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For in vitro diagnostic use only

The UREA test within the VITROS XT Chemistry Products UREA-CREA Slides quantitatively measures urea concentration, reported either as urea nitrogen or as urea (UREA), in serum, plasma, and urine using the VITROS XT 7600 Integrated System. Measurements obtained by this device are used in the diagnosis and treatment of certain renal and metabolic diseases

The CREA test within the VITROS XT Chemistry Products UREA-CREA Slides quantitatively measures creatinine (CREA) concentration in serum, plasma, and urine using the VITROS XT 7600 Integrated System. Creatinine measurements are used in the diagnosis and treatment of renal dialysis, and as a calculation basis for measuring other urine analytes.

Special conditions for use statement: For prescription use only.

The new device, the VITROS XT Chemistry Products UREA-CREA Slide is a single device that contains both a UREA test and a CREA test multilayered, analytical element coated on a polyester support separated by a plastic barrier sealed within a single slide frame. In this format, individual reactions occur and test results are generated for each analyte independently of the other analyte.

To perform the UREA test, a drop of patient sample is deposited on the slide and is evenly distributed by the spreading layer to the underlying layers. Water and nonproteinaceous components then travel to the underlying reagent layer, where the urease reaction generates ammonia. The semipermeable membrane allows only ammonia to pass through to the colorforming layer, where it reacts with the indicator to form a dye. The reflection density of the dye is measured and is proportional to the concentration of urea in the sample.

To perform the CREA test, a drop of patient sample is deposited on the slide and is evenly distributed by the spreading layer to the underlying layers. Creatinine diffuses to the reagent layer, where it is hydrolyzed to creatine in the rate-determining step. The creatine is converted to sarcosine and urea by creatine amidinohydrolase. The sarcosine, in the presence of sarcosine oxidase, is oxidized to glycine, formaldehyde, and hydrogen peroxide. The final reaction involves the peroxidase-catalyzed oxidation of a leuco dye to produce a colored product. Following addition of the sample, the slide is incubated. During the initial reaction phase, endogenous creatine in the sample is oxidized. The resulting change in reflection density is measured at 2 time points. The difference in reflection density is proportional to the concentration of creatinine present in the sample.

This document describes the analytical performance of the VITROS XT Chemistry Products UREA-CREA Slides for quantitatively measuring urea and creatinine concentrations. The information provided is for an in-vitro diagnostic device and does not involve AI assistance, human readers, or image analysis, thus many of the requested elements are not applicable.

1. Table of Acceptance Criteria and Reported Device Performance

The device performance is primarily assessed through method comparison (against predicate devices), precision, detection limits, and linearity. The "acceptance criteria" are implied by the measured performance demonstrating substantial equivalence to the predicate devices and meeting clinical laboratory standards for accuracy and precision.

2. Sample Size and Data Provenance

• Method Comparison Test Set:
  • UREA Serum: 124 samples
  • UREA Urine: 128 samples
  • CREA Serum: 130 samples
  • CREA Urine: 116 samples
• Precision Test Set: Not specified as a separate patient sample set, but rather "patient pools and quality control materials." Each precision study included "a minimum of 80 observations (2 replicates per run, 2 runs per day over 20 days)" for serum and urine pools/controls.
• Detection Limits (LoQ) Test Set: 72 determinations for serum (UREA and CREA) and 64 for urine (CREA). 72 for urine (UREA).
• Linearity Test Set: Twenty proportionally related admixtures of low and high test fluids, each tested in quadruplicate. Specific number of patient samples not stated, as it uses contrived samples.
• Specificity (Interference) Test Set: Not explicitly stated how many patient samples were used, but rather "96 test substances" and "88 test substances" were spiked into serum samples, and "two substances" and "nineteen test substances" for urine.
• Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). However, the studies used standard clinical laboratory protocols (e.g., CLSI EP09-A3, EP05-A3, EP17-A2, EP06-A) which typically involve fresh or appropriately preserved clinical samples. The reference interval studies mention "an internal study of 3160 apparently healthy adults" and "an external study" (for UREA) or "an external study of apparently healthy adults (serum: 180 males and 180 females)" and "a separate external study" (for CREA).

3. Number of Experts and Qualifications for Ground Truth

• This is an in-vitro diagnostic device (chemistry analyzer) measuring chemical concentrations. The "ground truth" is established by the reference methodology (predicate devices on a different system) and gravimetric/analytical preparation of calibrators and quality controls. It does not involve human expert interpretation of images or other subjective assessments. Therefore, the concept of "experts establishing ground truth" in the context of radiology or pathology (e.g., radiologists interpreting images) is not applicable here.

4. Adjudication Method for the Test Set

• Not applicable. This is not a study involving human reader interpretation requiring adjudication. Performance is assessed analytically against quantitative measurements.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done

• No, an MRMC study was not done. This device is an automated in-vitro diagnostic assay, not an AI-assisted diagnostic tool for human readers.

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

• Yes, this study represents a standalone analytical performance evaluation of the device's ability to accurately measure urea and creatinine concentrations. "Algorithm" in this context refers to the chemical reactions and measurement principles of the assay, not a software algorithm that processes medical images or data for interpretation. The performance metrics (method comparison, precision, detection limits, linearity, specificity) directly quantify the device's analytical capabilities without human intervention in the measurement process itself.

7. The type of ground truth used

• The ground truth is established through:
  • Reference Methods/Predicate Devices: For method comparison, the results generated by the predicate devices (VITROS BUN/UREA Slides and VITROS CREA Slides on the VITROS 5600 Integrated System) serve as the comparative ground truth.
  • Analytically Prepared Materials: For precision, detection limits, and linearity, the "ground truth" concentrations of control materials, patient pools, and serially diluted samples are established through precise gravimetric and volumetric preparations, often traceable to certified reference materials.
  • Clinical Laboratory Standards (CLSI Protocols): The studies adhered to widely accepted CLSI guidelines for analytical performance evaluation, implying that the methodologies used to establish "ground truth" for each parameter meet industry standards for accuracy and rigor in a clinical lab setting.

8. The Sample Size for the Training Set

• This is not an AI/machine learning study that involves "training sets" in the conventional sense. The device's performance is based on the inherent chemical and optical principles of the dry-slide technology. There's no AI model being trained with data.

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

• Not applicable, as there is no AI training set.

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The S TEST Reagent Cartridge Blood Urea Nitrogen (BUN) is intended for the quantitative measurement of BUN in serum, lithium heparin plasma, K3 EDTA plasma, and sodium citrate plasma on the Hitachi Clinical Analyzer E40. The test system is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only. BUN measurements are used in the diagnosis and treatment of certain renal and metabolic diseases.

The S TEST Reagent Cartridge Creatinine (CRE) is intended for the quantitative measurement of creatinine in serum, lithium heparin plasma, K3 EDTA plasma, and sodium citrate plasma on the Hitachi Clinical Analyzer E40. The test system is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes.

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, c.g., expiration dating, 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 scrum or plasma and results are available in approximately 15 minutes per test. This submission is for reagent cartridge test systems for glucose.

The provided text describes the performance of the Hitachi S TEST Reagent Cartridge Blood Urea Nitrogen (BUN) and S TEST Reagent Cartridge Creatinine (CRE) for use with the Hitachi Clinical Analyzer E40. These are in vitro diagnostic devices, not AI/ML-driven as commonly understood in medical imaging or other AI applications. Therefore, many of the requested categories (e.g., number of experts, adjudication method, MRMC study, training set ground truth) are not applicable to this type of device.

Below is a summary of the acceptance criteria and reported device performance based on the provided document, adapted for an in vitro diagnostic device regulatory submission.

1. Table of Acceptance Criteria and Reported Device Performance

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

• Analytical Sensitivity (LoD): No specific sample size for a test set is provided, as this is typically determined by testing multiple replicates of low-concentration samples.
• Linearity/Reportable Range: Not specified as a distinct "test set" sample size beyond the creation of concentration series.
• 20-day In-house Precision:
  • BUN: n=80 per level (3 levels), so 240 measurements in total.
  • CRE: n=80 per level (4 levels), so 320 measurements in total.
• Interference Testing: Two serum pools per analyte, spiked with various concentrations of interfering substances. Specific number of total samples not explicitly stated but implies multiple measurements for each.
• Method Comparison (Internal):
  • BUN: 162 clinical specimens.
  • CRE: 100 clinical specimens.
• Matrices Comparisons:
  • BUN: 36 matched serum/plasma samples.
  • CRE: 39 matched serum/plasma samples.
• External Site Precision: Each of 3 sites tested 3 blinded serum samples (low, middle, high levels) 6 times a day for 5 days. For each level, n=30 replicates per site.
• External Site Method Comparison:
  • BUN: Approximately 75 serum specimens at each of 3 sites (total ~225).
  • CRE: Approximately 45 serum specimens at each of 3 sites (total ~135).

Data Provenance: The studies were performed "in-house" (Hitachi Chemical Diagnostics, Inc.) and at "three external POL-type sites" (Physician Office Laboratory). The clinical specimens are implied to be human serum or plasma. No country of origin is explicitly stated for the clinical data, but the company is in the USA. The studies are prospective in the sense that they were designed and executed to evaluate the device performance for this 510(k) submission.

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

This is not applicable to this type of in vitro diagnostic device. The "ground truth" for chemical analyzers is established through reference methods and calibrated samples, not expert consensus in the way a radiologist would interpret an image. The comparative methods used in the method comparison studies serve as the reference.

4. Adjudication Method for the Test Set

Not applicable. This is a quantitative chemical assay. Discrepancies are resolved through re-testing or investigation of analytical issues, not by expert adjudication of interpretations.

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

Not applicable. This device is an automated chemical analyzer, not an AI-assisted diagnostic imaging tool that involves human readers interpreting cases.

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

Yes, the device operates in a standalone (algorithm only) manner. It is an automated instrument that performs the assay and calculates results based on the detected absorbance. Humans are involved in operating the instrument, loading samples, and interpreting the numerical output, but the measurement and calculation itself is automated. The performance metrics listed (precision, linearity, method comparison, etc.) reflect this standalone analytical performance.

7. The Type of Ground Truth Used

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

• Reference materials/calibrators: Used for linearity, detection limits, and precision studies.
• Comparative methods/Standard laboratory systems: The results from the Hitachi system are compared against established, legally marketed systems (e.g., Roche Cobas c systems) which serve as the reference or "ground truth" for method comparison and accuracy studies. These are not "expert consensus, pathology, or outcomes data" in the traditional sense, but rather established analytical methods.

8. The Sample Size for the Training Set

Not applicable. This device is a wet chemistry system, not an AI/ML model that requires a training set in that context. The "training" of such a system involves chemical reagent formulation and instrument calibration, not data-driven model training.

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

Not applicable. As noted above, this is not an AI/ML model with a data-driven training set.

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The ACE BUN/Urea Reagent is intended for the quantitative determination of blood urea nitrogen (BUN) concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. BUN measurements are used in the diagnosis and treatment of certain renal and metabolic diseases. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Creatinine Reagent is intended for the quantitative determination of creatinine concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Uric Acid Reagent is intended for the quantitative determination of uric acid concentration in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Uric acid measurements are used in the diagnosis and treatment of numerous renal and metabolic disorders, including renal failure, gout, leukemia, psoriasis, starvation or other wasting conditions and of patients receiving cytotoxic drugs. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE CK Reagent is intended for the quantitative determination of creatine kinase activity in serum and lithium heparin plasma using the ACE, ACE Alera, and ACE Axcel Clinical Chemistry Systems. Measurement of creatine kinase is used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

In the ACE BUN/Urea Reagent assay, urea in serum is hydrolyzed in the presence of urease to yield ammonia and carbon dioxide. The ammonia formed then reacts in the presence of glutamate dehydrogenase with 2-oxoglutarate and NADH to yield glutamate and NAD. NADH absorbs strongly at 340 nm, whereas NAD+ does not. The initial rate of decrease in absorbance, monitored bichromatically at 340 nm/647 nm, is proportional to the urea concentration in the sample.

In the ACE Creatinine Reagent assay, creatinine reacts with picric acid in an alkaline medium to form a red-orange colored complex, which absorbs strongly at 505 nm. The rate of complex formation, determined by measuring the increase in absorbance bichromatically at 505 nm/573 nm during a fixed time interval, is directly proportional to the creatinine concentration in the sample.

In the ACE Uric Acid Reagent assay, uric acid in serum is oxidized by uricase to allantoin and hydrogen peroxide. The hydrogen peroxide then acts to oxidatively couple dichlorohydroxybenzene sulfonic acid and 4-aminoantipyrine in a reaction catalyzed by peroxidase, producing a red colored quinoneimine complex, which absorbs strongly at 505 nm. The amount of chromogen formed is determined by measuring the increase in absorbance bichromatically at 505 nm/610 nm, and is directly proportional to the uric acid concentration in the sample.

In the ACE CK Reagent assay, serum creatine kinase initiates the conversion of creatine phosphate to creatine with the transfer of a phosphate group to adenosine diphosphate (ADP), forming ATP. The ATP is then used in the phosphorylation of D-glucose to form D-glucose-6-phosphate and ADP. This reaction is catalyzed by hexokinase. The enzyme glucose-6-phosphate dehydrogenase catalyzes the reduction of D-glucose-6-phosphate and nicotinamide adenine dinucleotide phosphate (NADP+). The series of reactions triggered by serum creatine kinase and ending in the formation of NADPH. NADPH strongly absorbs at 340 nm, whereas NADP+ does not. Therefore, the rate of conversion of NADP+ to NADPH can be determined by monitoring the increase in absorbance bichromatically at 340 nm/378 nm. This rate of conversion from NADP+ to NADPH is a function of the activity of CK in the sample.

Here's a summary of the acceptance criteria and supporting studies for the Alfa Wassermann ACE Reagents (BUN/Urea, Creatinine, Uric Acid, CK), based on the provided 510(k) summary.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from comparisons to a predicate device (Alfa Wassermann ACE K930104 reagents) and performance characteristics such as precision, accuracy (correlation/regression with predicate), linearity, detection limits, and interference. The reported device performance is from in-house studies and Point-of-Care (POL) studies.

Note: The document does not explicitly state "acceptance criteria" numerical targets. Instead, it presents performance data for the candidate device, implying that the data's comparability to the predicate and established analytical standards is the basis for acceptance. I will present the reported performance, which demonstrates the device's meeting the necessary equivalency.

Studies Proving Acceptance Criteria:

The studies are described under "Performance Data" and "Device Comparison with Predicate" sections of the 510(k) summary. These studies aim to demonstrate substantial equivalence to the previously cleared predicate device (Alfa Wassermann ACE BUN/Urea Reagent, ACE Creatinine Reagent, ACE Uric Acid Reagent, and ACE CK Reagents, K930104).

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

• Test Set (Matrix Comparison: Serum vs. Plasma):

  • BUN: 95 pairs (ACE), 96 pairs (Alera), 51 pairs (Axcel)
  • Creatinine: 102 pairs (ACE), 102 pairs (Alera), 55 pairs (Axcel)
  • Uric Acid: 97 pairs (ACE), 95 pairs (Alera), 55 pairs (Axcel)
  • CK: 94 pairs (ACE), 96 pairs (Alera), 55 pairs (Axcel)
  • Data Provenance: The document states "In-House Precision" and "In-House Matrix Comparison". This typically implies that the data was generated within the manufacturer's laboratory or a testing facility under their control. The country of origin is not explicitly stated but is implicitly the US, given the 510(k) submission to the FDA. The data is retrospective, as it's being used to characterize reagent performance.

• Test Set (POL - Method Comparison):

  • BUN: 53-54 samples per POL lab for comparison with In-House ACE.
  • Creatinine: 51 samples per POL lab for comparison with In-House ACE.
  • Uric Acid: 49 samples per POL lab for comparison with In-House ACE.
  • Creatinine Kinase: 48-50 samples per POL lab for comparison with In-House ACE.
  • Data Provenance: "POL - Method Comparison" indicates data from Physician Office Laboratories (POLs), likely external to the main testing facility but still considered part of the overall validation. The document refers to "In-House ACE (x) vs. POL 1 ACE (y)", "POL 2 ACE (y)", etc., indicating comparisons against internal reference methods. The data is retrospective.

• Test Set (Detection Limits, Linearity, Interferences, Alera Precision): The sample sizes for these specific studies are not explicitly detailed in the provided summary beyond "Low level tested," "Upper level tested," and "number of replicates for precision measurements (i.e. '3.2, 4.0%') implies multiple measurements. These are likely in-house, retrospective studies.

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

This information is not provided in the document. For in vitro diagnostic devices like these reagents, the "ground truth" is typically established by reference methods or validated comparative methods, often run on established clinical chemistry analyzers. The expertise lies in operating these reference instruments and ensuring proper laboratory practices, rather than expert interpretation of images or clinical cases.

4. Adjudication Method for the Test Set

This concept is not applicable to this type of device. Adjudication methods (like 2+1, 3+1) are common in studies involving subjective interpretations (e.g., medical image analysis by radiologists) where discrepancies among readers need to be resolved to establish ground truth. For quantitative IVD reagents, the reference method provides a direct numerical result, not a subjective interpretation requiring adjudication.

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

This is not applicable to this type of device. MRMC studies are used to assess the effectiveness of an AI system (or any diagnostic aid) for human readers, particularly in medical imaging. The current device is a diagnostic reagent, which directly measures chemical concentrations, not an AI intended to assist human interpretation of cases.

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

This is not applicable in the context of an IVD reagent. The "algorithm" here is the chemical reaction and photometric measurement itself. The performance data presented (precision, linearity, method comparison, etc.) is the standalone performance of the reagent on the specified analyzers, without human interpretive input altering the result.

7. Type of Ground Truth Used

The ground truth for all performance studies (precision, matrix comparison, method comparison, linearity) is established by comparison against a reference method or a substantially equivalent predicate method performed on existing, validated clinical chemistry analyzers (specifically, the predicate ACE Clinical Chemistry System and the candidate ACE, ACE Alera, and ACE Axcel systems themselves acting as the "reference" for their own performance claims, and for method comparisons, the "In-House ACE" results). This is a common and accepted approach for demonstrating substantial equivalence for IVD reagents.

8. Sample Size for the Training Set

This information is not provided and is generally not applicable in the way it is asked for AI/ML devices. These are chemical reagents, not AI/ML algorithms that require "training sets" in the conventional sense of machine learning. The development process would involve formulation, optimization, and internal testing to define assay parameters, which is a different concept than an AI training set.

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

As stated above, the concept of a "training set" with established ground truth in the AI/ML sense is not applicable to these chemical reagents. The "ground truth" during their development and optimization would be based on established analytical chemistry principles and performance measurements against known standards or reference materials.

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The ACE BUN/Urea Reagent is intended for the quantitative determination of blood urea nitrogen (BUN) concentration in serum using the ACE Axcel Clinical Chemistry System. BUN measurements are used in the diagnosis and treatment of certain renal and metabolic diseases. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Creatinine Reagent is intended for the quantitative determination of creatinine concentration in serum using the ACE Axcel Clinical Chemistry System. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis, and as a calculation basis for measuring other urine analytes. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Uric Acid Reagent is intended for the quantitative determination of uric acid concentration in serum using the ACE Axcel Clinical Chemistry System. Uric acid measurements are used in the diagnosis and treatment of numerous renal and metabolic disorders, including renal failure, gout, leukemia, psoriasis, starvation or other wasting conditions and of patients receiving cytotoxic drugs. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE CK Reagent is intended for the quantitative determination of creatine kinase activity in serum using the ACE Axcel Clinical Chemistry System. Measurement of creatine kinase is used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy. 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 BUN/Urea Reagent assay, urea in serum is hydrolyzed to yield ammonia and carbon dioxide in the presence of urease. The ammonia formed then reacts with 2-oxoglutarate and NADH in the presence of glutamate dehydrogenase to yield glutamate and NAD. Two moles of NADH are oxidized for each mole of urea present. NADH absorbs strongly at 340 nm, whereas NAD+ does not. The initial rate of decrease in absorbance, monitored bichromatically at 340 nm/647 nm, is proportional to the urea concentration in the sample.

In the ACE Creatinine Reagent assay, creatinine reacts with picric acid in an alkaline medium to form a red-orange colored complex, which absorbs strongly at 505 nm. The rate of complex formation, determined by measuring the increase in absorbance bichromatically at 505 nm/573 nm during a fixed time interval, is directly proportional to the creatinine concentration in the sample.

In the ACE Uric Acid Reagent assay, uric acid in serum is oxidized by uricase to allantoin and hydrogen peroxide. The hydrogen peroxide then acts to oxdatively couple dichlorohydroxybenzene sulfonic acid and 4-aminoantipyrine in a reaction catalyzed by peroxidase, producing a red colored quinoneimine complex, which absorbs strongly at 505 nm. The amount of chromogen formed, determined by measuring the increase in absorbance bichromatically at 505 nm/610 nm, is directly proportional to the uric acid concentration in the sample.

In the ACE CK Reagent assay, serum creatine kinase initiates the conversion of creatine phosphate to creatine with the transfer of a phosphate group to adenosine diphosphate (ADP), forming ATP. The ATP is then used in the phosphorylation of D-glucose to form D-glucose-6-phosphate and ADP. This reaction is catalyzed by hexokinase. The enzyme glucose-6-phosphate dehydrogenase catalyzes the reduction of D-glucose-6-phosphate and nicotinamide adenine dinucleotide phosphate (NADP+). The series of reactions triggered by serum creatine kinase and ending in the formation of NADPH. NADPH strongly absorbs at 340 nm, whereas NADP+ does not. Therefore, the rate of conversion of NADP+ to NADPH can be determined by monitoring the increase in absorbance bichromatically at 340 nm/378 nm. This rate of conversion from NADP+ to NADPH is a function of the activity of CK in the sample.

The ACE BUN/Urea Reagent consists of a single reagent bottle. The reagent contains alpha-ketoglutarate, urease, glutamate dehydrogenase, adenosine diphosphate (ADP), nicotinamide adenine dinucleotide and reduced (NADH).

The ACE Creatinine Reagent consists of two reagent bottles (Sodium Hydroxide Reagent and Picric Acid Reagent). The Sodium Hydroxide Reagent (R1) contains sodium hydroxide. The Picric Acid Reagent (R2) contains picric Acid.

The ACE Uric Acid Reagent consists of a single reagent bottle. The reagent contains 4-aminoantipyrine, dichlorohydroxybenzene sulfonic acid, peroxidase and uricase.

The ACE CK Reagent consists of two reagent bottles (Buffer and Substrate). The Buffer Reagent (R1) contains: imidazole buffer, glucose, N-acetyl-cysteine, magnesium acetate, EDTA, NADP and hexokinase. The Substrate Reagent (R2) contains: creatine phosphate, ADP, AMP, diadenosine pentaphosphate, EDTA and glucose-6-phosphate dehydrogenase.

This 510(k) summary describes the analytical performance of the Alfa Wassermann ACE BUN, Creatinine, Uric Acid, and CK Reagents when used with the ACE Axcel Clinical Chemistry System. The study aims to demonstrate substantial equivalence to a predicate device by evaluating precision, accuracy, and detection limits.

1. Table of Acceptance Criteria (Implied) and Reported Device Performance

The acceptance criteria for this type of device are generally understood to be that the performance of the new device (ACE Axcel System with new reagents) should be comparable to or better than a legally marketed predicate device (Alfa Wassermann ACE Clinical Chemistry System). While explicit numerical acceptance criteria are not strictly stated as "acceptance criteria" but rather as "reported performance," the goal is to show the device performs within acceptable analytical limits for clinical chemistry assays and is strongly correlated with the predicate.

Note: Acceptance criteria are implied based on typical expectations for clinical chemistry assays and the intent to demonstrate substantial equivalence to a predicate device. Specific numerical targets for acceptance were not explicitly stated in the provided text, but the strong correlation and low CVs indicate meeting such criteria.

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

• ACE BUN/Urea Reagent:

  • Accuracy (Correlation Study): 113 samples (clinical laboratory), and patient correlation studies at three Physician Office Laboratory (POL) sites (number of samples not explicitly stated for POL, but implied to be sufficient for regression analysis).
  • Precision: Four BUN levels over 22 days (laboratory study), and three POL sites over 5 days (levels not specified for POL).
  • Data Provenance: Not explicitly stated, but clinical laboratory and Physician Office Laboratory (POL) settings are mentioned, suggesting human serum samples. Whether these were retrospective or prospective is not specified, but typically, method comparison studies use prospective or collected retrospective clinical samples.

• ACE Creatinine Reagent:

  • Accuracy (Correlation Study): 136 samples (clinical laboratory), and patient correlation studies at three POL sites (number of samples not explicitly stated for POL).
  • Precision: Four creatinine levels over 22 days (laboratory study), and three POL sites over 5 days (levels not specified for POL).
  • Data Provenance: Not explicitly stated, but clinical laboratory and POL settings are mentioned, suggesting human serum samples.

• ACE Uric Acid Reagent:

  • Accuracy (Correlation Study): 106 samples (clinical laboratory), and patient correlation studies at three POL sites (number of samples not explicitly stated for POL).
  • Precision: Four uric acid levels over 22 days (laboratory study), and three POL sites over 5 days (levels not specified for POL).
  • Data Provenance: Not explicitly stated, but clinical laboratory and POL settings are mentioned, suggesting human serum samples.

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

Not applicable. This is an in vitro diagnostic (IVD) device for quantitative measurement of chemical analytes (BUN, Creatinine, Uric Acid, CK) in serum. The 'ground truth' for such devices is established by a reference method or a legally marketed predicate device, not by expert interpretation of images or clinical findings.

4. Adjudication Method for the Test Set

Not applicable. As noted above, this is an IVD device for quantitative chemical analysis. Adjudication methods are typically used for qualitative or interpretive diagnostic devices where human expert disagreement might occur (e.g., radiology, pathology). Here, the comparison is directly numerical between the candidate device and the predicate device.

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

Not applicable. This is an IVD device for laboratory chemical analysis, not an imaging or interpretive diagnostic device that involves human readers or AI assistance in interpretation.

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

Yes, in a sense. The described studies evaluate the performance of the algorithm/system only (the ACE Axcel Clinical Chemistry System with the new reagents) in quantifying the analytes in serum. The performance data (precision, accuracy, detection limit) are intrinsic to the device's analytical capability, independent of human interpretation of the results for the purpose of generating the values themselves. While trained personnel operate the system, the analytical performance is measured as a standalone function of the device.

7. The Type of Ground Truth Used

The "ground truth" for the accuracy studies was established by comparing the results from the Alfa Wassermann ACE Axcel Clinical Chemistry System (the new device, 'y') to a legally marketed predicate device, the Alfa Wassermann ACE Clinical Chemistry System ('x'). This is a common method for IVD substantial equivalence, where the predicate is considered the accepted reference for performance. For detection limits, it would typically involve analyzing samples with known, very low concentrations of the analytes or diluting higher concentration samples to determine the lowest measurable level.

8. The Sample Size for the Training Set

The provided text describes performance validation studies, not the development or training of an algorithm in the machine learning sense. Therefore, there is no "training set" for an algorithm to learn from in this context. The study focuses on verifying the performance of the already-developed reagent and instrument system.

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

Not applicable, as there is no "training set" in the machine learning sense for this type of IVD device submission.

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The ACE Urea Nitrogen Reagent is intended for the quantitative determination of urea nitrogen concentration in urine using the ACE and ACE Alera Clinical Chemistry Systems. Urea nitrogen measurements are used in the diagnosis and treatment of certain renal and metabolic diseases. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Calcium-Arsenazo Reagent is intended for the quantitative determination of calcium in urine using the ACE and ACE Alera Clinical Chemistry Systems. Calcium measurements are used in the diagnosis and treatment of parathyroid disease, a variety of bone diseases, chronic renal disease and tetany. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Creatinine Reagent is intended for the quantitative determination of creatinine in urine using the ACE and ACE Alera Clinical Chemistry Systems. Creatinine measurements are used in the diagnosis and treatment of renal diseases, in monitoring renal dialysis and as a calculation basis for measuring other urine analytes. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

The ACE Inorganic Phosphorus U.V. Reagent is intended for the quantitative determination of inorganic phosphorus concentration in urine using the ACE and ACE Alera Clinical Chemistry Systems. Measurements of inorganic phosphorus are used in the diagnosis and treatment of various disorders, including parathyroid gland and kidney diseases and vitamin D imbalance. This test is intended for use in clinical laboratories or physician office laboratories. For in vitro diagnostic use only.

Alfa Wassermann Diagnostic Technologies, LLC ACE Urine Standard is intended for the calibration of quantitative urine reagents on Alfa Wassermann Clinical Chemistry Systems. For in vitro diagnostic use only.

In the ACE Urea Nitrogen Reagent assay, urea in urine is hydrolyzed to yield ammonia and carbon dioxide in the presence of urease. The ammonia formed then reacts with 2-oxoglutarate and NADH in the presence of glutamate dehydrogenase to yield glutamate and NAD. Two moles of NADH are oxidized for each mole of urea present. NADH absorbs strongly at 340 nm, whereas NAD+ does not. The initial rate of decrease in absorbance, monitored bichromatically at 340 nm/647 nm, is proportional to the urea concentration in the urine sample.

In the ACE Calcium-Arsenazo Reagent assay, calcium reacts with Arsenazo III in an acidic solution to form a blue-purple colored complex, which is measured bichromatically at 647 nm/692 nm. The intensity of color produced is directly proportional to the calcium concentration in the urine sample.

In the ACE Creatinine Reagent assay, creatinine reacts with picric acid in an alkaline medium to form a red-orange colored complex, which absorbs strongly at 505 nm. The rate of complex formation, determined by measuring the increase in absorbance bichromatically at 505 nm/573 nm during a fixed time interval, is directly proportional to the creatinine concentration in the urine sample.

In the ACE Inorganic Phosphorus U.V. Reagent assay, under acidic conditions, inorganic phosphorus reacts with ammonium molybdate to form an unreduced phosphomolybdate complex, which absorbs strongly at 340 nm The increase in absorbance measured bichromatically at 340 nm/378 nm, is directly proportional to the amount of phosphorus in the urine sample.

The ACE urine standard is a liquid, aqueous-based, ready-to-use calibration solution with known gravimetric concentrations of several analytes.

Here's an analysis of the acceptance criteria and supporting studies for the Alfa Wassermann ACE Reagents and Urine Standard, based on the provided 510(k) summary:

Acceptance Criteria and Device Performance

The acceptance criteria are not explicitly stated as distinct numerical targets in the provided document. Instead, the document presents performance data from studies and implies that these results demonstrate substantial equivalence to predicate devices, thus meeting acceptable performance standards. The reported device performance metrics are precision (within-run CV and total CV), accuracy (correlation coefficient, standard error estimate, confidence interval slope, and confidence interval intercept compared to predicate methods), and detection limit.

Table of Acceptance Criteria (Implied) and Reported Device Performance for Urine Analytes

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For the quantitative determination of Blood Urea Nitrogen and creatinine in whole blood. Creatinine values are used as indications of renal function. Blood Urea Nitrogen values are valuable in the diagnosis of renal diseases. For professional in vitro diagnostic use only.

Not Found

The provided document is a 510(k) clearance letter from the FDA for a device called "Cholestech BUN/Creatinine Test System II". This document does not contain the detailed information necessary to answer all the questions about acceptance criteria and study design as typically found in a clinical study report or a more comprehensive summary of safety and effectiveness.

However, based on the information available in the document, here's what can be deduced, along with what cannot be provided:

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

• Acceptance Criteria: Not explicitly stated in this document. 510(k) clearances are based on substantial equivalence, meaning the new device performs as well as, or better than, a legally marketed predicate device. The specific performance criteria (e.g., accuracy, precision targets) that Cholestech had to meet are not detailed here. They would typically be found in the 510(k) submission itself.
• Reported Device Performance: Not detailed in this clearance letter. The letter only states that the FDA "determined the device is substantially equivalent... to devices marketed in interstate commerce prior to May 28, 1976." This implies that performance data was submitted and found acceptable, but the actual data (e.g., bias, CV, correlation) is not presented.

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

• This information is not available in the provided document.

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 information is not applicable as this is an in vitro diagnostic device, not an imaging device requiring expert interpretation for ground truth. For IVD devices, ground truth is typically established using a reference method or a well-characterized predicate device. The number and qualifications of individuals performing these reference tests are not in this document.

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

• This information is not applicable for an in vitro diagnostic device in the context of expert consensus/adjudication. If adjudication refers to discrepancy resolution between the new device and a reference method, that detail is not provided.

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 as this is an in vitro diagnostic device, not an AI-powered diagnostic imaging interpretation device for human readers.

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

• This device is an in vitro diagnostic test system that provides quantitative results. Its "standalone performance" would be its analytical performance (accuracy, precision, linearity, etc.) when tested in a laboratory setting. The specific results of such standalone performance are not detailed in this document. The indications for use state "For professional in vitro diagnostic use only," implying it's used by human operators, but the "performance" is of the device/reagent system itself, not an AI algorithm.

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

• For an in vitro diagnostic device like the Cholestech BUN/Creatinine Test System II, the "ground truth" for determining its performance (e.g., accuracy) would typically be established by:
  • Reference laboratory methods: Assays performed in a high-complexity laboratory using established, often more expensive or time-consuming, gold standard methods for BUN and Creatinine.
  • Predicate device comparison: Directly comparing results from the new device with a legally marketed predicate device on the same patient samples.
• The document does not specify which type of ground truth was used for their submission.

8. The sample size for the training set

• This information is not available in the provided document. The concept of a "training set" is more directly relevant to machine learning/AI development, though IVD systems also involve extensive development and testing with samples.

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

• This information is not available in the provided document. Similar to point 7, it would likely involve reference methods or predicate device comparison if a training phase (e.g., for algorithm development in a more complex IVD) was explicitly conducted.

Summary of available information from the document:

• Device Name: Cholestech BUN/Creatinine Test System II
• Intended Use: Quantitative determination of Blood Urea Nitrogen and Creatinine in whole blood. Creatinine values are used as indications of renal function. Blood Urea Nitrogen values are valuable in the diagnosis of renal diseases. For professional in vitro diagnostic use only.
• Regulatory Outcome: Found "Substantially Equivalent" (K972012) to a predicate device.
• Regulatory Class: Not explicitly stated in the letter, but implied as a general controls device with potential for additional controls if Class II or III.
• Product Code: CDN, JFY
• Date of Clearance: July 24, 1997

To obtain the detailed information requested, one would typically need to refer to the full 510(k) submission document or a summary of safety and effectiveness (SSE) for K972012, which are sometimes publicly available through the FDA website but are not part of this clearance letter.

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