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The ARCHITECT Cyclosporine assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of cyclosporine in human whole blood on the ARCHITECT i System. The ARCHITECT Cyclosporine assay is used as an aid in the management of heart, liver, and kidney transplant patients receiving cyclosporine therapy.

The ARCHITECT Cyclosporine Calibration are for the ARCHITECT i System when used for the quantitative determination of cyclosporine in human whole blood.

The ARCHITECT Cyclosporine Whole Blood Precipitation Reagent is for the extraction of cyclosporine from samples (human whole blood patient specimens, controls, and ARCHITECT Cyclosporine Calibrators) to be tested on the ARCHITECT i System.

The ARCHITECT Cyclosporine assay is a two-step immunoassay for the quantitative determination of cyclosporine in human whole blood using CMIA technology with flexible assay protocols, referred to as Chemiflex.

Prior to the initiation of the automated ARCHITECT sequence, a manual pretreatment step is performed in which the whole blood sample is lysed with a solubilization reagent, extracted with a precipitation reagent and centrifyged. The supernatant is decanted into a Transplant Pretreatment Tube, which is placed onto the ARCHITECT i System.

In the first step, sample, assay diluent, and anti-cyclosporine coated paramagnetic microparticles are combined to create a reaction mixture. Cyclosprorine present in the sample binds to the anti-cyclosporine coated microparticles. After washing, cyclosporine acridiniumlabeled conjugate is added to create a reaction mixture in the second step. Following another wash cycle, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured as relative light units (RLUs). An indirect relationship exists between the amount of cyclosporine in the sample and the RLUs detected by the ARCHITECT i System optics.

Here's a breakdown of the acceptance criteria and the studies performed for the ARCHITECT Cyclosporine Assay, based on the provided 510(k) summary:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" for precision, linearity, functional sensitivity, or analytical sensitivity in numerical terms (e.g., "Precision must be

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The ADVIA Centaur Cyclosporine assay is an in vitro diagnostic immunoassay for the quantitative determination of cyclosporine in human whole blood using the ADVIA Centaur systems. This assay is intended for use as an aid in the management of cyclosporine therapy in kidney, heart, and liver transplant patients.

The ADVIA Centaur® Cyclosporine assay is a competitive immunoassay using direct chemiluminescent technology. Cyclosporine in the patient sample competes with acridinium ester-labeled cyclosporine in the Lite Reagent for a limited amount of biotin-labeled monoclonal mouse anti-cyclosporine antibody. Biotinlabeled anti-cyclosporine binds to streptavidin that is covalently coupled to paramagnetic particles in the Solid Phase. In the ADVIA Centaur® Cyclosporine assay the sample is manually pretreated to lyse the cells and solubilize the cyclosporine. An inverse relationship exists between the amount of cyclosporine present in the patient sample and the amount of relative light units (RLUs) detected by the system.

Here's a breakdown of the acceptance criteria and study details for the ADVIA Centaur® Cyclosporine Assay, based on the provided text:

Acceptance Criteria and Reported Device Performance

The provided document describes comparison studies for the ADVIA Centaur® Cyclosporine assay against two reference methods: Tandem Mass Spectrometry (Tandem-MS) and the Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay (and also Abbott AxSym). The "acceptance criteria" are implied by the ranges of statistical measures (slope, intercept, and correlation coefficient) that demonstrate substantial equivalence to the predicate devices and reference method. While explicit acceptance thresholds aren't stated as pass/fail criteria, the reported performance metrics indicate the device's acceptable agreement with established methods.

Here's a table summarizing the reported device performance, categorized by the comparative method and patient group/site:

Table 1: Acceptance Criteria (Implied) and Reported Device Performance for ADVIA Centaur® Cyclosporine Assay

2. Sample Size and Data Provenance

• Test Set Sample Size:

  • Against Tandem-MS:
    • Kidney transplant patients: 108 samples
    • Liver transplant patients: 75 samples
    • Heart transplant patients: 67 samples
    • Total against Tandem-MS: 250 samples (across all transplant types)
    • Total against Tandem-MS (by site): 250 samples (97 at site 1, 105 at site 2, 48 at site 3)
    • Total against Tandem-MS (by trough/peak): 250 samples (182 trough, 68 peak)
  • Against Abbott TDx: 242 samples (97 at site 1, 97 at site 2, 48 at site 3)
  • Against Abbott AxSym: 219 samples (at site 1)

• Data Provenance: The samples were from "three transplant patient groups (heart, kidney and liver)" and "three external sites." The text does not specify the country of origin, but given the submitter is Siemens Healthcare Diagnostics in Tarrytown, New York, USA, and the FDA submission, it's highly likely the data includes US patients. The study is retrospective, as it uses existing patient samples for comparison.

3. Number of Experts and Qualifications for Ground Truth

The study does not involve human readers/experts in the traditional sense of interpreting images or clinical data. Instead, it compares the performance of the ADVIA Centaur® Cyclosporine assay against established analytical methods. Therefore, the concept of "experts establishing ground truth" as it applies to subjective assessments is not directly relevant here.

The "ground truth" is established by:

• Tandem Mass Spectrometry (Tandem-MS): This is a highly accurate and precise analytical method often considered a gold standard for quantifying small molecules like cyclosporine. The operators of these machines are typically highly trained laboratory professionals.
• Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay: This is a legally marketed predicate device, representing an established and accepted method for cyclosporine measurement.
• Abbott AxSym: Another legally marketed device for comparison.

4. Adjudication Method for the Test Set

No adjudication method is described, as the "test set" involves analytical measurements rather than subjective interpretations requiring consensus. The "comparison" is statistical (Deming regression) between the new device and established reference methods.

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

No, an MRMC comparative effectiveness study was not done. This type of study is typically used for diagnostic imaging or subjective clinical assessments where multiple human readers interpret cases. The ADVIA Centaur® Cyclosporine assay is an in vitro diagnostic assay that produces a quantitative numerical result; its performance is evaluated by comparison to other quantitative methods, not by improvements in human reader performance.

6. Standalone (Algorithm Only) Performance

Yes, this entire study is a standalone performance study. The ADVIA Centaur® Cyclosporine assay itself (the "algorithm" in this context, albeit a chemical immunoassay) is being tested for its direct, unassisted performance in quantifying cyclosporine. There is no human-in-the-loop component being evaluated for its direct impact on the assay's result.

7. Type of Ground Truth Used

The ground truth used is based on:

• Analytical Reference Method: Tandem Mass Spectrometry (Tandem-MS), which is typically considered a highly accurate and precise reference method for cyclosporine quantification.
• Predicate Device Performance: The results from the legally marketed Abbott TDx®TDxFLx® Cyclosporine Monoclonal Whole Blood assay and Abbott AxSym are used as a comparative "truth" to establish substantial equivalence.

8. Sample Size for the Training Set

The document does not provide information about a separate "training set" for the assay. Immunoassays like the ADVIA Centaur® Cyclosporine assay are developed and optimized through laboratory procedures, reagent formulation, and calibration curves, rather than being "trained" on a dataset in the way a machine learning algorithm would be. The data presented in the tables are for performance validation (the "test set" in an ML context).

9. How Ground Truth for the Training Set Was Established

As noted above, the concept of a "training set" and its "ground truth" doesn't directly apply here in the way it would for a machine learning model. The assay's internal calibration and performance characteristics would have been established during its development and manufacturing process, likely using characterized reference materials and calibrators, not through a "ground truth" dataset in the clinical study sense. The reference calibrators themselves (ADVIA Centaur® Cyclosporine Calibrator) have their own manufacturing and quality control processes to establish their known concentrations.

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The CSAE method is an in vitro diagnostic test for the quantitative measurement of cyclosporine A (CSA) in human whole blood on the Dimension Vista® system. Measurements of CSA are used as an aid in the management of heart, liver and kidney transplant patients.

The Dimension Vista® CSAE Flex® reagent cartridge is a pre-packaged in-vitro diagnostic test method (assay) that is specifically designed to be used on the Dimension Vista® Integrated system, a floor model, fully automated microprocessor-controlled, integrated instrument system. The Dimension Vista® system was previously cleared with seven associated test methods (K051087). This Special 510(k) is submitted for a packaging modification to the Dimension® Cyclosporine Extended Range (CSAE) Flex® reagent cartridge (K052017), an in-vitro diagnostic device that has been cleared under the 510(k) process for use on Dimension® clinical chemistry systems. The packaging change is to allow use on the Dimension Vista® system. The modifications also include a change in method parameters (sample size and reagent volume) but the final concentration of sample/reagent ratio in test milieu remains the same.

The reagents contained in the Dimension Vista® CSAE Flex® reagent cartridges are the same as those contained in the Dimension® CSAE Flex® reagent cartridges manyfactured for the Dimension® clinical chemistry systems, another family of Siemens analyzers. The packaging modification does not affect the intended use of the devices, nor does it alter the fundamental scientific technology of the device.

The CSAE method uses an immunoassay technique in which free and CSA bound antibody-enzyme species are separated using magnetic particles. The CSAE Flex® reagent cartridge contains a pretreatment reagent, B-galactosidase-CSA antibody conjugate, CSA immobilized on chromium dioxide particles, chlorophenol red B-dgalactopyranoside (CPRG) substrate, and diluent to hydrate the tablets. To perform the CSAE assay, a sample cup containing the whole blood sample to be analyzed and a CSAE Flex® reagent cartridge are placed appropriately on the Dimension Vista® system. The Dimension Vista® system mixes and lyses the whole blood sample. The lysed sample is then mixed with the antibody conjugate reagent. The CSA present in the sample is bound by the CSA antibody conjugate reagent. Magnetic particles coated with cyclosporine A are added to bind free (unbound) antibody-enzyme conjugate. The reaction mixture is then separated magnetically. Following separation, the supernatant containing the CSA antibody-enzyme complex is transferred to a cuvette and mixed with the substrate. B-galactosidase catalyzes the hydrolysis of CPRG (chlorophenol red B-dgalactopyranoside) to produce CPR (chlorophenol red) that absorbs light maximally at 577mm. The change in absorbance at 577nm due to the formation of CPR is directly proportional to the amount of CSA in the patient's sample and is measured using a bichromatic (577, 700nm) rate technique.

Here's a breakdown of the acceptance criteria and study information for the Dimension Vista® CSAE Flex® reagent cartridge, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document defines acceptance criteria implicitly through the demonstration of "substantial equivalence" to a predicate device. The primary performance metric presented is the method comparison study results.

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

• Sample Size: 116 transplant samples.
• Data Provenance: Not explicitly stated, but the samples were human "transplant samples." No information on country of origin or whether they were retrospective or prospective.

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

• Not Applicable. This study is a method comparison between two in-vitro diagnostic devices, not a study evaluating human interpretation against a ground truth established by experts. The "ground truth" for comparison is the measurement obtained from the predicate device.

4. Adjudication Method for the Test Set

• None. This was a quantitative method comparison study between two instruments. Adjudication is typically used when human interpretation or subjective assessments are involved.

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

• No. This study is a technical comparison of an in-vitro diagnostic assay on a new instrument platform against an established assay on an older platform. It does not involve human readers or assess the effectiveness of AI assistance.

6. Standalone (Algorithm Only) Performance Study

• Yes, in essence. The entire evaluation is a standalone performance assessment of the Dimension Vista® CSAE Flex® reagent cartridge's ability to quantitatively measure Cyclosporine A. There is no human-in-the-loop component for the measurement process itself, as it's an automated in-vitro diagnostic method. The algorithm here refers to the instrument's measurement and calculation process.

7. Type of Ground Truth Used

• Comparison to a Legally Marketed Predicate Device. The "ground truth" for this study is the analytical measurement obtained from the Dimension® CSAE Flex® reagent cartridge (K052017), which is the legally marketed predicate device. The study aims to show that the new device's measurements are substantially equivalent to the predicate.

8. Sample Size for the Training Set

• Not applicable / Not explicitly stated. This document describes a Special 510(k) for a packaging and platform modification, not the development of a novel algorithm that requires a "training set" in the machine learning sense. The assay chemistry and fundamental technology are consistent with the predicate device. If there was any internal development or optimization, the details of a "training set" are not provided in this regulatory summary.

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

• Not applicable. As a Special 510(k) for a modified existing device, there isn't a "training set" in the context of a new algorithm development. The core methodology and reagents are the same as the predicate device, which would have undergone its own qualification and validation studies when it was initially cleared.

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The CSA method is an in vitro diagnostic test for the quantitative measurement of Cyclosporine A (CSA) in human whole blood on the Dimension Vista™ System. Measurements of CSA are used as an aid in the management of heart, liver and kidney transplant patients.
The Dimension Vista™ Cyclosporine (CSA) Flex® reagent cartridge is an in vitro device intended to quantitatively determine cyclosporine concentrations in human whole blood. Measurements of CSA are used as an aid in the management of heart, liver, and kidney transplant patients receiving therapy with this drug.

Dade Behring Dimension Vista™ Flex® reagent cartridges are prepackaged in-vitro diagnostic test methods (assays) that are specifically designed to be used on the Dade Behring Dimension Vista™ Integrated system, a floor model, fully automated, microprocessor-controlled, integrated instrument system. The Dimension Vista™ system was previously cleared with seven associated test methods (K051087). This Special 510(k) is submitted for a packaging modification to the Dimension® Cyclosporine (CSA) Flex® reagent cartridge (K023065), an in-vitro diagnostic device that has been cleared under the 510(k) process. The packaging change is to allow use on the Dimension Vista™ system. The reagents contained in the Dimension Vista™ CSA Flex® reagent cartridges are the same as those contained in the CSA Flex® reagent cartridges manufactured for the Dimension® clinical chemistry systems, another family of Dade Behring analyzers. The packaging modification, does not affect the intended use of the device, nor does it alter the fundamental scientific technology of the device.

The provided text describes a 510(k) Special submission for a packaging modification of a device, the Dimension Vista™ Cyclosporine (CSA) Flex® reagent cartridge. This submission is primarily about demonstrating that the modified device (for use on the Dimension Vista™ system) is substantially equivalent to an existing predicate device (the Dimension® Cyclosporine (CSA) Flex® reagent cartridge, K023065).

The information provided focuses on the comparison between the new device and the predicate device, rather than a detailed study proving the new device's performance against specific acceptance criteria. The core of the submission is that the reagents and fundamental scientific technology are the same, and the packaging change does not affect its intended use.

Therefore, the study supporting this submission is not a typical clinical trial with detailed performance metrics against a defined ground truth, but rather a comparative study demonstrating substantial equivalence based on the device's characteristics and functionality.

Here's an analysis based on the provided text, addressing your questions where information is available:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria in this context are not explicitly stated as numerical performance targets (e.g., specific sensitivity/specificity values). Instead, the acceptance is based on demonstrating substantial equivalence to the predicate device. This means showing that the new device performs comparably to the predicate device and that any differences do not raise new questions of safety or effectiveness.

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

The document does not explicitly state the sample size used for any specific testing to demonstrate substantial equivalence, nor does it specify data provenance (country of origin, retrospective/prospective). Given that this is a Special 510(k) for a packaging modification with the same reagents, the focus would likely be on analytical performance aspects (e.g., precision, accuracy using control materials or spiked samples) rather than a large-scale clinical study with patient samples. The only stated change with a potential impact on sample requirements is the "Sample Size" of 1.9 µL for the new device vs. 5 µL for the predicate. This would require validation that the reduced sample volume does not compromise performance.

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

Not applicable for this type of submission. The ground truth for in vitro diagnostic devices like this is typically established by reference methods or validated control materials, not expert consensus in the way a diagnostic imaging device might use radiologists.

4. Adjudication Method for the Test Set

Not applicable. As noted above, the validation focuses on analytical performance characteristics of the assay rather than a subjective interpretation needing 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

Not applicable. This is an in vitro diagnostic reagent cartridge; it does not involve human readers or AI in the context of interpretation of medical images or other clinical data.

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

The device itself is a standalone assay system once integrated onto the Dimension Vista™ analyzer. Performance is measured by the accuracy and precision of the quantitative cyclosporine measurement. The "study" mentioned here is the comparison to the predicate device to demonstrate substantial equivalence, which would involve assessing the quantitative output of the device.

7. The Type of Ground Truth Used

The ground truth for this type of in vitro diagnostic quantitative assay would typically be established using:

• Reference materials/calibrators: Materials with a known, accurately assigned concentration of cyclosporine.
• Split samples: Comparing results from the new device with results from the predicate device (or another validated method) on the same patient samples.
• Spiked samples: Samples (e.g., whole blood matrix) to which a known amount of cyclosporine has been added, allowing for recovery studies.

The document does not specify the exact type of ground truth used, but these are standard practices for IVD validation.

8. The Sample Size for the Training Set

Not applicable. This device is a reagent cartridge for a quantitative assay; it does not employ machine learning or AI models that require a "training set" in the conventional sense. Its performance is based on the chemical reactions and optical measurement principles of the assay.

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

Not applicable, as there is no training set for this type of device.

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The Emit® 2000 Cyclosporine Specific Assay is for in vitro quantitative analysis of cyclosporine (CsA) in human whole blood as an aid in the management of cyclosporine therapy in kidney, heart and liver transplant patients.

The Emit® 2000 Cyclosporine Specific Assay employs a homogeneous enzyme immunoassay technique used for the analysis of cyclosporine in whole blood. The assay contains mouse monoclonal antibodies with a high specificity for cyclosporine. The Emit® 2000 Cyclosporine Specific Assay is based on competition for cyclosporine antibody binding sites. Cyclosporine in the sample competes with cyclosporine in Enzyme Reagent B that is labeled with the enzyme glucose-6-phosphate dehydrogenase (G6PDH). Active (unbound) enzyme converts the oxidized nicotinamide adenine dinucleotide (NAD) in Antibody Reagent A to NADH, resulting in a kinetic absorbance change that can be measured spectrophotometrically. Enzyme activity decreases upon binding to the antibody, allowing the cyclosporine concentration in the sample to be measured in terms of enzyme activity. Endogenous serum G6PDH does not interfere because the coenzyme NAD functions only with the bacterial (Leuconostoc mesenteroides) enzyme employed in the assay.

The provided text describes the 510(k) submission for the Emit® 2000 Cyclosporine Specific Assay. It outlines the device's intended use and presents comparative method studies to demonstrate its performance against predicate devices and a reference method.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the results of the comparative method studies demonstrating substantial equivalence to the predicate devices and an established reference method (LC/MS). The performance is presented in terms of linear regression analysis (slope, intercept, and correlation coefficient 'r').

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

• Sample Sizes for Test Set:
  • LC/MS Comparison: 138 samples (33 Heart, 40 Liver, 59 Kidney)
  • Abbott TDx®/TDxFLx® Comparison: 134 samples (33 Heart, 40 Liver, 59 Kidney)
• Data Provenance: Banked retrospective samples from 3 transplant patient groups (heart, liver, and kidney). The studies were conducted at two external sites, but the country of origin is not specified.

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

This information is not applicable to this type of device and study. The "ground truth" for this assay is established by quantitative measurement methods (LC/MS and predicate immunoassays), not by expert interpretation of images or clinical cases.

4. Adjudication Method for the Test Set

This information is not applicable to this type of device and study. Adjudication methods (like 2+1, 3+1) are typically used for establishing ground truth in studies involving expert review of qualitative data (e.g., medical images). Here, the comparison is against established quantitative measurement methods.

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

No. This is not a diagnostic imaging device or an AI-assisted interpretation tool. It is a quantitative assay, and therefore, an MRMC comparative effectiveness study involving human readers with and without AI assistance is not relevant or performed for this device.

6. Standalone Performance Study

Yes, a standalone performance was essentially done. The "Comparative Method" studies analyze the Emit® 2000 Cyclosporine Specific Assay's measurements directly against the reference (LC/MS) and predicate immunoassay results. This demonstrates the algorithm's (assay's) performance in generating quantitative values for cyclosporine in whole blood.

7. Type of Ground Truth Used

The ground truth used consisted of:

• A "gold standard" quantitative measurement: Liquid Chromatography / Mass Spectrometry (LC/MS) for cyclosporine concentration.
• A legally marketed predicate device: Abbott TDx®/TDxFLx® Cyclosporine Monoclonal Whole Blood Assay. This serves as a comparative benchmark to demonstrate substantial equivalence.

8. Sample Size for the Training Set

The document does not explicitly mention a "training set" or its sample size. This assay is a chemical immunoassay, not a machine learning model that typically requires a distinct training phase with labeled data. The development of the assay reagents and protocols would involve internal validation and optimization, but not in the same sense as a machine learning training set.

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

As there is no explicit "training set" in the context of a machine learning model, this question is not strictly applicable. The "ground truth" (reference measurements) for the assay's development and validation would have been established through a combination of methods, including the use of known concentration standards, spiked samples, and potentially comparisons to existing reference methods during assay development. However, the document does not detail these developmental stages, focusing instead on the performance evaluation for regulatory submission.

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The Cyclosporine CSAE Flex® reagent cartridge is an in vitro diagnostic test intended to quantitatively measure cyclosporine A (CSA) in human whole blood for the Dimension® clinical chemistry system. Measurements of CSA are used as an aid in the management of heart, liver and kidney transplant patients.

The Dimension® CSAE Cyclosporine Flex® reagent cartridge (DF108) is an in vitro rine Differences that consists of prepackaged reagents in a plastic eight well cartridge for use on the Dade Behring Dimension® clinical chemistry system for the quantitative determination cyclosporine A (CSA) in human whole blood.

Here's an analysis of the provided text regarding the Dimension® Cyclosporine CSAE Flex® reagent cartridge, focusing on acceptance criteria and supporting studies:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria for most performance characteristics. Instead, it reports the performance values observed during the studies. For linearity and functional sensitivity, implicit criteria can be inferred.

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The AxSYM Cyclosporine assay is a Fluorescence Polarization Immunoassay (FPIA) in vitro reagent system for the quantitative measurement of cyclosporine (cyclosporine A) in human whole blood as an aid in the management of cardiac, liver, and renal transplant patients.

The AxSYM Cyclosporine assay requires the use of the AxSYM System, a random and continuous access immunoassay analyzer performs all sample and reagent transfers, incubations, and data processing, and completes the assay with a printed report. Samples (calibrators, controls, and specimens) are pretreated to minimize interference from endogenous protein-bound fluorescent compounds. Sample pretreatment consists of lysing the erythrocytes in the whole blood with Solubilization Reagent and precipitating protein with Precipitation Reagent. Cyclopsorine is dissolved into the liquid phase. The mixture is centrifuged to generate a clarified extract. The AxSYM Cyclopsorine assay is performed on the clarified extract. The AxSYM Cyclosporine Reagents and pretreated sample are pipetted in the following sequence:

• Pretreated sample, Cyclosporine Antibody, Cyclosporine Pretreatment and Solution 4 (Line Diluent) required for one test are pipetted by the Sample Probe into one well of a Reaction Vesssel (RV) to form a Sample Solution,
• Cyclosporine Fluorescein Tracer is added to a second well of the RV.
• The RV is immediately transferred into the Processing Center. Further pipetting is done in the Processing Center by the Processing Probe.
• Aliquots of Solution 4 and Sample Solution are dispensed into the RV curvette.
• The polarized fluorescent background is measured by the FPIA optical assembly.
• Second aliquots of Solution 4 and Sample Solution, and an aliquot of . Cyclosporine Fluorescein Tracer are dispensed into the same RV curvette.
• The intensity of polarized fluorescent light is measured by the FPIA optical assembly.

The Abbott AxSYM® Cyclosporine assay is a new device, and its performance was evaluated by comparing it to a predicate device, the Abbott TDx®/TDxFLx® Cyclosporine Monoclonal Whole Blood assay.

1. Table of Acceptance Criteria and Reported Device Performance

The submission does not explicitly state pre-defined acceptance criteria (e.g., minimum correlation coefficient, slope range, intercept range). Instead, it presents the results of a comparison study and concludes that the device is "substantially equivalent" to the predicate. The performance is reported in terms of a linear regression analysis.

2. Sample Size and Data Provenance

• Test Set Sample Size: 754 specimens.
  • Heart transplant patients: 194
  • Kidney transplant patients: 330
  • Liver transplant patients: 230
• Data Provenance: Not explicitly stated regarding country of origin. The study appears to be retrospective, comparing the new device against the existing predicate device on collected samples.

3. Number of Experts and Qualifications for Ground Truth

This study compares a new quantitative assay (Abbott AxSYM Cyclosporine) against an existing, legally marketed quantitative assay (Abbott TDx/TDxFLx Cyclosporine Monoclonal Whole Blood). In such analytical performance studies for quantitative in vitro diagnostic devices, the "ground truth" is established by the reference method (the predicate device in this case) or a highly accurate laboratory method, rather than through expert human interpretation. Therefore, experts in the traditional sense (e.g., radiologists interpreting images) are not typically involved in establishing ground truth for this type of test.

4. Adjudication Method

Not applicable. As described above, this is an analytical comparison of two quantitative assays. Adjudication methods (like 2+1 or 3+1) are typically used when human interpretation of complex data (e.g., medical images) is involved to establish a consensus ground truth.

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

Not applicable. This is an analytical performance study of an in vitro diagnostic device, not a study involving human readers interpreting cases. Therefore, there is no discussion of how human readers improve with or without AI assistance.

6. Standalone Performance

Yes, a standalone performance study was done in the sense that the AxSYM Cyclosporine assay was run independently on the test samples, and its results were then compared to those generated by the predicate device. The performance metrics (correlation, slope, intercept) describe this standalone algorithm's (the AxSYM assay's) agreement with the predicate device.

7. Type of Ground Truth Used

The "ground truth" for comparison was the measurements obtained from the predicate device, the Abbott TDx®/TDxFLx® Cyclosporine Monoclonal Whole Blood assay. This is a common approach for demonstrating substantial equivalence for new in vitro diagnostic devices to existing, legally marketed ones.

8. Sample Size for the Training Set

The document does not provide details about a specific "training set" for the AxSYM Cyclosporine assay. Immunoassays like this are developed using established chemical and immunological principles, and calibration (using calibrators provided with the kit) is a standard part of their operation, not a "training set" in the machine learning sense. The linearity and operating range of the assay would typically be established during the development phase using various concentrations of cyclosporine.

9. How Ground Truth for the Training Set was Established

Not applicable in the machine learning context. For an immunoassay, the "ground truth" for calibrators (which function somewhat analogously to training data by defining the response curve) is established by precise preparations of known concentrations of the analyte (cyclosporine) using highly accurate methods, often traceable to international standards. The document mentions a calibrator range of 0 ng/mL to 800 ng/mL for the AxSYM Cyclosporine.

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The CEDIA Cyclosporine Plus Assay is for the quantitative determination of cyclosporine in human whole blood using automated clinical chemistry analyzers as an aid in the management of therapy in kidney, liver, and heart transplants. The CEDIA Cyclosporine Calibrators are used to calibrate the CEDIA Cyclosporine Plus Assay in human whole blood.

The CEDIA Cyclosporine Plus Assay is a two-reagent set intended to be used with automated clinical chemistry analyzers. The assay uses recombinant DNA technology (US Patent No. 4708929) to produce a unique homogeneous enzyme immunoassay system. The assay is based on the bacterial enzyme ß galactosidase, which has been genetically engineered into two inactive fragments, termed Enzyme Acceptor (EA) and Enzyme Donor (ED) spontaneously reassociate to form fully active enzyme that, in the assay format, cleaves a substrate, to generate a color change that can be measured spectrophotometrically.

In the CEDIA Cyclosporine Plus Assay, drug in the sample competes with drug conjugated to ED for antibody binding sites. If drug is present in the sample, it binds to antibody, leaving the EDdrug conjugate free to reassociate with EA to form active ß-galactosidase. If no drug is present in the sample, antibody binds to the ED-cyclosporine conjugate, inhibiting the reassociation of inactive B-galactosidase fragments, and thus reducing the amount of active enzyme formed. The amount of active enzyme formed, and resulting absorbance change, is proportional to the amount of CEDIA Cyclosporine Plus Assay present in the sample.

The provided 510(k) summary for the CEDIA® Cyclosporine Plus Assay details the device's technical specifications and a comparison to a predicate device, but does not describe an acceptance criteria table, a study explicitly proving the device meets said criteria, or several of the specific points requested (e.g., sample size for test set, number of experts, adjudication method, MRMC study, training set details).

The document focuses on demonstrating substantial equivalence to the EMIT 2000 Cyclosporine Specific Assay (P920031) through a comparison of their intended use, method principle, components, risk to patient, and clinical performance.

However, based on the information provided under "Clinical Performance," we can infer the performance metrics reported for the device, which serve as the basis for demonstrating its suitability.

Here's an attempt to answer the questions based on the available information:

Acceptance Criteria and Reported Device Performance

1. Table of acceptance criteria and the reported device performance

Since explicit "acceptance criteria" are not listed in the document, we infer them from the reported performance of the predicate device and the new device. The predicate device's performance often sets the benchmark for the new device to demonstrate substantial equivalence.

Note: The acceptance criteria are inferred based on the direct comparison with the predicate device's reported performance, indicating that the new device should perform equivalently or within acceptable clinical limits. Specific numeric acceptance thresholds are not explicitly stated as "acceptance criteria" in this document.

Study Details

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

• Sample Size for Test Set: Not specified in the provided document. The "Clinical Performance" section mentions "Method comparison of all transplant types to an HPLC reference method" but does not give a specific number of samples.
• Data Provenance: Not specified (e.g., country of origin). The studies appear to be clinical performance evaluations, but whether they are retrospective or prospective is not explicitly stated. The predicate device's data specifically mentions "studies at four separate sites," implying multi-center data, but this level of detail is not provided for the new device.

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

• This information is not applicable to this type of device (a quantitative assay). Ground truth for these assays is established by a reference method, not expert consensus.

4. Adjudication method for the test set

• Not applicable as the ground truth is established by an analytical reference method (HPLC), not human expert review.

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 an AI/imaging device. Therefore, an MRMC study is not applicable.

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

• Yes, the performance reported for the CEDIA® Cyclosporine Plus Assay is "standalone" in nature, meaning it represents the algorithm's direct measurement output compared to a reference method, without human intervention in the result determination process. The assay produces a quantitative value.

7. The type of ground truth used

• The ground truth for accuracy validation was established using a High-Performance Liquid Chromatography (HPLC) reference method. This is explicitly stated: "Method comparison of all transplant types to an HPLC reference method yielded the following results."

8. The sample size for the training set

• This information is not provided. For this type of immunoassay, while calibration and optimization are performed, explicit "training set" sizes in the context of machine learning are not typically defined or reported in this manner.

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

• Ground truth for assay calibration (analogous to a training set for machine learning) would be established using known concentrations of cyclosporine, likely prepared gravimetrically or against certified reference materials, and then analyzed by the assay to establish the calibration curve. Specific details are not provided in this document.

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The CSA Flex® reagent cartridge is an in vitro diagnostic test intended to quantitatively measure cyclosporine A (CSA) in human whole blood for the Dimension® clinical chemistry system. Measurements of CSA are used as an aid in the management of heart, liver, and kidney transplant patients.

The automated Dimension® CSA method uses an immunoassay technique in which free and CSA-bound antibody-enzyme species are separated using magnetic particles. Following separation, the CSA-antibody-enzyme complex is mixed with the substrate. Bgalactosidase catalyzes the hydrolysis of CPRG (chlorophenol red ß-d- galactopyranoside) to produce CPR (chlorophenol red) that absorbs light maximally at 577 nm. The change in absorbance at 577 nm due to the formation of CPR is directly proportional to the amount of CSA in the patient's sample and is measured using a bichromatic (577, 700 nm) rate technique.

The provided text describes the summary of safety and effectiveness information for the Dade Behring Inc. Cyclosporine (CSA) Flex® reagent cartridge. It primarily focuses on demonstrating substantial equivalence to a predicate device. 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" in a typical quantitative framework (e.g., "correlation coefficient must be > 0.90"). Instead, it presents a comparison to a predicate device and then reports the performance of the new device against that predicate, implying that the reported values met the implicit criteria for substantial equivalence.

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

• Sample Size: 667 clinical patient samples
• Data Provenance: The data is described as "clinical patient samples," suggesting it's from human subjects. The country of origin is not specified but is implicitly within the region where Dade Behring Inc. operates (Newark, DE, USA). The study appears to be retrospective in nature as it involved collecting and testing existing clinical samples to compare the two methods.

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

The document does not explicitly mention the use of experts to establish ground truth for this specific comparison study. The comparison is between two quantitative diagnostic assays (the investigational device, CSA Flex®, and the predicate device, Abbott TDx® CSA). In such cases, the "ground truth" for the comparison is typically the result from the established predicate method or a reference method.

4. Adjudication Method for the Test Set

Not applicable. This was a direct comparison study between two quantitative methods, not a study requiring expert adjudication of qualitative interpretations.

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

Not applicable. This is an in vitro diagnostic device for quantitative measurement of cyclosporine A, not an imaging or diagnostic interpretation 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, the study described is a standalone performance comparison. The CSA Flex® reagent cartridge on the Dimension® clinical chemistry system is a device that provides quantitative measurements. The comparison was directly between the quantitative results of the CSA Flex® and the predicate TDx® CSA assay, without human intervention in the result generation or interpretation that would change the quantitative output.

7. The Type of Ground Truth Used

The ground truth used for this comparison study was the results obtained from the predicate device, the Abbott TDx® Cyclosporine Monoclonal Whole Blood Assay. The study essentially compared the new device's performance against an established and legally marketed device.

8. The Sample Size for the Training Set

The document does not specify a separate "training set" for the CSA Flex® reagent cartridge. This type of FDA submission (510(k) for an in vitro diagnostic assay) typically focuses on performance validation rather than machine learning model training as understood in AI/ML contexts. The device's development would involve internal validation and optimization, but distinct "training set" reporting as might be found for AI models is not present here.

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

As no specific "training set" is mentioned in the context of machine learning for this device, the method for establishing its ground truth is not detailed. For chemical assays, the development process generally involves optimizing reagents and protocols against known standards and reference materials, rather than a labeled training dataset of patient samples.

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