note: The provided document is a 510(k) Summary. This type of summary focuses on demonstrating substantial equivalence to a legally marketed predicate device, rather than proving the device meets specific pre-defined acceptance criteria in the same way a novel device might. The "acceptance criteria" here are inferred from the performance characteristics presented to show equivalence. The studies are primarily comparative studies against predicate devices.

1. Table of Acceptance Criteria and Reported Device Performance

Device: Roche COBAS® INTEGRA Reagent Cassettes (AAT, IGA/IGAP, IGM/IGMP)

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

• α-1-Antitrypsin (AAT):
  • Sample Size: 288
  • Data Provenance: Not explicitly stated but implied to be clinical samples (serum/plasma). Origin (e.g., country) and retrospective/prospective nature are not specified.
• Immunoglobulin A (IGA/IGAP):
  • Sample Size: 584
  • Data Provenance: Not explicitly stated but implied to be clinical samples (serum/plasma). Origin (e.g., country) and retrospective/prospective nature are not specified.
• Immunoglobulin M (IGM/IGMP):
  • Sample Size: 556
  • Data Provenance: Not explicitly stated but implied to be clinical samples (serum/plasma). Origin (e.g., country) and retrospective/prospective nature are not specified.

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

Not applicable. This device is an in vitro diagnostic reagent, and the 'ground truth' is established by comparative measurements against predicate devices using laboratory methods, not human expert interpretation of images or clinical cases. The comparison is against established laboratory testing methods.

4. Adjudication Method for the Test Set

Not applicable. The 'test set' here consists of biological samples measured by the device and compared to results from predicate devices/methods. There is no human adjudication process described.

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

No. MRMC studies are typically for imaging devices or AI tools that assist human readers in interpretation. This is an IVD reagent, and the effectiveness is evaluated through analytical performance characteristics like accuracy, precision, and linearity when compared to established methods.

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

Yes, in a sense. The studies summarized are standalone performance evaluations of the reagent cassette on the COBAS INTEGRA Analyzer. The results are generated by the automated system, without "human-in-the-loop" needing to interpret the primary measurement, although human operators load samples and review results. The comparison is between the modified reagent's performance and that of other established laboratory methods (predicate devices).

7. The Type of Ground Truth Used

The ground truth used for these studies is comparative measurement data from legally marketed predicate devices and established laboratory methods. Specifically:

• AAT: Comparison against Boehringer Mannheim α-1-Antitrypsin Reagent (K972640) and Cleared COBAS INTEGRA α-1-Antitrypsin (K954992). The "vs. BM" implies using the Boehringer Mannheim method as a reference.
• IGA/IGAP: Comparison against Boehringer Mannheim Immunoglobulin A Reagent (K955907) and Cleared COBAS INTEGRA Immunoglobulin A (K954457). The "vs. BM/Hitachi" indicates comparison with these laboratory systems.
• IGM/IGMP: Comparison against Boehringer Mannheim Immunoglobulin M Reagent (K955908) and Cleared COBAS INTEGRA Immunoglobulin M (K954457). The "vs. BM/Hitachi" indicates comparison with these laboratory systems.

8. The Sample Size for the Training Set

Not applicable. These are reagent cassettes used with an existing analyzer. There is no mention of machine learning or AI models with "training sets" in the context of this 510(k) submission. The development and optimization of the reagent formulations and assay parameters would be part of a different internal R&D process, not typically described as a "training set" in this context.

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

Not applicable, as there is no "training set" in the context of this device and submission. The "ground truth" for evaluating the performance of these reagents is established through established analytical chemistry and immunology principles, validated against reference materials, and benchmarked against predicate diagnostic assays.

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The cassette COBAS INTEGRA Alkaline Phosphatase IFCC liquid (ALPL2 and ALPL6) contain an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of alkaline phosphatase in serum and plasma. Measurements of alkaline phosphatase or its isoenzymes are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

The cassette COBAS INTEGRA a-Amylase EPS Pancreatic (AMY-P / AMYUP) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of pancreatic or-amylase in serum, plasma, and urine. Amylase measurements are used primarily for the diagnosis and treatment of pancreatitis (inflammation of the pancreas).

The cassette COBAS INTEGRA C-reactive Protein (Latex), (CRPLX) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative immunological determination of human C-reactive protein in serum and plasma. Measurements of C-reactive protein aids in evaluation of the amount of injury to tissue.

The COBAS INTEGRA test applications contained in this submission are intended for use with the COBAS INTEGRA Analyzer, which is also known as the COBAS INTEGRA 700. The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents. Through this submission, it is the intention of Roche to gain clearance for three additional COBAS Reagent Cassettes. These are the COBAS INTEGRA Alkaline Phosphatase IFCC liquid (ALPL2 and ALPL6), the COBAS INTEGRA a-Amylase EPS Pancreatic (AMY-P / AMYUP), and the COBAS INTEGRA C-Reactive Protein (Latex), (CRPLX).

The provided text is a 510(k) Summary for Roche COBAS® INTEGRA Reagent Cassettes, detailing the characteristics and performance of three new reagent cassettes (Alkaline Phosphatase IFCC liquid, α-Amylase EPS Pancreatic, and C-Reactive Protein (Latex)) compared to their legally marketed predicate devices.

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

1. Table of Acceptance Criteria and Reported Device Performance

The documents do not explicitly state "acceptance criteria" as a set of predefined thresholds that the device must meet in the same way modern AI/ML device submissions would. Instead, the "Performance Characteristics" section for each proposed device is presented alongside the performance of its predicate device, implying that equivalence in these characteristics is the underlying acceptance criterion for substantial equivalence.

Since specific acceptance criteria are not called out, I will present the reported performance characteristics for the new devices. The implicit acceptance criterion is "comparable performance to the predicate device."

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

The "test set" in this context refers to the clinical samples used to evaluate the performance characteristics (precision and accuracy) of the new reagent cassettes.

• COBAS INTEGRA Alkaline Phosphatase IFCC liquid (ALPL2 and ALPL6):

  • Accuracy Sample Size (n): 252
  • Data Provenance: Not specified, but generally for in vitro diagnostic (IVD) devices, these studies use patient samples collected in a clinical laboratory setting. The origin (country) and retrospective/prospective nature are not detailed in this summary.

• COBAS INTEGRA α-Amylase EPS Pancreatic (AMY-P / AMYUP):

  • Accuracy Sample Size (n):
    • Serum: 246
    • Urine: 106
  • Data Provenance: Not specified, same general assumptions as above.

• COBAS INTEGRA C-Reactive Protein (Latex) (CRPLX):

  • Accuracy Sample Size (n): 244
  • Data Provenance: Not specified, same general assumptions as above.

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

This information is not provided in the document. For IVD devices like these, "ground truth" for method comparisons is typically established by running the same samples on a legally marketed predicate device or a highly accurate reference method. It does not involve human expert consensus in the way image-based diagnostics might.

4. Adjudication Method for the Test Set

This is not applicable and therefore not provided. Adjudication methods like 2+1 or 3+1 are used in studies where human readers interpret data, and their disagreements need to be resolved. For quantitative chemical assays, the measurement itself is the "reader," and comparison is made to another assay.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, and the effect size of how much human readers improve with AI vs without AI assistance

This is not applicable as the device is an in-vitro diagnostic reagent cassette for automated analyzers, not an AI or imaging device involving human readers.

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

Yes, the performance data presented (assay range, sensitivity, precision, accuracy) represent the standalone performance of the reagent cassettes on the COBAS INTEGRA Analyzer. There is no human-in-the-loop component being evaluated for the measurement itself, only for the instrument's operation and result interpretation by laboratory personnel.

7. The Type of Ground Truth Used

For these types of in vitro diagnostic assays, the "ground truth" for the accuracy studies is implicitly established by comparing the results from the new device to those obtained from the legally marketed predicate device (or a recognized reference method). The correlation coefficients and linear regression data are direct comparisons to the predicate. For example, the accuracy section "Corr. Coefficient (r)" and "Linear regression" are direct comparisons between the proposed device and the cleared predicate device.

8. The Sample Size for the Training Set

This information is not provided and is likely not applicable in the same way it would be for an AI/ML device. For chemical reagents, "training" typically refers to the R&D and optimization phase to develop the reagent formulation and instrument application. It's not a discrete "training set" of patient data used to optimize an algorithm parameters that are then locked.

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

Similar to point 8, this is not provided and likely not applicable in the context of an AI/ML device. The "ground truth" during reagent development would involve analytical methods to confirm the chemical properties and performance of the reagents.

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The cassette COBAS INTEGRA Serum Barbiturates contains an in vitro diagnostic reagent system intended for use on the COBAS INTEGRA analyzer for the detection of barbiturates and their metabolites in human serum or heparinized plasma. This reagent system is intended for use in toxicological screenings where the analytical result is used in the management of barbiturate use or overdose.

The Abuscreen ONLINE Serum Barbiturates Calibrators are designed for calibration of the cassette COBAS INTEGRA Serum Barbiturates on the COBAS INTEGRA chemistry systems. The calibrators are used in the determination of values in the measurement of barbiturates in human specimens.

The cassette COBAS INTEGRA Serum Benzodiazepines contains an in vitro diagnostic reagent system intended for use on the COBAS INTEGRA analyzer for the detection of benzodiazepines and their metabolites in human serum or heparinized plasma. This reagent system is intended for use in toxicological screenings where the analytical result is used in the management of benzodiazepine use or overdose.

The Abuscreen ONLINE Serum Benzodiazepines Calibrators are designed for calibration of the cassette COBAS INTEGRA Serum Benzodiazepines on the COBAS INTEGRA chemistry systems. The calibrators are used in the determination of values in the measurement of benzodiazepines in human specimens.

The COBAS INTEGRA test applications contained in this submission are intended for use with the COBAS INTEGRA Analyzer, which is also known as the COBAS INTEGRA 700. The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents. Through this submission, it is the intention of Roche to gain clearance for two additional COBAS Reagent Cassettes and their associated calibrator sets. These are: the COBAS INTEGRA Serum Barbiturates (SBARB) Reagent Cassette, the Abuscreen ONLINE Serum Barbiturates Calibrators, the COBAS INTEGRA Serum Benzodiazepines (SBENZ) Reagent Cassette, and the Abuscreen ONLINE Serum Benzodiazepines Calibrators.

Here's an analysis of the acceptance criteria and study information for the Roche COBAS® INTEGRA Reagent Cassettes and Calibrators, based on the provided text:

Important Note: The provided document is a 510(k) Summary for a medical device cleared in 1998. It focuses on demonstrating substantial equivalence to predicate devices rather than establishing novel safety and effectiveness through a standalone, comprehensive clinical trial with pre-defined acceptance criteria in the way a new, high-risk device might today. The "acceptance criteria" detailed below are derived from the performance characteristics presented for comparison with the predicate device. The study is primarily a comparative effectiveness study against the predicate, alongside internal analytical validation.

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a pass/fail format with specific targets that the device must meet in a prospective study. Instead, it presents performance characteristics of the new device alongside those of its predicate for comparison, implying that the new device's performance should be comparable or substantially equivalent to the predicate. The "reported device performance" refers to the values presented for the COBAS INTEGRA system.

A. COBAS INTEGRA Serum Barbiturates (SBARB)

B. COBAS INTEGRA Serum Benzodiazepines (SBENZ)

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

• COBAS INTEGRA Serum Barbiturates (SBARB):

  • Accuracy (compared to GC/MS): 47 samples (37 positive, 10 negative)
  • Accuracy (compared to Predicate ADX): 47 samples (35 positive, 12 negative)
  • Precision: Not explicitly stated, but typically involves multiple replicates across several runs for each level tested. Given the three levels and %CV calculation, a common practice would be 20 replicates for 2-3 levels over 2-3 days, resulting in at least 40-60 measurements per level. The exact number of individual patient samples used to derive these mean and CV values is not specified, but these are typically control or spiked samples.
  • Data Provenance: Not explicitly stated (e.g., country of origin). The studies appear to be retrospective analytical performance evaluations conducted by the manufacturer as part of the submission to demonstrate equivalence.

• COBAS INTEGRA Serum Benzodiazepines (SBENZ):

  • Accuracy (compared to GC/MS): 74 samples (46 positive, 28 negative)
  • Accuracy (compared to Predicate TDX): 66 samples (46 positive, 20 negative)
  • Precision: Similar to SBARB, not explicitly stated, but common practice would imply multiple replicates for each of the three levels tested.
  • Data Provenance: Not explicitly stated. Likely retrospective analytical performance evaluation.

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

• For both assays (Barbiturates and Benzodiazepines), the ground truth for accuracy was established using GC/MS (Gas Chromatography/Mass Spectrometry). GC/MS is considered a "gold standard" analytical method for drug confirmation and quantification in toxicology.
• The document does not specify the number of human experts involved in interpreting the GC/MS results or their qualifications. The interpretation of GC/MS data is typically performed by trained laboratory personnel (e.g., analytical chemists, toxicologists) within a certified laboratory environment.

4. Adjudication Method for the Test Set

• For the accuracy studies using GC/MS as the ground truth, there is no mention of an adjudication method in the traditional sense (e.g., 2+1 physician review). The GC/MS result itself serves as the definitive determination. Discrepancies between the device and GC/MS would be investigated analytically rather than through expert consensus on the clinical classification.

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

• No, an MRMC comparative effectiveness study was not done. This submission concerns in vitro diagnostic (IVD) reagent assays, which are standalone laboratory tests, not imaging devices or AI-assisted diagnostic tools that involve human readers. Therefore, the concept of "human readers improving with AI assistance" is not applicable here.

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

• Yes, this entire submission effectively represents a standalone performance evaluation. The COBAS INTEGRA system, with these reagent cassettes, performs automated analysis. Its performance characteristics (precision, accuracy, sensitivity, assay range, cutoff) are measured directly based on the analytical results produced by the instrument and reagents, without immediate human intervention in the result generation itself. Human interaction would occur in sample loading, result review, and clinical interpretation.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

• The primary ground truth for the accuracy claims was:
  • GC/MS (Gas Chromatography/Mass Spectrometry): This is a highly specific and sensitive analytical method for confirming and quantifying drugs, serving as the gold standard in toxicology for this type of test.

8. The Sample Size for the Training Set

• The document does not specify the sample size for a training set. For IVD assays based on established chemical principles (like fluorescence polarization immunoassay), there isn't a "training set" in the same way there would be for a machine learning or AI algorithm. The assay's parameters (e.g., antibody concentrations, reaction times, calibration curves) are developed and optimized by the manufacturer using internal R&D processes, but these are not explicitly detailed as a "training set" in the context of this 510(k) summary. The performance data presented are for the final, developed product.

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

• As a "training set" is not explicitly mentioned or applicable in the AI/machine learning sense for this device, the question of how its ground truth was established is not directly answerable from the provided text. The development and optimization of such assays rely on well-characterized samples (e.g., spiked samples, confirmed positive/negative clinical samples, reference materials) to establish robust analytical performance, but these are part of the R&D process rather than a formalized "training set" with ground truth in the context of this regulatory submission.

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The cassette COBAS INTEGRA Acid / Prostatic Phosphatase contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of total and prostatic acid phosphatase in serum.

The cassette Roche COBAS INTEGRA Benzodiazepines contains an in vitro diagnostic reagent system intended for use on the COBAS INTEGRA for the semi-quantitative detection of benzodiazepines in human urine using the enzyme ß-glucuronidase.

The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents.

The provided text describes two in vitro diagnostic reagent systems: COBAS INTEGRA Acid/Prostatic Phosphatase (ACPP) and COBAS INTEGRA Benzodiazepines with β-glucuronidase (BNZGL). The 510(k) summary focuses on demonstrating their substantial equivalence to previously marketed devices rather than establishing novel acceptance criteria or performing a comparative effectiveness study in the typical sense of AI/human reader studies.

Here's an analysis of the provided information against your requested categories, acknowledging that some categories may not be directly applicable to this type of device and submission:

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

The document presents performance characteristics for the new devices and compares them to their predicate devices, implying these are the "acceptance criteria" for demonstrating substantial equivalence. Exact numerical acceptance criteria (e.g., "CV must be 95% confidence | 5.0 ng/mL of nordiazepam at > 95% confidence |
| Accuracy: Positive Samples (INTEGRA vs GC/MS) | 50 (INTEGRA +)/50 (GC/MS +) ; 0 (INTEGRA -)/0 (GC/MS -) from table | 50 (INTEGRA +)/50 (GC/MS +) ; 0 (INTEGRA -)/0 (GC/MS -) from table; i.e., 100% agreement when positive |

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

• ACPP Accuracy Test Set:
  • Total Acid Phosphatase: n = 260 samples.
  • Prostatic Acid Phosphatase: n = 264 samples.
  • Data Provenance: Not explicitly stated (e.g., country of origin). The studies appear to be retrospective comparisons to predicate devices' performance claims.
• BNZGL Accuracy Test Set:
  • Positive Samples: n = 50 samples for INTEGRABNZGL vs GC/MS comparison.
  • The table indicates accuracy for positive samples where both INTEGRA with and without β-glucuronidase, and GC/MS all show 50 positive samples and 0 negative samples. This implies 50 positive samples were tested, and perhaps an additional number of negative samples that are not detailed in this specific comparison row, but rather in "overall agreement" data that is not fully presented.
  • Data Provenance: Not explicitly stated (e.g., country of origin). Appears to be retrospective.

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

This information is not provided in the document. For in vitro diagnostic devices, ground truth for quantitative measurements (like acid phosphatase levels) typically comes from reference methods or established laboratory procedures, not from human experts adjudicating images or other subjective interpretations. For benzodiazepine detection, GC/MS is treated as the reference ground truth, which is an analytical method.

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

Not Applicable for these types of in vitro diagnostic tests, which rely on quantitative measurements compared to reference methods (e.g., GC/MS) or predicate biochemical assays. There is no human adjudication process described.

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 document describes in vitro diagnostic assays, not AI-powered medical image analysis tools or other devices that involve human readers/interpreters. Therefore, no MRMC study or AI assistance effect size is discussed.

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

This refers to the performance of the device without human intervention. In the context of these IVD devices, the stated performance characteristics (e.g., precision, accuracy, sensitivity, assay range) are the standalone performance of the reagent system on the COBAS INTEGRA Analyzer. There is no human-in-the-loop component for the analytical part of these tests.

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

• COBAS INTEGRA Acid/Prostatic Phosphatase:
  • Ground truth for accuracy was established by comparison to the predicate device, "Roche Reagent for Acid Phosphatase" (K831834). This is a method comparison study where the predicate acts as the reference or "ground truth."
• COBAS INTEGRA Benzodiazepines with β-glucuronidase:
  • Ground truth for accuracy was established by comparison to Gas Chromatography/Mass Spectrometry (GC/MS) (as indicated in the "Accuracy Positive Samples" table for the predicate device, which is then compared for the new device). GC/MS is a widely accepted confirmatory method for drug detection and serves as the gold standard ground truth in this context.

8. The sample size for the training set

The document does not explicitly identify or specify a "training set" in the context of machine learning. For these diagnostic assays, the development and optimization of the reagent formulation and instrument parameters are analogous to "training" in a broader sense, but there's no data given for this phase. The presented performance data are from validation/verification studies, which would be considered test sets.

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

As there is no explicitly defined "training set" in the machine learning sense, this question is not applicable. The ground truth for the performance evaluations (test sets) is described in point 7.

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The cassette COBAS INTEGRA HDL - Cholesterol Direct (HDL-D) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of HDL - cholesterol direct concentration in serum and plasma.

The COBAS INTEGRA HDL-D reagent cassette is intended for use with the COBAS INTEGRA Analyzer. The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8°C. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents.

The COBAS INTEGRA HDL-D reagent cassette is an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of High Density Lipoprotein cholesterol direct (HDL-D) in serum and plasma.

The principle of the COBAS INTEGRA HDL-D reagent cassette is based on the absorption of synthetic polyanions to the surface of lipoproteins. LDL, VLDL, and chylomicrons are transformed into a detergent-resistant form. whereas HDL is not. Combined action of polyanions and detergent solubilizes cholesterol from HDL, but not from LDL, VLDL, and chylomicrons. Solubilized cholesterol is oxidized by the sequential enzymatic action of cholesterol esterase and cholesterol oxidase. The hydrogen peroxide produced in this reaction is reacted with chromogens to form a colored dye. The increase in absorbance at 552 nm is directly proportional to the HDL cholesterol concentration of the sample.

Here's an analysis of the acceptance criteria and study as presented in the provided text for the Roche COBAS INTEGRA® HDL-D Reagent Cassette:

1. Table of Acceptance Criteria and Reported Device Performance

The document compares the new device (COBAS INTEGRA HDL-D reagent cassette) to a predicate device (COBAS INTEGRA HDL reagent system) rather than explicitly stating acceptance criteria a priori. However, the performance characteristics of the new device serve as its reported performance, and by demonstrating substantial equivalence to the predicate, it implicitly meets the established performance expectations for such devices.

Note: The document presents the performance of both the "new device" (COBAS INTEGRA HDL-D reagent cassette) and the "predicate device" (COBAS INTEGRA HDL reagent system) side-by-side. The acceptance criteria for the new device are implied to be achieving comparable performance to the predicate, demonstrating substantial equivalence. The table above uses the predicate's performance as the benchmark for "acceptance criteria."

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

• Sample Size for Accuracy: 258 clinical samples were used for the accuracy study of the COBAS INTEGRA HDL-D reagent cassette.
• Data Provenance: The document does not explicitly state the country of origin or whether the data was retrospective or prospective. Given the nature of medical device submissions, it would typically be prospective clinical data collected under controlled conditions.

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

The document describes an assay for quantitative determination of HDL-Cholesterol Direct. The "ground truth" in this context refers to the true concentration of HDL cholesterol in the samples.

• Experts: Not applicable in the traditional sense for establishing ground truth for a quantitative assay. The ground truth for such assays is established through a reference method or a predicate device that has already been validated and accepted. The predicate device (COBAS INTEGRA HDL reagent system) served as the comparator for accuracy.
• Qualifications of Experts: Not relevant here as ground truth is determined by chemical analysis or comparative measurement, not expert opinion.

4. Adjudication Method for the Test Set

Not applicable. Adjudication is typically used when human interpretation or subjective assessment is part of the ground truth determination (e.g., in imaging studies). For a quantitative chemical assay, the comparison is directly between the result of the new device and the result of the reference/predicate method.

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

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted. MRMC studies are typically used for imaging or diagnostic tools where human readers interpret results, and the study aims to assess the impact of AI assistance on human performance. This submission is for a quantitative in vitro diagnostic reagent, which does not involve human interpretation in the same manner.

6. Standalone (Algorithm Only) Performance Study

Yes, a standalone performance study was conducted. The accuracy, precision, and sensitivity results presented in Table 2 for the COBAS INTEGRA HDL-D reagent cassette represent its standalone performance without human-in-the-loop assistance. The device directly measures HDL-D concentration.

7. Type of Ground Truth Used

The ground truth used for performance evaluation, particularly for accuracy, was based on comparison to a legally marketed predicate device (COBAS INTEGRA HDL reagent system). This predicate device itself quantifies HDL cholesterol using an enzymatic, colorimetric method. In essence, the new device's measurements were compared against the established measurements from the predicate device to show agreement.

8. Sample Size for the Training Set

The document does not provide information regarding a separate training set. For in vitro diagnostic reagents like this, the development process typically involves internal method development and optimization, but the specific term "training set" (common in AI/ML contexts) is not used, nor is a sample size provided for such a set. The presented data appears to be for verification and validation of the final product.

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

As no training set information is provided, there is no information on how ground truth for a training set (if one existed during development) was established. For chemical assays, the development process would involve optimizing reagents and reaction conditions against known standards or reference methods to ensure accurate measurement across a range of concentrations.

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COBAS INTEGRA Ammonia (NH3): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the ammonia concentration in plasma (test NH3, 0-045).

COBAS INTEGRA aAmylase EPS (AMYLL): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of amylase in serum, plasma (test AMY-L, 0998) and urine (test AMY-UL 0-999).

COBAS INTEGRA Cholesterol (CHOLL): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of total cholesterol (test CHOLL, 0-001) and HDL cholesterol concentration in serum and plasma in clinical laboratories.

COBAS INTEGRA HDL Cholesterol Application (HDLL): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of total cholesterol and HDL - cholesterol (test HDLL, 0-002) concentration in serum and plasma in clinical laboratories.

COBAS INTEGRA Creatinine Enzymatic (CREAE): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the creatinine concentration in serum (test CREAE, 0-014), and urine (test CREEU, 0-114).

COBAS INTEGRA Digitoxin (DIGIT): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of digitoxin in serum or heparinized plasma (test DIGIT 0-259).

COBAS INTEGRA Gamma Glutamyltransferase (GGTL): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of GGT, (EC 2.3.2.2; y-glutamyl peptide: amino acid y-glutamyltransferase) in serum and plasma (test GGTL, 0-599).

COBAS INTEGRA Glucose HK Liquid (GLUCL): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the glucose concentration in serum, plasma (test GLUL, 0-991), urine (test GLULU, 0-992), and cerebrospinal fluid (test GLULC, 0-993).

COBAS INTEGRA Lipase (LIPL): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of lipase in serum and plasma (test LIPL, 0-200).

COBAS INTEGRA Lysergic acid diethylamide (LSD) contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the qualitative determination of lysergic acid diethylamide (LSD) in urine (test LSD, 0-001)

COBAS INTEGRA Urea/BUN (UREAL): contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the urea/BUN (blood urea nitrogen), in serum, plasma (test UREL, 0-003) and urine (test URELU, 0-004).

Roche TDM OnLine Digitoxin Calibrators: are intended for use with the Roche reagents for Digitoxin and the COBAS Chemistry systems for the quantitative determination of digitoxin in serum and plasma.

Roche TDM OnLine Digitoxin Controls: are quality control samples intended for use on COBAS chemistry systems with Roche reagents and calibrators for the quantitative determination of digitoxin assays.

The COBAS INTEGRA test applications contained in this submission are intended for use with the COBAS INTEGRA Analyzer. The COBAS INTEGRA Analyzer and COBAS INTEGRA Reagent cassettes together provide an integrated system for in vitro diagnostic testing. The COBAS INTEGRA Analyzer utilizes three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The analyzer has a throughput of up to 600 tests per hour with STAT samples prioritized and tested immediately. Random sample access, robotics and a user interface optimize time management and streamline workflow. The COBAS INTEGRA can store up to 68 COBAS INTEGRA Reagent Cassettes on board, 24 hours a day at 2-8℃. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free with the added convenience of long term on-board stability. Barcode readers are used to identify newly loaded reagent cassettes, samples for patient identification, and rack inserts and to read calibration and control data from the cassette label. COBAS INTEGRA tests include chemistry, drugs of abuse, immunology, ion selective electrodes, therapeutic drug monitoring, and hematology reagents. Through this submission, it is the intention of Roche Diagnostic Systems to gain clearance for an additional 4 COBAS INTEGRA Reagent Cassettes and 2 ancillary reagents as well as modifications to 7 previously cleared COBAS INTEGRA Reagent Cassettes. These reagents have been modified from granulate to liquid form.

The provided 510(k) summary (K972250) describes the acceptance criteria and study results for several Roche COBAS INTEGRA Reagent Cassettes and ancillary reagents. The studies are primarily focused on demonstrating substantial equivalence to predicate devices, rather than establishing de novo performance criteria against a fixed clinical standard. Consequently, the "acceptance criteria" are implied by the results of the comparative studies to be within acceptable analytical performance limits for equivalent devices.

Here's a breakdown of the requested information for each reagent, based on the provided text:

Roche COBAS® INTEGRA Reagent Cassettes & Ancillary Reagents (K972250)

The acceptance criteria are generally implied by the strong correlation and similar performance characteristics (assay range, precision, sensitivity, accuracy/linearity) when compared to the legally marketed predicate devices. The study's goal was to demonstrate substantial equivalence, meaning the new device performs comparably to the predicate.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for these in vitro diagnostic devices are demonstrated through a comparison of their performance characteristics (Assay Range, Precision, Sensitivity, Accuracy/Correlation Coefficient, and Linear Regression) against legally marketed predicate devices. The "reported device performance" is the performance of the COBAS INTEGRA (Liquid) reagents. The "acceptance criteria" are implied to be within comparable ranges to the predicate devices, indicating substantial equivalence.

Note: For each test, the predicate device's performance is presented alongside the new device's performance, and the linear regression typically shows correlation against the predicate. This comparative approach is the core of the acceptance criteria.

Ammonia (NH3)

Creatinine (CREAE) - Serum and Plasma

Creatinine (CREAE) - Urine

Digitoxin (DIGIT)

Lysergic acid diethylamide (LSD)

Note: For LSD, precision is presented in Optical Density (O.D.) for the new device vs. ng/mL for the predicate, making direct comparison of mean values challenging. However, the %CV for within-run are similar.

α-Amylase (AMYLL) - Serum and Plasma

α-Amylase (AMYLL) - Urine

Cholesterol (CHOLL)

HDL-Cholesterol Application (HDLL)

Note: There seems to be a typo for %CV (within run) in Level 1 of the HDLL liquid reagent (1.51.3).

Gamma-Glutamyltransferase (GGTL)

Glucose (GLUCL) - Serum and Plasma

Glucose (GLUCL) - Urine

Glucose (GLUCL) - CSF

Lipase (LIPL)

Urea/BUN (UREAL) - Serum and Plasma

Urea/BUN (UREAL) - Urine

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

The sample sizes for accuracy/correlation studies are provided in the tables above under "Sample size (n)". These values range from 114 to 240 for quantitative assays and 39 (positive) for LSD.

The data provenance is not explicitly stated as "country of origin" or "retrospective/prospective." However, given the context of a 510(k) submission for in vitro diagnostic reagents by Roche Diagnostic Systems, Inc. (located in Somerville, New Jersey, USA), it is highly likely these studies were conducted in a clinical laboratory setting in the USA. The studies are presented as direct comparisons between the new liquid reagents and existing granulate reagents or other legally marketed devices, implying they are prospective comparative studies assessing analytical performance.

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

For these chemical assays (e.g., ammonia, creatinine, cholesterol) and therapeutic drug monitoring (digitoxin), "ground truth" is typically established by the quantitative results of the predicate device or a reference method. The document does not mention "experts" in the sense of human readers adjudicating results, as these are quantitative in vitro diagnostic tests. The ground truth is the measured concentration or activity of the analyte as determined by the accepted reference method or predicate device functionality.

For LSD, which involves qualitative detection, the "ground truth" against which the COBAS INTEGRA LSD was compared appears to be GC/MS (Gas Chromatography/Mass Spectrometry), which is a gold standard analytical method for drug detection. The document does not specify the qualifications of individuals performing these GC/MS analyses or interpreting the results, but they would be trained laboratory personnel.

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

No adjudication method is mentioned. For these types of quantitative and qualitative analytical tests, "adjudication" by experts in the context of diagnostic imaging or pathology interpretation is not applicable. The comparison is based on numerical results compared to an established method or predicate.

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

No MRMC study was conducted. This type of study is relevant for medical imaging or pathology devices where human interpretation is a key component, often assisted by AI. The submitted devices are reagents for automated clinical analyzers, where the output is a numerical value or a qualitative positive/negative result, not an image requiring human interpretation. Therefore, there's no mention of AI assistance or human reader improvement.

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

Yes, the studies presented are effectively standalone performance evaluations of the reagent-analyzer system. These are not "algorithm-only" studies in the modern AI sense, but rather a direct assessment of the analytical performance of the new liquid reagent format on the COBAS INTEGRA Analyzer. The results (e.g., assay range, precision, accuracy) reflect the performance of the integrated system without direct human-in-the-loop interpretation impacting the primary measurement.

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

The type of ground truth used varies slightly based on the assay, but generally involves:

• Quantitative Assays (Ammonia, Creatinine, Cholesterol, HDL-Cholesterol, GGT, Glucose, Lipase, Urea/BUN): The ground truth for these assays is the quantitative result obtained from the predicate device method. The accuracy is assessed by correlating the results of the new liquid reagents with the predicate (often the granulate version of the same Roche COBAS INTEGRA reagents or another established method like Abbott TDx/TDxFLx for Digitoxin). Linear regression analysis is used to demonstrate agreement.
• Qualitative Assay (LSD): The ground truth for LSD detection is established by a more definitive analytical method, specifically Gas Chromatography/Mass Spectrometry (GC/MS).

8. The sample size for the training set

The document does not explicitly delineate a "training set" in the context of machine learning or AI development. For these chemical assays, the development of the reagents and their formulation would involve extensive R&D and optimization, which could be considered an iterative development process, but it's not described as a distinct "training set" with separate ground truth establishment. The data presented in the tables are for validation or verification of the final product.

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

As there is no explicitly defined "training set" in the submitted documentation related to AI/ML, there is no description of how ground truth for such a set was established. The development of reagents relies on established chemical and biochemical principles, and performance characteristics are determined through standard analytical validation procedures using reference materials and comparative studies against predicate methods.

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COBAS INTEGRA Gamma- Glutamyltransferase - IFCC: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of GGT, (EC 2.3.2.2, y-glutamyl peptide: amino acid y-glutamyltransferase) in serum and plasma (test GGTI, 0-562).

COBAS INTEGRA Lactate Dehydrogenase - IFCC: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the catalytic activity of LDH (EC 1.1.1.27; L-lactate: NAD oxidoreductase ) in serum and plasma (test LDHI, 0-181).

COBAS INTEGRA Total Protein - urine and CSF: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the total protein concentration in urine and cerebrospinal fluid (tests TPU, 0-123 and TPC, 0-223).

COBAS INTEGRA Lactate: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the lactate concentration in plasma and cerebrospinal fluid (tests LACT, 0-22 and LACTC, 0-122).

COBAS INTEGRA Tobramycin: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of tobramycin in serum or heparinized plasma (test TOBR, 0-92).

COBAS INTEGRA Immunoglobulin A: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the immunological determination of human immunoglobulin A in serum. In addition to the standard application (test IGA, 0-075), the sensitive application (test IGAP, 0-175) is designed for the quantitative determination of low IgA concentrations in e.g. pediatric samples.

COBAS INTEGRA Immunoglobulin G: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the immunological determination of human immunoglobulin G in serum. In addition to the standard application (test IGG, 0-076), the sensitive application (test IGGP, 0-176) is designed for the quantitative determination of low IgG concentrations in e.g. pediatric samples.

COBAS INTEGRA Immunoglobulin M: contains an in vitro diagnostic reagent system intended for use on COBAS INTEGRA for the quantitative determination of the immunological determination of human immunoglobulin M in serum. In addition to the standard application (test IGM, 0-077), the sensitive application (test IGMP, 0-177) is designed for the quantitative determination of low IgM concentrations in e.g. pediatric samples.

Through this submission it is the intention of Roche to gain clearance of an additional 5 new COBAS INTEGRA Reagent Cassettes and a modified version of 3 previously cleared reagent cassettes. All of the COBAS INTEGRA Reagent Cassettes contained in this submission are intended for use with the COBAS INTEGRA Analyzer. The Analyzer provides quantitative measurement of these analytes via three measuring principles, i.e., absorbance, fluorescence polarization and ion-selective electrodes. The COBAS INTEGRA Reagent Cassettes are compact and preparation-free. Sixty-eight COBAS INTEGRA Reagent Cassettes can be stored on board, 24 hours a day at 2-8 °C. Each cassette is barcoded. This barcode label provides the analyzer with specific reagent information such as the lot number, the expiration date and the number of tests.

Here's an analysis of the provided text regarding acceptance criteria and device performance:

Overview of the Device:

The document describes several COBAS INTEGRA Reagent Cassettes, including 5 new ones and 3 modified versions of previously cleared reagent cassettes, all intended for use with the COBAS INTEGRA Analyzer for quantitative determination of various analytes (Gamma-Glutamyltransferase, Lactate Dehydrogenase, Total Protein, Lactate, Tobramycin, Immunoglobulin A, Immunoglobulin G, Immunoglobulin M).

The claims of substantial equivalence are based on comparisons to legally marketed predicate devices. The acceptance criteria are implicit in the performance characteristics and comparisons presented against these predicate devices. The study is a non-clinical in vitro diagnostic reagent system performance evaluation.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct numerical targets (e.g., "Accuracy must be > 0.95"). Instead, the document presents comparative performance data against predicate devices or generally accepted analytical performance metrics (like precision and assay range). The implicit acceptance criterion is that the new or modified COBAS INTEGRA reagents perform equivalently to or better than the identified predicate devices, or demonstrate acceptable analytical performance for their intended use.

Below is a combined table showing the reported device performance, with the implicit acceptance criteria being that these values are acceptable for the intended use and comparable to or better than the predicate devices' performance.

Note: "Acceptance Criteria" here refers to the desirable performance characteristics expected for such diagnostic assays, inferred from the general context and comparison with predicate devices. The document does not explicitly state quantitative "acceptance criteria" but rather presents the performance achieved by the device and a predicate for comparison.

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

The sample sizes for the studies are provided in the "Accuracy" section for each analyte, indicating the number of samples ($n$) used for method correlation. The data provenance is generally implied as clinical and non-clinical studies for in vitro diagnostic assays. No specific countries of origin are mentioned, nor is it explicitly stated whether the studies were retrospective or prospective, though the nature of these tests (evaluating analytical performance) typically involves prospective or controlled laboratory studies.

• Gamma-Glutamyltransferase - IFCC: n = 202
• Lactate Dehydrogenase - IFCC: n = 106
• Total Protein - urine and CSF: n = 274 (for urine accuracy), no specific n for CSF accuracy is given separately though precision data is provided for CSF.
• Lactate: n = 224
• Tobramycin: n = 196
• Immunoglobulin A (Modified): n = 400 (standard application), n = 204 (pediatric application)
• Immunoglobulin G (Modified): n = 244 (standard application), n = 212 (pediatric application)
• Immunoglobulin M (Modified): n = 400 (standard application), n = 214 (pediatric application)

Data Provenance: "Clinical and nonclinical studies performed using the COBAS INTEGRA Reagent Cassettes." (Page 3). No further detail on country or retrospective/prospective nature.

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

This type of submission (510(k) for an in vitro diagnostic reagent cassette) does not typically involve human experts establishing ground truth in the way described for imaging or clinical decision support AI systems. The "ground truth" for these comparative studies is established by the predicate devices and well-established analytical methods. The performance of the new device is compared to these existing, legally marketed and validated methods. Therefore, the concept of "number of experts" and "qualifications of experts" like radiologists is not applicable here.

4. Adjudication Method for the Test Set

Since this is an in vitro diagnostic assay comparing quantitative measurements, adjudication methods like 2+1 or 3+1 (common in medical imaging for clinical endpoints) are not relevant. The "adjudication" is inherent in the analytical methods themselves, where the results from the new device are mathematically compared (e.g., using correlation coefficients and regression equations) against a reference method (the predicate device) or established laboratory standards.

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

No, an MRMC comparative effectiveness study was not done. This type of study is typically performed for AI-assisted diagnostic tools that involve human interpretation of medical images or other complex data where reader variability is a factor. The COBAS INTEGRA Reagent Cassettes are automated in vitro diagnostic tests, where the result is a quantitative analytical value from an instrument, not a human interpretation. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" is not applicable.

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

Yes, in a sense, the entire performance evaluation presented for each reagent cassette is a "standalone" study of the algorithm (i.e., the reagent's analytical method) without human intervention. The COBAS INTEGRA Analyzer is an automated system, and the reported precision and accuracy directly reflect the performance of the reagent and instrument system, which is analogous to an "algorithm only" performance. The device provides a quantitative result without a human interpreting an image or complex patterns.

7. Type of Ground Truth Used

The ground truth for these studies is established by comparison with legally marketed predicate devices using established analytical methodologies. For each assay:

• Gamma-Glutamyltransferase - IFCC: Compared against Roche COBAS INTEGRA, GGT (TRIS)
• Lactate Dehydrogenase - IFCC: Compared against Roche COBAS INTEGRA, LD (Lactate - Pyruvate)
• Total Protein - urine and CSF: Compared against SIGMA Diagnostics, Microprotein-PR
• Lactate: Compared against Boehringer Mannheim, Lactate
• Tobramycin: Compared against Abbott Diagnostics, TDX / TDX Flex Tobramycin
• Immunoglobulin A, G, M (Modified): Compared against Behring Diagnostics, N and NA Reagents (and implicitly, the previously marketed COBAS INTEGRA versions).

This approach relies on the well-established performance of predicate devices as the "ground truth" or reference standard for analytical accuracy.

8. Sample Size for the Training Set

The document does not specify a separate "training set" or "training set size." This is characteristic of traditional in vitro diagnostic device submissions, which do not typically employ machine learning or AI models that require distinct training and test data sets. The studies described are performance validation studies for the finished reagent product.

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

As there is no explicitly mentioned "training set" in the context of machine learning, this question is not directly applicable. The performance characteristics of these reagents are validated using standard analytical chemistry and immunoassay principles, with reference to the performance of predicate devices established through similar rigorous analytical validation.

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