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

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

The Alkaline Phosphatase assay is an automated clinical chemistry assay.

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

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

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

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

Acceptance Criteria and Reported Device Performance

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

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

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

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

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

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

7. The sample size for the training set:

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

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

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

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The Alinity i STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnl) in human plasma (lithium heparin) on the Alinity is ystem.

The Alinity i STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).

The Alinity i STAT High Sensitivity Troponin-I Reagent Kit contains:

• . Microparticles: 1 bottle (6.6 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse, monoclonal) coated microparticles in TRIS buffer with protein (bovine) stabilizer. Minimum concentration: 0.035% solids. Preservative: ProClin 300.
• . Conjugate: 1 bottle (6.1 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse-human chimeric, monoclonal) acridinium-labeled conjugate in MES buffer with protein (bovine) stabilizer and human IgG. Minimum concentration: 0.1 mg/L. Preservative: ProClin 300.

The Alinity i STAT High Sensitivity Troponin-I device is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of cardiac troponin I (cTnI) in human plasma (lithium heparin) on the Alinity i system, used as an aid in the diagnosis of myocardial infarction (MI).

The acceptance criteria and device performance are as follows:

1. Table of Acceptance Criteria and Reported Device Performance

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

• Dilution Recovery Study: Samples were prepared by volumetrically spiking lithium heparin plasma with purified recombinant human cardiac troponin IC complex.
  • Automated Dilution: Each sample was tested in replicates of 5. The total number of unique samples is not explicitly stated, but implies multiple samples across a range up to 60,000.0 ng/L.
  • Manual Dilution: The same samples were used, and each dilution was prepared by 2 technicians and tested. Again, the exact number of unique samples is not stated but implies multiple samples.
• Data Provenance: The document does not specify the country of origin for the data. The study appears to be prospective laboratory testing conducted to evaluate the device's performance characteristics.

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

Not applicable. This device is an in vitro diagnostic immunoassay, and the "ground truth" for the dilution recovery study was established by the known concentration of spiked cTnI in the plasma samples, rather than expert interpretation of images or clinical cases.

4. Adjudication Method for the Test Set

Not applicable. Given the nature of the dilution recovery study for an immunoassay, an adjudication method for establishing ground truth as typically understood in AI/imaging studies (e.g., 2+1, 3+1) is not relevant. The "ground truth" for recovery was the known spiked concentration.

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

No, a Multi Reader Multi Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic immunoassay; therefore, human reader performance or the improvement with AI assistance is not applicable.

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

Yes, the performance testing for dilution recovery was conducted as a standalone algorithm performance without human-in-the-loop performance. The Alinity i system automatically processes samples and measures relative light units to quantify cTnI. The study evaluated the accuracy of dilution performed by the instrument and manually.

7. The Type of Ground Truth Used

The ground truth for the dilution recovery study was known, spiked concentrations of purified recombinant human cardiac troponin IC complex in lithium heparin plasma. This represents an analytical ground truth based on controlled experimental conditions.

8. The Sample Size for the Training Set

The document does not provide information about a training set since this is not an AI/machine learning device that typically requires a large training set. The "subject device" is an immunoassay system, and its performance is evaluated based on its analytical characteristics.

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

Not applicable, as there is no mention or indication of a "training set" for this in vitro diagnostic immunoassay.

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The Alinity i STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnI) in human plasma (lithium heparin) on the Alinity i system.

The Alinity i STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).

The Alinity i STAT High Sensitivity Troponin-I Reagent Kit contains:

• . Microparticles: 1 bottle (6.6 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse, monoclonal) coated microparticles in TRIS buffer with protein (bovine) stabilizer. Minimum concentration: 0.035% solids. Preservative: ProClin 300.
• . Conjugate: 1 bottle (6.1 mL per 100 test cartridge / 33.8 mL per 600 test cartridge). Anti-troponin I (mouse-human chimeric, monoclonal) acridinium-labeled conjugate in MES buffer with protein (bovine) stabilizer and human IgG. Minimum concentration: 0.1 mg/L. Preservative: ProClin 300.

The Alinity i STAT High Sensitivity Troponin-I assay is an automated, two-step immunoassay for the quantitative determination of cTnI in human plasma (lithium heparin) using CMIA technology.

Sample and anti-troponin I antibody-coated paramagnetic microparticles are combined and incubated. The cTnI present in the sample binds to the anti-troponin I coated microparticles. The mixture is washed. Anti-troponin I acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of cTnI in the sample and the RLU detected by the system optics.

Acceptance Criteria and Study for Alinity i STAT High Sensitivity Troponin-I

1. Table of Acceptance Criteria and Reported Device Performance:

The document does not explicitly state formal acceptance criteria in a tabular format for the clinical performance. However, typical performance metrics for diagnostic assays like this include:

• Sensitivity: 85.29% to 98.46% (Female), 72.20% to 92.06% (Male) depending on time point.
• Specificity: 69.13% to 85.64% (Female), 74.22% to 88.98% (Male).
• PPV: 27.02% to 42.74% (Female), 33.78% to 50.00% (Male).
• NPV: 98.80% to 99.85% (Female), 97.05% to 99.19% (Male).

Overall cutoff (27 ng/L):

• Sensitivity: 78.43% to 94.44% (Female), 76.45% to 94.44% (Male)
• Specificity: 66.44% to 92.57% (Female), 66.44% to 88.34% (Male).
• PPV: 35.09% to 47.66% (Female), 29.06% to 44.07% (Male).
• NPV: 98.37% to 99.46% (Female), 97.40% to 99.35% (Male). | The high NPV across all time points and cutoffs is a strong indicator of the assay's ability to rule out MI. Sensitivities are also generally high. The lower PPV reflects the prevalence of non-MI conditions that can elevate troponin and emphasizes the need for combining results with clinical data. The study notes that lower specificity at ≥6 hours is due to study design and patient flow in the ED. |
  | AUC | Not explicitly stated as an acceptance criterion, but higher values indicate better diagnostic performance. Generally, AUC > 0.9 is considered excellent. | AUC: 0.9257 to 0.9777 (Female), 0.8994 to 0.9489 (Male) across different time points. | Consistently high AUC values, indicating excellent overall diagnostic accuracy for both sexes and at different time points. |

Study Proving Acceptance Criteria:

The study described is a multi-center prospective clinical study designed to assess the diagnostic accuracy of the Alinity i STAT High Sensitivity Troponin-I assay in patients presenting with chest discomfort or equivalent ischemic symptoms.

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

• Sample Size (Clinical Study):
  • Total Subjects: 6174
  • MI Subjects: 432 (124 female, 308 male)
  • Non-MI Subjects: 5742 (2128 female, 3614 male)
  • Total Specimens (serial sampling):
    • 891 from MI subjects
    • 8975 from non-MI subjects
• Data Provenance:
  • Country of Origin: United States (implied by the FDA 510(k) submission context for a US population reference range study). The study was conducted at 23 Emergency Departments (EDs) in the US, reflecting regional, urban, and rural patient populations.
  • Retrospective or Prospective: Prospective. Specimens were collected prospectively from subjects presenting to the ED.

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

• Number of Experts: A "panel of board-certified cardiologists" was used. The exact number is not explicitly stated, but "panel" implies more than one.
• Qualifications of Experts: Board-certified cardiologists.

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

• Adjudication Method: The subject diagnoses (MI or non-MI) were adjudicated by a panel of board-certified cardiologists based on the third universal definition of MI. The adjudicators were blinded to the Alinity i STAT High Sensitivity Troponin-I assay results. This indicates an expert consensus method, likely involving all panel members reaching a decision, but the specific voting scheme (e.g., 2+1, 3+1) is not detailed.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

• No, a MRMC comparative effectiveness study was not done. This document describes the performance of a lab assay (IVD - In Vitro Diagnostic), not an AI-assisted diagnostic tool that would typically involve human readers.

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

• Yes, a standalone performance study was done. The entire clinical study described assesses the performance of the Alinity i STAT High Sensitivity Troponin-I assay (the "algorithm" or device in this context) as a standalone diagnostic tool for aid in MI diagnosis. The results (sensitivity, specificity, PPV, NPV, AUC) are presented for the direct output of the assay. The wording "aid in the diagnosis" implies it's used in conjunction with other clinical information, but its individual performance is what's being evaluated.

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

• Expert Consensus and Clinical Definition: The ground truth for MI diagnosis was established by a panel of board-certified cardiologists based on the third universal definition of MI. This definition incorporates clinical observations, ECG, and other diagnostic information, which can include pathology and outcomes data indirectly but is primarily an expert consensus application of a standardized clinical definition.

8. The sample size for the training set:

• Not Applicable / Not Explicitly Stated for the Clinical Study. This document describes an IVD device, not an AI/machine learning model in the traditional sense that requires an explicit "training set" of patient data for model development. The "training" for such an assay involves the optimization of reagents, antibodies, and detection protocols during product development. The non-clinical studies (precision, linearity, interference) represent the internal testing and validation that inform the assay's operational parameters. The clinical study described functions as a validation/test set for the final device performance.

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

• Not Applicable. As noted above, for this IVD device, there isn't a "training set" of patient data with ground truth in the way there is for AI/ML algorithms. The ground truth for the assay's development and calibration would typically be established using manufactured controls, calibrators, and characterized reference materials with known concentrations of cTnI, following industry standards and guidelines (e.g., CLSI documents referenced in the non-clinical section).

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The ARCHITECT STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) used for the quantitative determination of cardiac troponin I (cTnl) in human plasma (dipotassium [K2] EDTA) on the ARCHITECT i2000SR System.

The ARCHITECT STAT High Sensitivity Troponin-I assay is to be used as an aid in the diagnosis of myocardial infarction (MI).

The ARCHITECT STAT High Sensitivity Troponin-I assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of cardiac troponin I (cTnI) in human plasma (dipotassium EDTA) using chemiluminescent microparticle immunoassay technology with flexible assay protocols, referred to as Chemiflex. The reagent kit contains anti-troponin I (mouse, monoclonal) coated microparticles and anti-troponin I (mouse-human chimeric, monoclonal) acridinium-labeled conjugate. The procedure involves combining sample and antibody-coated microparticles, incubation and wash, adding acridinium-labeled conjugate, another wash cycle, and then adding Pre-Trigger and Trigger Solutions. The resulting chemiluminescent reaction is measured as relative light units (RLUs), which are directly related to the amount of cTnI in the sample. The cTnI concentration is determined relative to a standard curve.

The provided text describes the Abbott Laboratories ARCHITECT STAT High Sensitivity Troponin-I assay (K191595). Here's a breakdown of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state "acceptance criteria" in a numerical or categorical format for diagnostic performance (e.g., "Sensitivity must be >X%"). Instead, it presents the performance characteristics observed in the clinical study, implying that these demonstrated values were deemed acceptable for substantial equivalence. The non-clinical performance (precision, linearity, limits of measurement, and analytical specificity) results are presented as the device performance and are implicitly accepted as demonstrating substantial equivalence to the predicate.

For the purpose of this response, I will consider the reported "Sensitivity" and "Specificity" values at different time points and cutoffs as the "reported device performance." The document states that the conclusion drawn from nonclinical laboratory studies and clinical performance is that the candidate assay (ARCHITECT STAT High Sensitivity Troponin-I) performance is substantially equivalent to the predicate Elecsys Troponin T Gen 5 STAT Immunoassay (K162895). This implies the presented performance metrics met the FDA's criteria for substantial equivalence.

Reported Device Performance (Clinical Study - Myocardial Infarction Diagnosis):

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

• Test Set Sample Size:

  • Clinical Study: 1065 subjects presenting to the ED with symptoms consistent with ACS.
    • 248 specimens with serial sampling from 116 MI subjects (31 female, 85 male).
    • 2488 specimens with serial sampling from 949 non-MI subjects (440 female, 509 male).
  • Reference Range Study: 1531 apparently healthy individuals.

• Data Provenance:

  • Clinical Study: Multi-center prospective study from 11 geographically diverse EDs in the US.
  • Reference Range Study: US population.
  • The document implies the studies are prospective as subjects were enrolled for acute clinical presentation (ACS symptoms) and for reference range establishment. Specimens were collected and frozen for subsequent evaluation.

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

• Number of Experts: Three.
• Qualifications of Experts: Board-certified cardiologists.

4. Adjudication method for the test set

• Adjudication Method: The final adjudicated diagnosis (ground truth) was made by majority agreement of the three board-certified cardiologists. This is often referred to as a 3+1 method where consensus among the human readers determines the outcome.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, a multi-reader multi-case (MRMC) comparative effectiveness study concerning human readers improving with or without AI assistance was not done. This device is an in vitro diagnostic (IVD) assay, a laboratory test system, not an AI or imaging diagnostic software that assists human readers.

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

Yes, the clinical study assessed the standalone performance of the ARCHITECT STAT High Sensitivity Troponin-I assay. The assay itself provides a quantitative measurement and these measurements, when compared against the adjudicated clinical diagnosis, determine its diagnostic accuracy (sensitivity, specificity, etc.). There is no "human-in-the-loop" explicitly described for interpreting the assay result itself, although clinicians use the results in conjunction with other clinical signs.

7. The type of ground truth used

• Clinical Study: The ground truth for the diagnosis of myocardial infarction (MI) was established by the adjudicated diagnosis of three board-certified cardiologists according to the 2007 universal definition of MI. The document also states that troponin results should always be used in conjunction with clinical signs and symptoms in accordance with the fourth universal definition of MI.
• Reference Range Study: Ground truth for "apparently healthy individuals" was based on participants having normal levels of cardiac B-type natriuretic peptide (BNP) and HbA1c, and glomerular filtration rate (GFR) values ≥ 60 mL/min.

8. The sample size for the training set

The document does not explicitly mention a "training set" in the context of machine learning or AI models. This device is an immunoassay (hardware and reagents), not an AI algorithm. Therefore, the concept of a "training set" as it relates to AI is not applicable here. The focus is on the analytical and clinical validation of the assay.

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

As noted above, the concept of a "training set" as related to AI is not applicable to this device submission.

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