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The HbA 1c (Hemoglobin A 1c) Advanced assay on the Beckman Coulter DxC700 AU Clinical Chemistry Analyzer, is intended for the quantitative determination of mmol/mol HbA1c (DCCT/NGSP) concentration in human venous whole blood. The determination of HbA1c is used as an aid in the diagnosis of diabetes mellitus, for the monitoring of long-term glucose control in individuals with diabetes mellitus and identifying patients who may be at risk for developing diabetes mellitus. For in vitro diagnostic use only.

The HbA1c Advanced reagent kit is in a liquid format and is ready to use. It contains four reagents HbA1c R1 and HbA1c R2, Total Hemoglobin R1 and Hemolyzing reagent R1. The HbA1c calibrator is supplied with the reagent, in a liquid, ready to use format and contains 5 x 2mL calibrator levels. The sample hemolysis is automated on the DxC700 AU Clinical Chemistry analyzer. Sample handling is performed as follows: 200 uL of hemolyzing reagent is aspirated from the Hemolyzing Reagent R1and dispensed into a cuvette. Tetradecyltrimethylammonium bromide (TTAB) in the hemolyzing reagent eliminates interference from leukocytes. 2 µL of whole blood sample is then aspirated from the patient sample and added to the hemolyzing reagent in the cuvette. This hemolyzed whole blood is then added to the THb assay cuvette and HbA1c assay cuvette as per the assay parameters. The concentrations of both HbA1c and Total Hemoglobin are determined. The HbA1c/Total Hemoglobin ratio is expressed either as mmol/mol (IFCC) or %HbA1c (DCCT/NGSP). Total Hemoglobin Reagent is used to measure total hemoglobin concentration by a colorimetric method. Change in absorbance is measured at 570/660 nm. HbA1c reagent is used to measure hemoglobin A1c concentration by a turbidimetric immunoinhibition method. In the reaction, hemoglobin A1c antibodies combine with HbA1c from the sample to form soluble antigen-antibody complexes. Polyhaptens from the reagent then bind with the excess antibodies and the resulting agglutinated complex is measured turbidimetrically. Change in absorbance is measured at 340/700 nm.

Here's an analysis of the acceptance criteria and study details for the HbA1c Advanced device, based on the provided document:

Acceptance Criteria and Device Performance

Study Details

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

   • Precision (EP05-A3): Four levels of HbA1c K2 EDTA human venous whole blood patient samples (approx. 5.0%, 6.5%, 8.0%, 12%, and 14%) and two whole blood controls. Samples were analyzed in duplicate, twice daily, over 20 working days on 3 different instrument lots. (n=2 for each sample/control, 2x daily, 20 days: 80 measurements per sample/control per instrument, total for all samples/controls/instruments: 8073 = 1680 individual measurements for precision)
   • Linearity (EP06-A): High and low pools of human whole blood were used to create a linearity series to span the analytical range. The exact number of samples in the linearity series is implied to be at least 9 (N: ≥ 9 for regression parameters).
   • Method Comparison (EP09-A3): 138 venous human frozen whole blood specimens (K2 EDTA anticoagulant type). These were patient samples. The provenance is not explicitly stated as country of origin, but they are referred to as "venous human frozen whole blood specimens." The study design is prospective in the sense that the samples were collected and then tested for the study; it is not explicitly called out as retrospective/prospective.
   • Analytical Specificity (Interference - EP07): Two % HbA1c concentrations (approx. 6.5% and 8.0% HbA1c) using low and high pools prepared from human whole blood. Interfering substances were tested at a minimum of 5 levels each, with 10 replicates per level. The interference assessment was done on human venous whole blood K2 EDTA samples.
   • Hemoglobin Variants: A minimum of 20 samples were tested for each variant (HbC, HbD, HbE, HbF, HbS, HbA2), totaling at least 120 samples. These are patient samples with identified hemoglobin variants.

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

   • For the Method Comparison study, the ground truth was established by an "NGSP Secondary Reference Laboratory (SRL) using a test system (method X - HA8180V HPLC)." The specific number and qualifications of experts at the SRL are not detailed in this document.
   • For Hemoglobin Variants, the reference methods used to establish the ground truth were "Trinity Biotech Hb9210 and Ultra2, Menarini HA8181V and TOSOH G8," which are demonstrated to be free from hemoglobin interference. Again, the number and qualifications of the operators of these reference methods are not specified.

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

   • The document does not describe an adjudication method involving multiple human readers for establishing ground truth. The ground truth for method comparison and hemoglobin variant studies relies on reference methods/laboratories.

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:

   • No MRMC comparative effectiveness study involving human readers or AI assistance was conducted or described, as this device is an in-vitro diagnostic (IVD) test system (HbA1c assay) and not an imaging AI device that would typically involve human reader interpretation.

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

   • Yes, the performance characteristics described are for the "HbA1c Advanced reagent on the DxC 700 AU Clinical Chemistry Analyzer" as a standalone device (algorithm only performance, in a laboratory setting). The entire submission details the analytical performance of the device itself.

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

   • Precision: Internal validation against the device's own specifications.
   • Linearity: Internal validation for demonstrating accurate measurement across specific concentration ranges.
   • Method Comparison: Comparison to an NGSP Secondary Reference Laboratory (SRL) standardized method (HA8180V HPLC).
   • Analytical Specificity (Interference): Comparison to baseline measurements of samples without interferents, assessed against a 7% recovery criteria.
   • Hemoglobin Variants: Comparison to reference methods demonstrated to be free from hemoglobin interference (Trinity Biotech Hb9210 and Ultra2, Menarini HA8181V and TOSOH G8).

7. The sample size for the training set:

   • This document describes the analytical validation of a biochemical assay on an automated analyzer. There is no "training set" in the context of machine learning, as the device is a reagent and instrument system, not an AI/ML algorithm that is trained on data. The device's performance is rigorously tested as described above.

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

   • Not applicable, as this is not an AI/ML device with a training set. The assay's analytical parameters are established through chemical and immunochemical principles and optimized during development.

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The HbAlc Controls Level 1 and 2 are intended for in vitro diagnostic use as quality control material for use to verify the performance of laboratory testing procedures of HbAlc on clinical chemistry systems. This in vitro diagnostic device is intended for prescription use only.

HbA1c Controls are manufactured at two levels, Level 1 and Level 2. Each control is prepared from haemolysed human blood with added constituents of human origin, chemicals, stabilizers and preservatives. They are supplied in lyophilised form in 2x0.5ml vials and require reconstitution with 0.5ml of distilled water.

The provided document describes the Randox HbA1c Controls Level 1 and 2, which are quality control materials for verifying the performance of laboratory testing procedures of HbA1c on clinical chemistry systems. The document focuses on demonstrating substantial equivalence to a predicate device rather than providing a detailed study proving the device meets an inherent set of acceptance criteria for its own performance.

Therefore, it is important to note that the acceptance criteria and study described below are derived from the information available in the 510(k) summary, primarily focusing on the value assignment process for the controls and the comparison to the predicate device, rather than a standalone clinical study on the device's diagnostic accuracy.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

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

The document does not describe a "test set" in the context of diagnostic accuracy or a clinical study for the quality control material itself. The "testing results" mentioned in the conclusion refer to the overall evaluation for substantial equivalence to the predicate device, which includes the value assignment process and stability data.

• Sample Size for Value Assignment: For value assignment, "at least two replicates on each clinical chemistry analyser" are used to calculate a target value. External laboratories contribute NGSP aligned values. The specific number of these external laboratories or the total number of replicates across all analyzers is not stated.
• Data Provenance: The NGSP aligned values are taken from "external laboratories." The country of origin is not specified, nor is whether the data is retrospective or prospective.

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

This section is not applicable in the traditional sense for a quality control device. The "ground truth" for the controls is the assigned target value.

• Number of Experts: Not applicable. The value assignment method relies on consensus mean from "external laboratories" using NGSP certified methods. These laboratories are assumed to have qualified personnel, but individual experts are not quantified or specified.
• Qualifications of Experts: Not specified. It's implied that the external laboratories use "NGSP certified methods," suggesting that the personnel performing these measurements are qualified to do so, but their specific qualifications (e.g., years of experience, specific certifications) are not detailed.

4. Adjudication Method for the Test Set

Not applicable. There is no "test set" for diagnostic performance in the context of human adjudication for this quality control material. The value assignment process uses a consensus mean.

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

No. An MRMC comparative effectiveness study is designed to assess the performance of a diagnostic device or algorithm in conjunction with human readers. This document describes a quality control material, not a diagnostic device intended to be used by human readers to interpret clinical cases.

6. If a Standalone Study Was Done

Yes, in the sense that the device's performance characteristics (stability and value assignment) were evaluated independently. However, this is not a "standalone" study in the typical AI/diagnostic algorithm context focusing on diagnostic accuracy.

• Standalone Performance: The stability studies (opened and unopened) and the value assignment process describe the performance of the Randox HbA1c Controls themselves.
  • Value Assignment: Target values are calculated as the mean of at least two replicates on each clinical chemistry analyzer, and an acceptance criterion for CV (≤ 10%) is applied. A +/-20% range is applied to the assigned target value.
  • Stability: Open stability is 1 month at 2-8°C. Unopened stability is until the expiration date at 2-8°C.

7. The Type of Ground Truth Used

The "ground truth" for the HbA1c Controls is their assigned target value. This is established through:

• Consensus Mean: Aggregation of values obtained from "external laboratories" using "NGSP certified methods."
• Traceability: Traceable to IFCC by a master equation and NGSP aligned values.
• Reference Material: Traceable to IFCC by master equation.

8. The Sample Size for the Training Set

Not applicable. This device is a quality control material and does not involve AI/machine learning algorithms that require a "training set" for model development.

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 hemoglobin A1c (HbA1c) test system with associated calibrators and controls is intended for quantitative in-vitro diagnostic determination of the hemoglobin A1c (HbA1c) concentration as a percentage of total hemoglobin in human whole blood using T60 Clinical Chemistry Analyzers. Measurement of percent HbA1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.

Not Found

This document is a 510(k) clearance letter from the FDA for a medical device called the "HbA1c Test System, Calibrator, Control normal, and Control abnormal." It primarily discusses the regulatory approval process and does not contain detailed information about the acceptance criteria and the study that proves the device meets those criteria.

Therefore, most of the requested information cannot be extracted from this document as it focuses on regulatory clearance rather than a detailed technical performance study.

Here's what can be inferred or stated based on the provided text:

• Device Name: HbA1c Test System, HbA1c Calibrators, HbA1c Control Normal, HbA1c Control Abnormal
• Intended Use: Quantitative in-vitro diagnostic determination of the hemoglobin A1c (HbA1c) concentration as a percentage of total hemoglobin in human whole blood using T60 Clinical Chemistry Analyzers. Measurement of percent HbA1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.
• Regulatory Status: Substantially equivalent to legally marketed predicate devices, Class II.

Regarding the specific questions about acceptance criteria and study details:

1. A table of acceptance criteria and the reported device performance: Not provided in the document. This type of information would typically be in the 510(k) submission itself (which is not this letter) and would detail performance metrics like accuracy, precision, linearity, and analytical measurement range, along with the criteria for acceptable performance (e.g., %CV < X, bias < Y%).
2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective): Not provided.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable. For IVD devices like this HbA1c test, "ground truth" is typically established by comparative methods using a reference laboratory method or a highly accurate, established method, not individual expert readers.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set: Not applicable for an IVD test's analytical performance evaluation.
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 (IVD) device, not an imaging AI diagnostic tool for human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: The device itself is a standalone test system (T60 Clinical Chemistry Analyzers with the HbA1c reagents). Its performance is inherently standalone in that the instrument processes the sample and provides a result. There isn't typically a "human-in-the-loop" performance of the algorithm in the same way an AI imaging tool would have. The interpreting physician uses the result.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc): For HbA1c tests, ground truth would typically be established by a reference method (e.g., HPLC or mass spectrometry-based methods) or by comparison to another FDA-cleared HbA1c method. The document does not specify which was used.
8. The sample size for the training set: Not applicable for this type of IVD chemical analyzer. There isn't a "training set" in the context of machine learning algorithms for this device. The system is calibrated using calibrators, and its performance is validated.
9. How the ground truth for the training set was established: Not applicable.

In summary, this document is a regulatory approval letter and does not contain the detailed technical study information requested. Such details would be found within the 510(k) submission itself, in sections describing analytical performance validation studies.

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Hemoglobin Alc Linearity is intended for use as quality control material to demonstrate linearity throughout the reportable range of Hemoglobin A1c (HbA1c%) for Immunoassay and HPLC test methods using protocols established in individual laboratories.

The HbAIc Linearity Set is prepared from human blood to which stabilizers are added. The control is provided in liquid form for user convenience.

This submission describes a medical device, the Cone Bioproducts' HbA1c Linearity Set, which is a quality control material. As such, the concept of "acceptance criteria" and "device performance" in the context of clinical efficacy (as with an AI diagnostic tool) does not directly apply. The submission focuses on demonstrating substantial equivalence to a predicate device for its intended use as a quality control material to verify linearity for HbA1c testing.

Therefore, many of the requested items (e.g., sample size for test set, ground truth experts, MRMC study, standalone performance) are not relevant to this type of device and its regulatory submission.

Instead, the "acceptance criteria" here are implicitly defined by the demonstration of substantial equivalence to the predicate device, LiniCAL Enzyme Calibration Verifiers (K040535), based on comparison of intended use and physical properties.

Here's an analysis based on the provided document:

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

As this is a quality control material seeking substantial equivalence, the "acceptance criteria" are not based on diagnostic performance metrics but rather on characteristics that establish its equivalence to a predicate. The "reported device performance" is essentially the detailed description of the subject device's characteristics compared to the predicate.

Notes on the table: The "acceptance criteria" column is derived from the characteristics of the predicate device. The submission argues that even with differences (e.g., single vs. multiple analytes, specific methodologies), the subject device is substantially equivalent for its stated intended use (HbA1c linearity) as a quality control material.

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 applicable and not provided in the submission. The submission is for a quality control material, not a diagnostic or screening device that would typically involve a "test set" of patient data. The demonstration of equivalence relies on comparing product characteristics and intended use, not on a clinical performance study using patient samples.

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 and not provided in the submission. There is no "test set" or "ground truth" establishment in the context of clinical interpretation by experts for this type of device.

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

This information is not applicable and not provided in the submission. There is no "test set" requiring expert adjudication.

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

This information is not applicable and not provided in the submission. This is a quality control material, not an AI-assisted diagnostic tool.

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

This information is not applicable and not provided in the submission. This is a quality control material, not an algorithm or AI system.

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

This information is not applicable and not provided in the submission. For a quality control material, the "truth" is established by the known concentration or characteristic of the control material itself, and its ability to demonstrate linearity is assessed through its performance on a laboratory analyzer, not by comparison to external clinical ground truth.

8. The sample size for the training set

This information is not applicable and not provided in the submission. The device is a manufactured product (quality control material), not a machine learning algorithm that requires a "training set."

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

This information is not applicable and not provided in the submission. As above, there is no "training set" for this type of device.

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HbA1C Enzymatic Assay is intended for the in vitro quantitative determination of stable HbA1c (glycated hemoglobin A1c; A1c) in human whole blood samples. Measurement of hemoglobin A1C is a valuable indicator for long-term diabetic control.

The Diazyme's HbA1C assay kit is a clinical test kit, intended for quantitative determination of HbA1C to monitor long-term glucose control in individuals with diabetes mellitus. The Diazyme's HbA1C assay kit is comprised of a Reagent 1, Reagent 2, Lysis Buffer, THb Reagent, and calibrators. Measurement of hemoglobin A1C is determined enzymaticly by subjecting lyseted samples to extensive protease digestion. This process releases amino acids including glycated valines from the hemoglobin octa peptide. Fructosyl valine oxidase (FVO) then serves as a substrate for fructosyl valine oxidase (FVO) which releases N-terminal valines and produces hydrogen peroxide. The hydrogen peroxide is measured using a peroxidase catalyzed reaction. Total hemoglobin is determined separately by conversion of all hemoglobin derivatives of the samples into hematin using an alkaline method. HbA1C concentration is expressed as a concentration ratio of glycated hemoglobin to total hemoglobin.

The provided text describes the Diazyme HbA1C Enzymatic Assay. Here's an analysis of its acceptance criteria and the study proving it meets those criteria:

1. Table of Acceptance Criteria and the Reported Device Performance:

Study that Proves the Device Meets Acceptance Criteria:

The study presented to prove the device meets the acceptance criteria is a comparison study against a legally marketed predicate device (Tosoh Medics, Inc. Automated HPLC Analyzer: HbA1c Variant Analysis Mode, K011434), along with internal performance evaluations for precision and interference.

• Comparison Study: Diazyme's HbA1C Enzymatic Assay showed a correlation coefficient of 0.92 with the predicate device. This high correlation is presented as evidence of substantial equivalence.
• Precision (Reproducibility) Study: Both Intra-Assay and Inter-Assay precision were evaluated at two HbA1c levels (5.3% and 12%). The CV% values are reported as shown in the table above.
• Interference Study: The assay was tested for interference from common substances (Triglyceride, Bilirubin, Ascorbic Acid, Uric Acid, Glucose) at clinically relevant concentrations. No significant interference was found.

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

• Sample Size for Test Set: The document mentions "actively testing clinical patient samples" for the comparison study, but does not specify the exact number of samples used for the correlation study or the precision/interference studies.
• Data Provenance: Not explicitly stated, but the mention of "clinical patient samples" implies retrospective or prospective clinical samples. The country of origin is not provided.

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

This information is not provided in the document. For an HbA1C assay, the "ground truth" for the comparison study would typically be the results generated by the predicate device and for internal studies, carefully prepared reference materials or controls. The document does not describe an expert panel establishing ground truth in the way it might for an imaging AI device.

4. Adjudication method for the test set:

Not applicable in the context of an HbA1C enzymatic assay. Adjudication methods like 2+1 or 3+1 are typically used for subjective clinical assessments where multiple experts independently rate cases, and discrepancies are resolved. For a quantitative assay like this, the "ground truth" is established by the reference method (predicate device) and analytical measurements.

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

Not applicable. This is an in vitro diagnostic device for quantitative determination of HbA1C, not an AI-assisted diagnostic imaging or classification tool that would involve human readers.

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

Yes, the device is inherently a standalone (algorithm/assay only) system. Its performance is evaluated purely on its analytical capabilities (precision, accuracy, correlation to a reference method, interference). It does not involve human interpretation in its primary function.

7. The type of ground truth used:

• For the comparison study, the results from the predicate device (Tosoh Medics, Inc. Automated HPLC Analyzer: HbA1c Variant Analysis Mode) served as the ground truth/reference method.
• For precision studies, presumably calibrated control materials with known HbA1C concentrations were used.
• For interference studies, spiked control materials with known concentrations of interfering substances were used.

8. The sample size for the training set:

Not applicable. This is a traditional in vitro diagnostic (IVD) assay based on enzymatic reactions, not a machine learning or AI algorithm that requires a "training set" in the computational sense. The development of the assay would involve various R&D experiments, but not a formally defined "training set" like for AI models.

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

Not applicable, as there is no "training set" in the AI/machine learning sense. The ground truth for developing and validating the assay relies on established biochemical principles, analytical chemistry techniques, and comparison to recognized reference methods.

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