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The Alkaline Phosphatase assay is used for the quantitation of alkaline phosphatase in human serum or plasma.

Measurements of alkaline phosphatase or its isoenzymes are to be used as an aid in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

The Alkaline Phosphatase assay is an automated clinical chemistry assay.

Alkaline phosphatase in the sample catalyzes the hydrolysis of colorless p-nitrophenyl phosphate (p-NPP) to give p-nitrophenol and inorganic phosphate. At the pH of the assay (alkaline), the p-nitrophenol is in the yellow phenoxide form. The rate of absorbance increase at 404 nm is directly proportional to the alkaline phosphatase activity in the sample. Optimized concentrations of zinc and magnesium ions are present to activate the alkaline phosphatase in the sample.

The FDA document provided is a 510(k) premarket notification for an in vitro diagnostic device, the Alkaline Phosphatase assay. This type of submission focuses on demonstrating substantial equivalence to a legally marketed predicate device, rather than proving safety and effectiveness de novo. Therefore, the information provided relates to testing done to establish equivalence for a pre-existing device with modifications, not a new device.

The study proves that the modified device meets acceptance criteria, primarily by demonstrating that it performs equivalently to the predicate device and that incremental changes do not adversely affect its performance.

Here's an analysis of the acceptance criteria and the study that proves the device meets those criteria, based on the provided text.

Acceptance Criteria and Reported Device Performance

The document provides a general statement that the device "met the pre-defined product requirements for all characteristics evaluated in the verification studies." It doesn't present a specific table of acceptance criteria vs. performance in the typical format of a clinical study, but rather a comparison of characteristics to a predicate device and a statement about the results of verification studies.

The key acceptance criterion discussed is substantial equivalence to the predicate device (K023807), particularly regarding:

• Intended Use and Indications for Use: The subject device is intended for the same use as the predicate: "quantitation of alkaline phosphatase in human serum or plasma," as an aid in diagnosis and treatment of various diseases.
• Methodology and Assay Principle: Both use para-nitrophenyl phosphate and a kinetic measurement method.
• Performance (specifically after IFCC calibration factor change): The 6.5% increase in reported results due to the optional IFCC calibration factor is deemed acceptable because it falls within the acceptable assay bias specifications (up to +/-10%) and the customer would be aware of this change.
• Risk Mitigation: The comprehensive risk-based assessment for all changes ensured that "the accumulated modifications did not impact the performance of the device."

Since this is an in vitro diagnostic device for measuring a specific analyte (Alkaline Phosphatase), the "performance" here refers to analytical performance characteristics rather than clinical diagnostic accuracy in the way a medical imaging AI would.

Here's a table summarizing the implicit acceptance criteria and the reported performance as derived from the document:

Study Details (based on the provided text, which is an FDA clearance letter for an IVD, not a detailed study report for AI/imaging device)

The document relates to modifications made to an existing in vitro diagnostic (IVD) device, not a new AI-powered diagnostic for imaging. Therefore, many of the typical questions for an AI/imaging device (e.g., sample size for test set, expert readers, MRMC study, ground truth for imaging) are not directly applicable or detailed in this type of FDA letter.

However, based on the information provided, we can infer some details relevant to an IVD device:

1. Sample Size used for the test set and the data provenance:

   • Sample Size: Not explicitly stated. The document refers to "verification studies" which typically involve testing samples across the measurement range, parallelism, interference, precision, etc. for an IVD. The exact number of samples (patients or analytical runs) isn't specified in this summary.
   • Data Provenance: Not specified regarding country of origin. The studies are described as "verification studies" and "comprehensive risk-based assessment." For IVDs, these are typically prospective laboratory studies conducted by the manufacturer to validate performance characteristics. It's safe to assume they were laboratory-controlled, likely prospective.

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

   • This question is not applicable in the context of this IVD device. "Ground truth" for an IVD like Alkaline Phosphatase is established by the analytical measurement itself, often compared to reference methods or known concentrations, or through internal validation against established performance claims. It does not involve human expert interpretation of an image or signal.

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

   • This question is not applicable for this IVD. Adjudication methods like 2+1 or 3+1 are used in AI/imaging studies where multiple human readers interpret data that then needs to be reconciled to establish a "ground truth" for comparison with AI. For an IVD, there isn't subjective interpretation of this kind. The measurement process itself generates the result.

4. 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:

   • This type of study is not applicable to this IVD. MRMC studies are specific to AI-assisted imaging diagnostics, evaluating the impact of AI on human reader performance. This device provides a quantitative biochemical measurement, not an image for human interpretation.

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

   • In a sense, yes, the fundamental performance of the IVD is "standalone" in that the automated analyzer (ARCHITECT c System) quantitatively measures alkaline phosphatase activity. The "algorithm" here is the chemical reaction and photometric measurement, and its output is a numerical value (U/L). The verification studies would assess this standalone analytical performance (e.g., precision, accuracy, linearity, detection limits) against pre-defined specifications. The IFCC factor is a mathematical change to this standalone output.

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

   • For an IVD like this, "ground truth" is typically established through:
     • Reference Methods: Comparison of results to established, highly accurate reference methods for alkaline phosphatase.
     • Known Concentrations: Testing samples with precisely known concentrations of alkaline phosphatase.
     • Clinical Correlation: Demonstrating that the assay measures the analyte in patient samples consistently and reliably across relevant patient populations, although the primary ground truth is analytical.
   • The document implies that the "pre-defined product requirements" and "acceptable assay bias specifications" served as the benchmarks for determining if the device performed acceptably. The 6.5% shift from the IFCC factor was evaluated against these analytical specifications.

7. The sample size for the training set:

   • This question is not directly applicable in the context of a traditional IVD chemical assay development, as there isn't an "AI model" that requires a training set in the typical sense. The "training" for such a system would be the chemical formulation and instrument calibration based on extensive R&D and optimization, not a data-driven machine learning process. The "validation" of the final product involves the verification studies mentioned.

8. How the ground truth for the training set was established:

   • As above, not directly applicable. The IVD operates on established biochemical principles. Its "ground truth" for development and optimization would be based on fundamental chemistry, enzyme kinetics, and metrological traceability to international standards (e.g., IFCC reference methods for calibrator values).

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The Alkaline Phosphatase2 assay is used for the quantitation of alkaline phosphatase in human serum or plasma on the ARCHITECT c System.

Measurements of alkaline phosphatase or its isoenzymes are to be used as an aid in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

The Alkaline Phosphatase2 assay is an automated clinical chemistry assay for the quantitation of alkaline phosphatase in human serum or plasma on the ARCHITECT c System. Alkaline Phosphatase in a sample catalyzes the hydrolysis of colorless para-nitrophenyl phosphate (p-NPP) to give para-nitrophenol (yellow phenoxide form at alkaline pH) and inorganic phosphate. The rate of absorbance increase at 404 nm is directly proportional to the alkaline phosphatase activity in the sample. Optimized concentrations of zinc and magnesium ions are present to activate the alkaline phosphatase in the sample.

The provided document is a 510(k) Premarket Notification for a clinical chemistry assay (Alkaline Phosphatase2) and does not describe an AI medical device. Therefore, the questions related to AI-specific acceptance criteria, ground truth establishment by experts, adjudication methods, multi-reader multi-case studies, and human-in-the-loop performance are not applicable.

The document focuses on the analytical performance of the Alkaline Phosphatase2 assay, demonstrating its substantial equivalence to a legally marketed predicate device. The information details various non-clinical performance studies to establish the device's reliability and accuracy for quantitating alkaline phosphatase in human serum or plasma.

Here's a breakdown of the relevant information from the document, tailored to the context of a diagnostic assay's performance evaluation, substituting the AI-specific questions with applicable details:

Acceptance Criteria and Device Performance for Alkaline Phosphatase2 Assay

This submission (K223317) is for a clinical chemistry assay, not an AI medical device. The acceptance criteria and performance studies are focused on the analytical performance of the assay to demonstrate its intended use for quantitative measurement of alkaline phosphatase.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a "table of acceptance criteria" for regulatory review, but it details various performance studies with implicit acceptance ranges. The reported device performance metrics are presented instead.

Performance Metrics of Alkaline Phosphatase2 Assay (Representative Values)

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Yumizen C1200 ALP reagent is intended for the quantitative in vitro diagnostic determination of alkaline phosphatase in human serum and plasma based on a kinetic photometric test using p-Nitropherylphosphate. Measurements of alkaline phosphatase or its isoenzymes are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

Yumizen C1200 Albumin reagent is intended for the quantitative in vitro diagnostic determination of albumin in human serum and plasma by colorimetry. Albumin measurements are used in the diagnosis and treatment of numerous diseases involving primarily the liver or kidneys.

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The provided text describes analytical performance characteristics and comparison studies for two in vitro diagnostic reagents, Yumizen C1200 ALP and Yumizen C1200 Albumin, intended for use on the Yumizen C1200 clinical chemistry analyzer. The document is a 510(k) summary, demonstrating substantial equivalence to predicate devices.

Here's an analysis of the acceptance criteria and the studies performed, structured according to your request:

Acceptance Criteria and Reported Device Performance

For both assays, the acceptance criteria are implicitly defined by the successful demonstration of performance characteristics within established guidelines (CLSI) and comparison to their respective predicate devices. The "Results are within predefined acceptance criteria" statements affirm that the tested parameters met the company's internal benchmarks, which are aligned with industry standards for analytical performance.

Here's a table summarizing the reported device performance for key analytical characteristics:

Study Details:

1. Sample Size Used for the Test Set and Data Provenance:

   • Yumizen C1200 ALP:
     • Measuring Range/Linearity: Data not explicitly stated for individual samples, but the study showed linearity from 0 to 1620 U/L.
     • Precision: "Single site: 20x2x2" and "Multi site: 3x5x2x3". This notation often refers to runs x replicates x instrument/lots, but the exact number of unique "samples" (control and general) for precision is stated as N=240 for single site, and N=90 for multi-site across various levels (control and patient samples). The provenance of these samples is not specified (e.g., country of origin) but they are "control" or "patient" samples. It's an analytical performance study, not a clinical study on specific patient populations.
     • Interferences: Specific sample numbers for this study are not provided, but the tested interferent concentrations are listed.
     • Method Comparison: 165 native serum samples.
     • Matrix Comparison: 40 lithium-heparin plasma samples (individual donors).
   • Yumizen C1200 Albumin:
     • Measuring Range/Linearity: Data not explicitly stated for individual samples, but the study showed linearity from 0 to 60.2 g/L.
     • Precision: "Single site: 20x2x2" and "Multi site: 3x5x2x3". Again, N=240 for single site and N=90 for multi-site across various levels.
     • Interferences: Specific sample numbers for this study are not provided.
     • Method Comparison: 111 native serum samples.
     • Matrix Comparison: 70 lithium-heparin plasma samples (individual donors).
   • Data Provenance: The document does not specify the country of origin for the samples. The studies are described as analytical performance validations, which are typically retrospective using banked/collected samples. The term "native serum samples" and "individual donors" implies real patient samples.

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

   • This is an in vitro diagnostic device (measurement of lab analytes), not an imaging AI or diagnostic AI device where human experts establish "ground truth" in the typical sense of clinical interpretation.
   • The ground truth for the test set is established by the predicate devices (Roche Diagnostics ALP IFCC Gen2 on COBAS INTEGRA systems, and HORIBA ABX SAS ABX Pentra Albumin CP on ABX Pentra 400/Pentra C400) or by established analytical methods for measuring concentrations (e.g., gravimetric for linearity, standard additions for LoD/LoQ).
   • The "experts" involved are likely laboratory professionals, biochemists, and statisticians who design and execute these analytical validation studies according to CLSI (Clinical and Laboratory Standards Institute) guidelines. Their specific qualifications (e.g., MD, PhD) or number are not explicitly stated in this document but are assumed to be standard for medical device development.

3. Adjudication Method for the Test Set:

   • Not applicable in the context of analytical performance studies of laboratory reagents. Adjudication (e.g., 2+1, 3+1 consensus) is typical for clinical studies involving subjective interpretations (e.g., radiology reads). For a quantitative IVD, the "truth" is the measured value from a reference method or known concentration.

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

   • No, an MRMC study was not done. This type of study is relevant for diagnostic imaging interpretation or other scenarios where human readers make subjective judgments, and AI provides assistance. This document is for quantitative lab reagents, where the assessment is about the accuracy and precision of the measurement itself.

5. If a Standalone Performance Study Was Done:

   • Yes, the entire document describes standalone performance of the Yumizen C1200 ALP and Albumin reagents on the Yumizen C1200 analyzer. This is not an "algorithm only without human-in-the-loop" performance as the device itself is an integrated system of reagent, instrument, and software. "Standalone" in this context means the performance of the new device/reagent system as a complete unit, not in comparison to human interpretation.

6. The Type of Ground Truth Used:

   • External Reference Measurement: For method comparison studies, the "ground truth" is the result obtained from the legally marketed predicate device (Roche Diagnostics ALP IFCC Gen2 for ALP, and HORIBA ABX SAS ABX Pentra Albumin CP for Albumin).
   • Known Concentrations/Standards: For linearity, limit of detection/quantitation, and interference studies, the ground truth is established by preparing samples with known concentrations of analytes and/or interferents.
   • Consensus/Literature: For reference ranges, the ground truth is based on established bibliographic references and a verification study using "normal samples" from a blood bank.

7. The Sample Size for the Training Set:

   • This document describes the validation/test phase for regulatory submission (510(k)). It does not detail the training set used for the development of the reagents or the analyzer's measurement algorithms. For IVDs, the "training" analogous to machine learning often involves extensive R&D, chemical optimization, and instrument calibration development using a variety of samples, but these are not explicitly quantified in terms of a "training set" size in this regulatory summary.

8. How the Ground Truth for the Training Set Was Established:

   • As above, details about the "training set" are not provided. However, for the development of quantitative IVD assays, ground truth for initial development/training would typically be established through:
     • Primary Reference Methods: Highly accurate and precise methods (e.g., isotope-dilution mass spectrometry) for specific analytes, often used for calibrator assignment.
     • Certified Reference Materials: Materials with an assigned value and uncertainty for an analyte, traceable to recognized metrological standards.
     • Large Sample Cohorts: A diverse range of clinical samples (with values determined by established methods) to ensure robustness across different patient populations and disease states.
     • Experimental Design: Controlled experiments to characterize reagent stability, reaction kinetics, and potential interferents.

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The Comprehensive Metabolic Panel is intended to be used for the quantitative determination of Alkaline Phosphate (ALP), Alanine Aminotransferase (ALP/GPT), Aspartate Aminotransferase (AST/GOT), Blood Urea Nitrogen (BUN) and Creatinine (CREA) in concentrations in lithium-heparinized venous whole blood, heparinized plasma, or serum in a clinical laboratory setting or point-of-care location.

• Alkaline phosphatase or its isoenzymes measurements are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

• Alanine aminotransferase measurements are used in the diagnosis and treatment of certain liver diseases (e.g., viral hepatitis and cirrhosis) and heart diseases.

• Aspartate aminotransferase measurements are used in the diagnosis and treatment of certain types of liver and heart disease.

• Blood urea nitrogen measurements are used in the diagnosis and treatment of certain types of renal and metabolic diseases.

• Creatinine measurements are used in the diagnosis and treatment of renal dialysis, and as a calculation basis for measuring other urine analytes.

The skyla Clinical Chemistry Analyzer is an in-vitro diagnostic device for the quantitative determination of clinical chemistry analytes in lithium-heparinized venous whole blood, heparinized plasma, or serum. It is for clinical laboratory and point-of-care use.

The Minicare C300 Clinical Analyzer is an in-vitro diagnostic devices for the quantitative determination of clinical chemistry analytes in lithium-heparinized venous whole blood, heparinized plasma, or serum. It is for clinical laboratory and point-of-care use.

The skyla Clinical Chemistry Analyzer, Minicare C300 Clinical Chemistry Analyzer (private label) and Comprehensive Metabolic Panel is an automatic chemistry system intended for use in clinical laboratories or point-of-care locations. The system consists of a portable analyzer and single-use disposable reagent panel discs.

The analyzer utilizes precision photometric measurement technology, combined with the use of specific reagent panel disc, to measure the amount of substance in blood. The analyzer measures absorbance change of each reaction well in reagent panel disc and covert it to a concentration value for each analyte included on the panel.

The skyla and Minicare Comprehensive Metabolic Panel reagent disc (which contains the Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Blood Urea Nitrogen and Creatinine test systems) is designed to separate a heparinized venous whole blood sample into plasma and blood cells. The disc meters the required quantity of plasma and diluent, mixes the plasma with diluent, and delivers the mixture to the reaction cuvettes along the disc perimeter. The diluted plasma mixes with the reagent beads, initiating the chemical reactions that are then monitored by the analyzer.

The Lite-On Technology Corp.'s Comprehensive Metabolic Panel, skyla Clinical Chemistry Analyzer, and Minicare C300 Clinical Chemistry Analyzer (K171971) were evaluated for substantial equivalence. The acceptance criteria and performance data are primarily based on precision, matrix comparison, detection limits, linearity, and interference testing.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are generally implied by the predicate device's performance and the established clinical laboratory standards (e.g., CLSI guidelines, recovery within 90-110% for interference). The reported device performance aligns with these expectations.

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

• Internal Precision/Reproducibility: 80 runs per level (quadruplicate testing a day for 20 working days) for each of the three serum levels for all 5 analytes. Data provenance is not specified (e.g., country of origin) but refers to "patient serum samples." Implied prospective collection for the study.
• Matrix Comparison: 40 human samples. Data provenance not specified. Implied prospective collection for the study.
• Detection Limit: LoB: 60 measurements of a near-zero sample over 10 days. LoD/LoQ: serum samples containing very low concentrations, tested in triplicate using 2 lots of reagent discs for 10 days. Data provenance not specified. Implied prospective collection.
• Linearity: 9 intermediate dilutions created from high and low human serum pool samples, plus spiked samples. Data provenance not specified. Implied prospective collection.
• Endogenous Interferences: Not explicitly stated, but implies multiple samples to test two different concentrations (normal and abnormal) of analytes against specified interference levels. Data provenance not specified. Implied prospective collection.
• Exogenous Substances: Two concentrations (low and high level) of samples for each of the 10 potential interferents. Data provenance not specified. Implied prospective collection.
• Point-of-Care (POC) Method Comparison: Over 120 heparinized venous whole blood and serum samples for each analyte. Data provenance not specified; likely collected from the three POC sites, implying prospective collection.
• Point-of-Care (POC) Precision Studies: Three levels of human serum samples from POC sites, assayed in quadruplicate twice a day for 20 days. Data provenance not specified. Implied prospective collection.
• Point-of-Care (POC) Whole Blood Precision: Not explicitly stated, but tabular data suggests multiple analyses (mean, SD, CV) for low, medium, and high samples across 3 POC sites and multiple operators (OP1, OP2, OP3).

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

This type of submission (510k for a clinical chemistry analyzer) does not typically involve human experts establishing a "ground truth" for the test set in the same way an image analysis or diagnostic AI device would. Instead, the ground truth is established by:

• Reference Methods/Materials: Traceability to established reference methods (e.g., IFCC reference method for ALT/ALP/AST, CDC reference method for BUN, IDMS Reference Method for CREA) and reference materials (NIST SRM967).
• Comparative Clinical Analyzers: For method comparison studies, the Beckman Coulter AU2700 clinical analyzer served as the comparative (reference) method.

Therefore, the "experts" in this context are the established, validated, and traceable laboratory methods and instruments, rather than individual human practitioners.

4. Adjudication Method for the Test Set

Not applicable. Diagnostic test performance for clinical chemistry analyzers is typically evaluated by statistical comparison to a reference method or established clinical ranges, not by an adjudication process as seen in clinical trial settings for diagnostic imaging.

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

No, an MRMC comparative effectiveness study was not done. This type of study is relevant for diagnostic imaging devices where multiple human readers interpret cases with and without AI assistance. This submission is for a clinical chemistry analyzer.

However, the "POC Precision studies" did evaluate performance across multiple operators (9 operators) at three POC sites. This demonstrates inter-operator variability, which is a related concept to multi-reader studies in a laboratory context, but it does not measure an "improvement with AI vs. without AI assistance" since the device itself is the primary measurement tool, not an AI assistant to a human reader.

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

Yes, the studies presented are generally "standalone" performance evaluations of the device (skyla/Minicare Clinical Chemistry Analyzer with Comprehensive Metabolic Panel) itself. The device automatically measures analytes and displays results; there isn't an "algorithm only" component separate from the integrated device performance. All performance data (precision, linearity, detection limits, interference) are solely based on the device's output.

7. The Type of Ground Truth Used

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

• Traceability to Reference Methods/Materials: For calibration and analytical accuracy (e.g., IFCC, CDC, IDMS reference methods, NIST reference materials).
• Comparative Clinical Analyzers: The Beckman Coulter AU2700 served as the comparative method for method comparison studies, essentially acting as the "ground truth" or reference for evaluating the test device's performance on patient samples.
• Known Concentrations: For studies like linearity, detection limits, and interference, samples with known or spiked concentrations are used.

8. The Sample Size for the Training Set

This document does not specify a separate "training set" in the context of machine learning or AI. This device is a traditional in-vitro diagnostic (IVD) clinical chemistry analyzer. Its development would involve internal validation and optimization processes by the manufacturer, which might loosely be considered "training," but it's not described as an AI model training set with a specific size or provenance.

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

As this is a traditional IVD device, the concept of a "training set" for an AI model's ground truth is not applicable in the way it would be for AI-powered diagnostic software. The "ground truth" for the development and internal validation of such a device is established through:

• Chemical Principles and Reactions: The underlying scientific principles of colorimetry and specific reagent reactions form the fundamental 'ground truth' for measurement.
• Calibration Standards: The device is calibrated using standards whose concentrations are traceable to recognized reference methods and materials, ensuring accurate quantitative measurements.
• Quality Control Materials: Known quality control materials are used to ensure the device performs within expected ranges over time.

These elements collectively serve as the basis for ensuring the device's accuracy and reliability during its design, development, and manufacturing phases.

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ALP IFCC Gen.2 is an in vitro test intended for the quantitative determination of the catalytic activity of alkaline phosphatase in human serum and plasma on COBAS INTEGRA systems. Measurements of alkaline phosphatase or its isoenzymes are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

The Roche ALP IFCC Gen.2 assay provides quantitative measurement of the catalytic activity of alkaline phosphatase in human serum and plasma in accordance with a standardized method.. The reagents are packaged in a cassette with two bottles labeled with their instrument positioning, R1 (position B) and SR (position C).

In the presence of magnesium and zinc ions, p-nitrophenyl phosphate is cleaved by phosphatases into phosphate and p-nitrophenol. The p-nitrophenol released is directly proportional to the catalytic ALP activity. It is determined by measuring the increase in absorbance.

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

This document is a 510(k) summary for a diagnostic assay, not an AI/ML device. Therefore, many of the typical questions for AI/ML studies (like MRMC studies, reader performance, training set details, etc.) are not applicable here. The acceptance criteria and performance are for an in vitro diagnostic (IVD) reagent and its analytical performance.

1. Table of Acceptance Criteria and Reported Device Performance

The document describes modifications to an existing device (ALP IFCC Gen.2). The acceptance criteria are implicit in the "Pass/Fail criteria" for the verification and validation tests performed. The "reported device performance" refers to the characteristics of the modified device and the confirmation that it met these criteria.

Summary of the Study:

The document describes a Special 510(k) Premarket Notification for modifications to an existing in vitro diagnostic device, ALP IFCC Gen.2. The core purpose was to change the traceability standard of the assay and add specific interference claims. The "study" refers to the verification, validation, and testing activities conducted to confirm that these modifications did not adversely affect the device's performance and that the new claims were supported.

Breakdown of Information Request:

1. Table of acceptance criteria and reported device performance: See table above.

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

   • Sample Size: Not explicitly stated. The document mentions "verification, validation and testing activities" including "recovery in controls, linearity, method comparison, within run precision and interference characteristics." For these types of analytical studies, samples typically include:
     • Controls: Multiple replicates, often 2-3 levels, run over several days/runs for precision and recovery.
     • Linearity samples: A series of diluted or spiked samples across the measuring range.
     • Method Comparison samples: A set of patient samples (often 40-100+) covering the assay range, compared against a reference method or the predicate device.
     • Interference samples: Patient samples or spiked samples tested with various concentrations of interferents (hemoglobin, bilirubin, lipids).
   • Data Provenance: Not explicitly stated, but standard practice for Roche Diagnostics (a global company with manufacturing in Germany and operations in the US) would be internal lab testing, likely at their R&D facilities in Germany or the US. It would be prospective testing of the modified device.

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 question is not applicable in the context of an IVD reagent analytical performance study. "Ground truth" for an IVD assay's performance would be established by:
     • Highly accurate reference measurement procedures (e.g., the IFCC (2011) reference method cited for traceability).
     • Certified reference materials.
     • Comparison against a legally marketed predicate device or a clinical laboratory's established, validated method.
   • No "experts" in the sense of clinical reviewers are typically used to establish ground truth for analytical performance, but rather highly skilled laboratory scientists and metrologists ensure the accuracy of the reference methods and measurements.

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

   • This question is not applicable. Adjudication methods like "2+1" or "3+1" are characteristic of clinical studies involving human interpretation (e.g., image reading), where disagreements among reviewers need resolution. This document describes analytical performance testing of a reagent where results are quantitative and objective.

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:

   • This is not applicable. An MRMC study assesses the performance of human readers, often with and without AI assistance, on a set of cases. This document is about the analytical performance of an in vitro diagnostic reagent, not an AI/ML device or human reader performance.

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

   • This is not applicable. The device is an in vitro diagnostic reagent executed on an automated instrument (COBAS INTEGRA systems). Its performance is inherently "standalone" in functionality (it performs the assay automatically), but it's not an algorithm in the AI/ML sense that would have an "algorithm only" performance study. Its performance is the instrument's performance running the reagent.

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

   • For this type of analytical IVD study, the "ground truth" for method comparison and traceability would be:
     • Reference Measurement Procedures: Specifically, the modified IFCC (2011) reference method for ALP activity.
     • Certified Reference Materials/Calibrators: These provide established, highly accurate values.
     • Comparison to Predicate Device: The performance of the modified device was compared to the legally marketed predicate, which itself would have been validated against established clinical laboratory methods or reference methods.

8. The sample size for the training set:

   • This is not applicable. This is an IVD reagent, not an AI/ML algorithm that requires a "training set." The reagent's formulation and associated analytical procedures are developed through biochemical and analytical chemistry principles, not machine learning training.

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

   • This is not applicable for the same reason as point 8.

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The Randox RX Daytona Plus Alkaline Phosphatase (ALP) test system is intended for the quantitative in vitro determination of Alkaline Phosphatase (ALP) activity in serum and lithium heparinized plasma. Measurements of alkaline phosphatase are used in the diagnosis, treatment and investigation of hepatobiliary disease and in bone disease.

The Randox RX Daytona Plus Alkaline Phosphatase (ALP) assay consists of ready to use reagent solutions.

Here's a breakdown of the acceptance criteria and study information for the Randox RX Daytona Plus Alkaline Phosphatase (ALP) device, based on the provided text:

Acceptance Criteria and Device Performance

Study Details

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

• Precision/Reproducibility: Not explicitly stated for specific test sets, but 80 determinations per sample (QC or serum) were performed for each of the two reagent lots. Human serum samples (altered and unaltered, some spiked or diluted) were used. Data provenance is not explicitly stated beyond "human serum samples."
• Linearity/Reportable Range: 11 levels of samples were prepared. Each level was run in replicates of five. Provenance of these samples is not specified.
• Detection Limit: Not explicitly stated for a separate "test set" size, but the LoD was based on 240 determinations using 4 low-level samples. Provenance not specified.
• Analytical Specificity: Not explicitly stated for a separate "test set" size for each interferent, but the study implies testing at ALP concentrations of 80 U/I and 240 U/I. Provenance not specified.
• Method Comparison with Predicate Device: 106 serum patient samples. Data provenance is not explicitly stated but implies patient samples from the UK, given the manufacturer's location. The study was retrospective, comparing the new device results against an existing predicate device using collected samples.
• Matrix Comparison: 46 matched patient sample pairs (serum and lithium heparin plasma). Provenance not explicitly stated.
• Expected Values/Reference Range Verification: Human serum from 30 normal donors. Provenance not explicitly stated.

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

• Not Applicable. This document describes the analytical performance of an in vitro diagnostic device (a laboratory test for Alkaline Phosphatase activity). The "ground truth" for such devices is typically established through reference methods, certified standards, or consensus values from established quality control materials, rather than expert interpretation of images or patient data. The document does not mention the use of experts to establish ground truth for the analytical performance studies.
  • For the precision study, control materials and altered/unaltered human serum samples were used.
  • For linearity, pooled samples with known concentrations were used.
  • For method comparison, the predicate device (Siemens Alkaline Phosphatase (ALPAMP) Assay, K991576) served as the reference for comparison.

4. Adjudication Method for the Test Set:

• Not Applicable. As noted above, this study evaluates the analytical performance of an in vitro diagnostic device, not interpretive performance requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, What was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance:

• Not Applicable. This is an evaluation of an in vitro diagnostic device for quantitative chemical analysis, not an AI-powered diagnostic imaging system requiring human reader studies.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-loop Performance) Was Done:

• Yes, a standalone study was done. The entire submission details the performance of the Randox RX Daytona Plus Alkaline Phosphatase (ALP) system itself, comprising reagents and the RX Daytona Plus analyzer. This is the inherent nature of an in vitro diagnostic test; its performance is measured independently of human interpretation of the result, though human operators perform the test and interpret the clinical significance of the result. The performance metrics (precision, linearity, detection limits, accuracy/method comparison) are all measures of the device's standalone analytical capabilities.

7. The Type of Ground Truth Used:

• Reference Methods/Comparative Devices and Spiked/Diluted Samples:
  • Precision and Linearity: Values derived from known concentrations in quality control materials, spiked samples, or diluted samples where the true value is calculable.
  • Method Comparison: The predicate device (Siemens Alkaline Phosphatase (ALPAMP) Assay, K991576) served as the comparative "ground truth" to establish substantial equivalence.
  • Detection Limits: Determined statistically using defined protocols (CLSI guideline EP17-A2).
  • Analytical Specificity: Known concentrations of interferents added to known ALP concentrations.

8. The Sample Size for the Training Set:

• Not Applicable. The document describes a traditional analytical performance study for an in vitro diagnostic assay, not an AI/machine learning model that requires a training set. The device is a chemical reagent and analyzer system.

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

• Not Applicable. See point 8.

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The ACE Alkaline Phosphatase Reagent is intended for the quantitative determination of alkaline phosphatase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurements of alkaline phosphatase are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE Amylase Reagent is intended for the quantitative determination of α-amylase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Amylase measurements are used primarily for the diagnosis and treatment of pancreatitis (inflammation of the pancreas). This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE ALT Reagent is intended for the quantitative determination of alanine aminotransferase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Alanine aminotransferase measurements are used in the diagnosis and treatment of certain liver diseases (e.g., viral hepatitis and cirrhosis) and heart diseases. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

The ACE AST Reagent is intended for the quantitative determination of aspartate aminotransferase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurements of aspartate aminotransferase are used in the diagnosis and treatment of certain types of liver and heart disease. This test is intended for use in clinical laboratories and physician office laboratories. For in vitro diagnostic use only.

In the ACE Alkaline Phosphatase Reagent assay, alkaline phosphatase catalyzes the hydrolysis of colorless p-nitrophenyl phosphate to p-nitrophenol and inorganic phosphate. In an alkaline solution (pH 10.5), p-nitrophenol is in the phenoxide form and has a strong absorbance at 408 nm. The rate of increase in absorbance, monitored bichromatically at 408 nm/486 nm, is directly proportional to the alkaline phosphatase activity in the sample.

In the ACE Amylase Reagent assay, α-amylase hydrolyzes the 2-chloro-p-nitrophenyl-α-D-maltotrioside substrate to release 2-chloro-p-nitrophenol and form 2-chloro-p-nitrophenyl-α-D-maltoside, maltotriose and glucose. The rate of increase in absorbance, monitored bichromatically at 408 nm/ 647 nm, is directly proportional to the α-amylase activity in the sample.

In the ACE ALT Reagent assay, alanine aminotransferase converts the L-alanine and α-ketoglutarate substrates in the reagent to L-glutamate and pyruvate, respectively. Lactate dehydrogenase (LDH) catalyzes the oxidation of the reduced cofactor to the cofactor. The rate of conversion of the reduced cofactor to the cofactor can be determined by monitoring the decrease in absorbance bichromatically at 340 nm/647 nm. This rate of conversion from the reduced cofactor to the cofactor is a function of the activity of ALT in the sample.

In the ACE AST Reagent assay, aspartate aminotransferase converts the L-aspartate and α-ketoglutarate in the reagent to oxaloacetate and L-glutamate, respectively. The oxaloacetate undergoes reduction, with concurrent oxidation of NADH to NAD+ in the malate dehydrogenase-catalyzed indicator reaction. NADH absorbs strongly at 340 nm, whereas NAD+ does not. Therefore, the rate of conversion of NADH to NAD+ can be determined by monitoring the decrease in absorbance bichromatically at 340 nm/647 nm. This rate of conversion from NADH to NAD+ is a function of the activity of AST in the sample. Lactate dehydrogenase is added to prevent interference from endogenous pyruvate, which is normally present in blood.

Here's an analysis of the provided information regarding the acceptance criteria and study for the ACE reagents:

Summary of Acceptance Criteria and Reported Device Performance

The acceptance criteria for these in vitro diagnostic reagents (ALP, Amylase, ALT, AST) appear to be primarily demonstrated through comparisons with predicate devices and comprehensive performance characteristics like precision, linearity, and interference. The documentation focuses on demonstrating that the new devices perform equivalently to the existing predicate devices and meet established performance expectations for clinical chemistry assays.

1. Table of Acceptance Criteria and Reported Device Performance

Since this document describes multiple reagents and doesn't explicitly state pass/fail acceptance values for each performance metric, I will summarize the demonstrated performance and what can be inferred as the "acceptance criteria" (i.e., that the results are comparable to established predicate device performance and within acceptable clinical ranges).

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

• Precision (Serum vs. Plasma):
  • In-House: Each dataset (low, mid, high for serum and plasma) involved "n=20" (number of replicates, likely over multiple days, contributing to within-run and total precision calculations).
  • POL Precision (ACE & Alera): For each analyte (ALP, AMY, ALT, AST) and each POL site (POL 1, POL 2, POL 3), there were 2 to 3 sample levels (Low, Mid, High), with a reported "n" for each (e.g., n=24 for ALT/AST in initial in-house, but the POL tables don't explicitly state the 'n' for each specific mean/SD/CV, implying a standard number of replicates as per precision studies).
• Matrix Comparison (Serum vs. Plasma):
  • ALP: ACE (108 pairs), ACE Alera (108 pairs), ACE Axcel (62 pairs).
  • Amylase: ACE (104 pairs), ACE Alera (101 pairs), ACE Axcel (52 pairs).
  • ALT: ACE (54 pairs), ACE Alera (52 pairs), ACE Axcel (56 pairs).
  • AST: The number of pairs for AST in the serum vs. plasma matrix comparison is not explicitly stated in the provided snippet. However, based on the pattern of other analytes, it would likely be similar (e.g., 50+ pairs).
• Method Comparison (In-House vs. POL Sites):
  • ALP: 49-50 samples per site.
  • Amylase: 51 samples per site.
  • ALT: 44-49 samples per site.
  • AST: 50 samples per site.
• Linearity: Not explicitly stated as an "n" for samples, but rather as "low level tested," "upper level tested," and "linear to" values, which typically involve preparing a dilution series from a high concentration sample.
• Data Provenance: The studies are labeled "In-House" and "POL" (Point of Care). This suggests:
  • Country of Origin: Likely the USA, given the FDA 510(k) submission.
  • Retrospective or Prospective: These types of performance studies for IVDs are typically prospective, with samples analyzed specifically for the study. The method comparison data often uses a mix of native patient samples and spiked samples to cover the measuring range.

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

This document describes the performance of IVD reagents on clinical chemistry systems. The "ground truth" here is not subjective, human interpretation (like in imaging AI), but rather the quantitative measurement of analytes.

• Number of Experts: Not applicable in the context of IVD reagent performance. The "ground truth" is established by the analytical method itself, or by comparison to a recognized reference method or a legally marketed predicate device.
• Qualifications of Experts: Not applicable. The "experts" would be qualified laboratory professionals operating the instruments and performing the biochemical assays according to established protocols.

4. Adjudication Method for the Test Set

Not applicable. As described above, the "truth" for these quantitative measurements is derived directly from the biochemical reactions and instrument readings, not subjective human judgment requiring adjudication. The predicate device's established performance serves as a comparative benchmark.

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

No. This is a submission for in vitro diagnostic reagents, not an AI-assisted diagnostic device that involves human readers interpreting images or complex data. Therefore, an MRMC study is not relevant.

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

Yes, in essence, the performance data presented is "standalone" in the context of the device's function. The ACE reagents, when used on the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems, operate as an automated system to quantify the target analytes. The performance metrics (precision, linearity, method comparison, interferences) reflect the intrinsic analytical performance of the regent-analyzer combination without human intervention influencing the measurement itself. Human operators are involved in sample loading, quality control, and result review, but not in directly influencing the quantitative output in a way that would require a human-in-the-loop comparison for algorithm performance.

7. The Type of Ground Truth Used

The "ground truth" in this context is established by:

• Comparison to Predicate Devices: The primary method is demonstrating substantial equivalence to previously cleared devices (K113253, K931786, K930104, K113436, K113382). This means the new reagents provide results that are analytically comparable to those already accepted by the FDA.
• Expected Analytical Performance: Meeting industry-standard requirements for precision (low CV%), accuracy (linearity, inter-instrument/site agreement via regression analysis), and specificity (minimal interference).
• Expected Values/Ranges: The devices are expected to produce results that align with established "expected values" for healthy individuals.

8. The Sample Size for the Training Set

Not applicable. These are chemical reagents for quantitative diagnostic tests, not machine learning algorithms that require a "training set" in the conventional sense. The "training" for such systems involves analytical validation experiments to define reagent stability, reaction kinetics, and instrument parameters.

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

Not applicable for the same reason as point 8. The "ground truth" for developing and validating these reagents is based on fundamental principles of analytical chemistry, biochemical reactions, and extensive internal testing to ensure the reagents perform as intended within the specified analytical parameters.

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The S TEST Reagent Cartridge Alkaline Phosphatase (ALP) is intended for the quantitative measurement of alkaline phosphatase activity in serum, lithium heparinized plasma, or sodium citrate plasma using the HITACHI Clinical Analyzer. The S TEST Reagent Cartridge Alkaline Phosphatase (ALP) is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

Measurements of alkaline phosphatase are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases.

The Hitachi Clinical Analyzer is an automatic, bench-top, wet chemistry system intended for use in clinical laboratories or physician office laboratories. The instrument consists of a desktop analyzer unit, an operations screen that prompts the user for operation input and displays data, a printer, and a unit cover. The analyzer unit includes a single probe, an incubation rotor, carousels for sample cups and reagent cartridges, and a multi-wavelength photometer. The single-use reagent cartridges may be placed in any configuration on the carousel, allowing the user to develop any test panel where the reagent cartridges are available.

The S TEST reagent cartridges are made of plastic and include two small reservoirs capable of holding two separate reagents (R1 and R2), separated by a reaction cell/photometric cuvette. The cartridges also include a dot code label that contains all chemistry parameters, calibration factors, and other production-related information, e.g., expiration dating. The dimensions of the reagent cartridges are: 13.5 mm (W) × 28 mm (D) × 20.2 mm (H).

System operation: After the sample cup is placed into the carousel, the analyzer pipettes the sample, pipettes the reagent, and mixes (stirs) the sample and reagent together. After the sample and reagent react in the incubator bath, the analyzer measures the absorbance of the sample, and based on the absorbance of the reactions, it calculates the concentration of analyte in the sample. The test system can measure analytes in serum or plasma and results are available in approximately 15 minutes per test. This submission is for Reagent Cartridge ALP.

Chemistry reactions: Alkaline phosphatase (ALP) in the sample reacts with its substrate, pnitrophenyl phosphate (p-NPP), in ethylaminoethanol (EAE) buffer, to release p-nitrophenol (yellow). The ALP activity is determined by measuring the rate of p-nitrophenol production.

The provided text describes the performance characteristics and acceptance criteria for the Hitachi S TEST Reagent Cartridge Alkaline Phosphatase (ALP).

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" as a separate column for all metrics. However, the performance data provided implies that the reported results met the internal development criteria for each study. Where a specific acceptance range or threshold is mentioned (e.g., for interference testing), it is included.

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

• Analytical Sensitivity (Limits of Detection): Not specified, but likely involved multiple replicates for statistical analysis as per CLSI EP17-A.
• Linearity: Not specified, but involved samples spanning 5 U/L to 1,000 U/L as per CLSI EP-6A.
• 20-day In-house Precision: Three levels of samples, each tested in two runs, twice a day, for 20 days. This means 80 data points per level (2 runs/day * 2 times/run * 20 days). Total around 240 data points across 3 levels.
• Interference Testing: Two serum pools tested.
• Method Comparison (in-house): 97 clinical specimens. Data provenance: Not explicitly stated, but implied to be in-house or from a domestic source. Retrospective.
• Matrices Comparisons: 38 matched serum/plasma samples. Data provenance: Not explicitly stated, but implied to be in-house or from a domestic source. Retrospective.
• External Site Precision: Each site tested three blinded serum samples, six times per day for five days. This means 30 replicates per sample per site. With 3 sites and 3 samples, approximately 270 data points (30 * 3 * 3).
• External Site Method Comparison: Approximately 70 serum specimens per site, for a total of around 210 specimens (3 sites * ~70 samples/site). Data provenance: Not explicitly stated, but typically from within the country where the study is conducted (likely USA, given the FDA submission). Retrospective.

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

This information is not applicable as the device is a quantitative chemical analyzer. The "ground truth" for the test sets (samples used in the studies) is established by the reference methods or known concentrations, not by expert interpretation.

4. Adjudication Method for the Test Set:

This information is not applicable as the device is a quantitative chemical analyzer. Ground truth is determined objectively through reference methods or known concentrations, not through expert adjudication.

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:

This information is not applicable. The device is a diagnostic instrument (chemistry analyzer) and not an AI-based imaging or diagnostic aid that involves human readers.

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

The studies described (precision, linearity, method comparison, interference, matrices comparison) represent the standalone performance of the Hitachi Clinical Analyzer with the S TEST Reagent Cartridge ALP. This is the direct measurement by the instrument, without a human interpretation step.

7. The Type of Ground Truth Used:

The ground truth for the performance studies was established using:

• Reference Methods: For method comparison studies, the Hitachi system was compared against a "standard laboratory system" (predicate device or another established method).
• Known Concentrations/Values: For linearity, precision, and interference studies, samples with known or carefully characterized concentrations of ALP and potential interferents were used.
• CLSI Guidelines: Studies followed established Clinical and Laboratory Standards Institute (CLSI) guidelines (e.g., EP17-A for detection limit, EP-6A for linearity, EP5-A2 for precision, EP7-A2 for interference).

8. The Sample Size for the Training Set:

This information is not applicable. This device is a traditional chemical analyzer, not an AI/machine learning system that requires a "training set" in the computational sense. The device's parameters are set during its manufacturing and calibration process, not through a data-driven training phase.

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

This information is not applicable for the reason stated in point 8.

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The ACE Axcel Clinical Chemistry System is an automated, discrete, bench-top, random access analyzer that is intended for in vitro diagnostic use in the quantitative determination of constituents in blood and other fluids.

The ACE Alkaline Phosphatase Reagent is intended for the quantitative determination of alkaline phosphatase activity in serum using the ACE Axcel Clinical Chemistry System. Measurements of alkaline phosphatase are used in the diagnosis and treatment of liver, bone, parathyroid, and intestinal diseases. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Amylase Reagent is intended for the quantitative determination of a-amylase activity in serum using the ACE Axcel Clinical Chemistry System. Amylase measurements are used primarily for the diagnosis and treatment of pancreatitis (inflammation of the pancreas). This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE LDH-L Reagent is intended for the quantitative determination of lactate dehydrogenase activity in serum using the ACE Axcel Clinical Chemistry System. Lactate dehydrogenase measurements are used in the diagnosis and treatment of liver diseases such as acute viral hepatitis, cirrhosis, and metastatic carcinoma of the liver, cardiac diseases such as myocardial infarction and tumors of the lung or kidneys. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Axcel Clinical Chemistry System consists of two major components, the chemistry instrument and an integrated Panel PC. The instrument accepts the physical patient samples, performs the appropriate optical or potentiometric measurements on those samples and communicates that data to an integral Panel PC. The Panel PC uses keyboard or touch screen input to manually enter a variety of data, control and accept data from the instrument, manage and maintain system information and generate reports relative to patient status and instrument performance. The Panel PC also allows remote download of patient requisitions and upload of patient results via a standard interface.

In the ACE Alkaline Phosphatase Reagent assay, alkaline phosphatase in serum catalyzes the hydrolysis of colorless p-nitrophenyl phosphate to p-nitrophenol and inorganic phosphate. In an alkaline solution (pH 10.5), p-nitrophenol is in the phenoxide form and has a strong absorbance at 408 nm. The rate of increase in absorbance, monitored bichromatically at 408 nm/486 nm, is directly proportional to the alkaline phosphatase activity in the sample.

In the ACE AST Reagent assay, a-amylase hydrolyzes the 2-chloro-p- nitrophenyl-a-D-maltotrioside substrate to release 2-chloro-p- nitrophenol and form 2-chloro-p- nitrophenyl-a-D-maltoside, maltotriose and glucose. The rate of increase in absorbance, monitored bichromatically at 408 nm/ 647 nm, is directly proportional to the a- amylase activity in the sample.

In the ACE LDH-L Reagent assay, lactate dehydrogenase catalyzes the conversion of L-lactate to pyruvate. Nicotinamide adenine dinucleotide (NAD+) acts as an acceptor for the hydrogen ions released from the L- lactate and is converted to reduced nicotinamide adenine dinucleotide (NADH). NADH absorbs strongly at 340 nm whereas NAD+ does not. Therefore, the rate of conversion of NAD+ to NADH can be determined by monitoring the increase in absorbance bichromatically at 340 nm/647 nm. This rate of conversion from NAD+ to NADH is directly proportional to the lactate dehydrogenase activity in the sample.

Here's an analysis of the provided text regarding the acceptance criteria and the study that proves the device meets those criteria:

Acceptance Criteria and Device Performance for ACE Alkaline Phosphatase, Amylase, and LDH-L Reagents on the ACE Axcel Clinical Chemistry System

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as numerical targets in the provided text. Instead, the study aims to demonstrate substantial equivalence to a predicate device (Alfa Wassermann ACE Clinical Chemistry System and ACE Reagents, K931786) by showing a high degree of correlation and acceptable precision. The reported device performance is compared to the predicate device.

ACE Alkaline Phosphatase Reagent

ACE Amylase Reagent

ACE LDH-L Reagent

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

• ACE Alkaline Phosphatase Reagent:

  • Accuracy (Correlation Study): 112 samples.
  • Accuracy (POL Patient Correlation): Not specified (implied to be numerous patient samples tested at 3 POL sites).
  • Precision (Central Lab): Data collected over 22 days, with 4 alkaline phosphatase levels tested. The exact number of individual samples run per level/day is not specified but is typical for precision studies (e.g., n=2 or n=3 replicates).
  • Precision (POL Sites): Data collected over 5 days at 3 separate Physician Office Laboratories (POLs), with 4 alkaline phosphatase levels tested. The exact number of individual samples run per level/day is not specified.
  • Data Provenance: Not explicitly stated, but the mention of "Central Lab" and "Physician Office Laboratory (POL) sites" suggests clinical laboratory settings. It does not specify country of origin or if retrospective/prospective, but stability studies and clinical accuracy studies usually involve prospective collection or use of banked clinical samples. Given it is a 510(k) submission, it is likely representing real-world clinical samples.

• ACE Amylase Reagent:

  • Accuracy (Correlation Study): 111 samples.
  • Accuracy (POL Patient Correlation): Not specified (implied to be numerous patient samples tested at 3 POL sites).
  • Precision (Central Lab): Data collected over 22 days, with 4 amylase levels tested.
  • Precision (POL Sites): Data collected over 5 days at 3 separate POL sites, with 4 amylase levels tested.
  • Data Provenance: Similar to Alkaline Phosphatase, suggesting clinical laboratory settings in the US, likely using prospective or banked clinical samples.

• ACE LDH-L Reagent:

  • Accuracy (Correlation Study): 121 samples.
  • Accuracy (POL Patient Correlation): Not specified (implied to be numerous patient samples tested at 3 POL sites).
  • Precision (Central Lab): Data collected over 22 days, with 4 LDH levels tested.
  • Precision (POL Sites): Data collected over 5 days at 3 separate POL sites, with 4 LDH levels tested.
  • Data Provenance: Similar to the previous reagents, suggesting clinical laboratory settings in the US, likely using prospective or banked clinical samples.

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

This device is a clinical chemistry analyzer, not an imaging or diagnostic AI device that requires expert adjudication for "ground truth." The "ground truth" for the accuracy studies is established by the performance of the predicate device (Alfa Wassermann ACE Clinical Chemistry System). The predicate device itself would have been validated against established reference methods or clinical outcomes when it was initially cleared/approved. Therefore, no human experts directly establish "ground truth" in the way it might for image interpretation.

4. Adjudication Method for the Test Set

Not applicable for this type of device (clinical chemistry analyzer). Adjudication methods like 2+1 or 3+1 are used for subjective interpretations or classifications (e.g., by radiologists or pathologists) to reach a consensus "ground truth." For quantitative measurements, the "truth" is typically a measurement from a reference method or a well-established, previously validated method (in this case, the predicate device).

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

No. This type of study is typically for evaluating the performance of AI algorithms in conjunction with human readers, often in image interpretation tasks. This submission is for a clinical chemistry analyzer and reagents.

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

Yes, the studies presented are essentially "standalone" performance evaluations of the new ACE Axcel Clinical Chemistry System with the specific reagents. The system measures analyte concentrations automatically, and its performance (precision, accuracy, detection limit) is assessed without direct human intervention in the measurement process itself, although human operators load samples and maintain the system. The "comparison" is to the predicate device, which is also a standalone automated system.

7. The Type of Ground Truth Used

The "ground truth" used for accuracy (correlation) studies is the measurement result from the legally marketed predicate device: the Alfa Wassermann ACE Clinical Chemistry System and its corresponding ACE Reagents (K931786). This is a common approach for demonstrating substantial equivalence for in vitro diagnostic devices when a recognized gold standard method might not be readily available for routine testing or if the goal is to show equivalence to an existing market performer.

8. The Sample Size for the Training Set

Not applicable. This is not an AI/machine learning device that requires a training set in the conventional sense. The device is a traditional clinical chemistry analyzer based on established photometric and enzymatic reaction principles. The "training" for such a system would involve instrument calibration (which uses control materials, not a "training set" of patient data) and reagent manufacturing/quality control.

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

Not applicable, as there is no "training set" for an AI algorithm. For instrument calibration, the "ground truth" for calibrators would be established by the manufacturer using reference methods or certified reference materials, and then verified through quality control materials.

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ELITech Clinical Systems ALP IFCC SL is intended for the quantitative in vitro diagnostic determination of alkaline phosphatase in human serum and plasma on ELITech Clinical Systems Selectra analyzers.
It is not intended for use In Point of Care settings.
Alkaline phosphatase or its isoenzymes measurements are used in the diagnosis and treatment of liver, bone, parathyroid and intestinal diseases.

The device for this submission is available as kit only. It consists of 2 reagents R1 & reagent R2.
Reagent R1 contains: 2-Amino-2-methyl-1-propanol (AMP) buffer (pH 10.45), Magnesium ions, Zinc ions.
Reagent R2 contains: p-Nitrophenylphosphate (p-NPP), sodium azide.

The provided text describes a 510(k) premarket notification for the ELITech Clinical Systems ALP IFCC SL device, which is an in vitro diagnostic for measuring alkaline phosphatase. The document focuses on establishing substantial equivalence to a predicate device (Roche Diagnostics ALP2S).

Here's an analysis of the acceptance criteria and the study data, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated as distinct numerical targets. Instead, the document presents a comparison of performance characteristics between the new device (ELITech Clinical Systems ALP IFCC SL) and the predicate device (Roche Diagnostics ALP2S). The "acceptance criteria" are implicitly demonstrated by showing comparable or superior performance to the predicate.

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

The document does not explicitly state the sample size for the test set used for performance validation studies (e.g., precision, method comparison, interference). It only provides the results (CVs, regression equations, interference limits).

The data provenance (country of origin, retrospective/prospective) is not explicitly stated. However, given the manufacturer (SEPPIM S.A.S. in FRANCE) and the submission to the FDA, it's highly probable the studies were conducted by the manufacturer, likely in Europe, with data collected prospectively for the purpose of regulatory submission. The samples used would typically be human serum and plasma, as per the intended use.

3. Number of Experts and Qualifications for Ground Truth

This device is an in vitro diagnostic for measuring a biochemical analyte (alkaline phosphatase). The concept of "ground truth" for such a device is typically established through:

• Reference Methods: Highly accurate and precise laboratory methods.
• Certified Reference Materials: Solutions with known concentrations of the analyte.
• Clinical Samples with Established Values: Values determined by existing, validated diagnostic methods.

The document does not mention the use of human experts (like radiologists) for establishing ground truth, as this is not a device that relies on human interpretation of images or other qualitative data. The ground truth for chemical analytes is quantitative and typically relies on analytical methods.

4. Adjudication Method for the Test Set

Adjudication methods (like 2+1, 3+1) are typically used for qualitative assessments, especially in image interpretation tasks, where multiple experts review cases and resolve discrepancies. Since this is an in vitro diagnostic for a quantitative measurement, such adjudication methods are not applicable and thus not mentioned.

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

An MRMC study was not done. MRMC studies are relevant for devices that involve human readers (e.g., radiologists, pathologists) interpreting data, potentially with AI assistance. This device is an automated biochemical analyzer, and therefore, human-in-the-loop performance or comparison is not relevant to its validation.

6. Standalone (Algorithm Only) Performance

This device is a standalone algorithm/device in the context of its function. It is a reagent kit used on an automated analyzer (ELITech Clinical Systems Selectra analyzers) to quantitatively determine alkaline phosphatase. Its performance metrics (precision, linearity, interference, method comparison) are inherently "standalone" in that they describe the performance of the device itself (reagent + analyzer) in measuring the analyte without human interpretation as part of the primary measurement.

7. Type of Ground Truth Used

The ground truth used for validating this type of device would typically be:

• Reference Standards/Calibrators: Solutions with precisely known concentrations of alkaline phosphatase.
• Comparison to a Predicate Device/Established Method: The "Method comparison" section (y= 1.025 x - 1 U/L, r= 0.998) explicitly indicates that the new device's results were compared against those obtained from an existing, validated method (likely the predicate device or a reference method for the x-axis values). The high correlation coefficient (r=0.998) demonstrates agreement with this established truth.
• Internal Quality Control Materials: Often assayed with known target ranges.

8. Sample Size for the Training Set

The document does not mention a "training set" in the context of machine learning or AI. This device is a traditional chemical assay kit. As such, there isn't a "training set" in the sense it's used for AI models. The development and optimization of the assay would involve various experiments, but not a formally defined "training set" as in AI.

9. How Ground Truth for the Training Set Was Established

Since there is no "training set" in the AI sense, this question is not applicable. The assay's chemical principles, reagent concentrations, and reaction conditions are established through chemical and biological experimentation, aiming to accurately reflect the activity of alkaline phosphatase. Performance characteristics, like those listed in the comparison table, are then verified through rigorous testing with known standards and clinical samples.

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