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The ADVIA® Chemistry Hemoglobin A1c method is for in vitro diagnostic use in the quantitative determination of Hemoglobin A1c, a diabetes marker, in whole blood on the ADVIA Chemistry systems. Such measurements are used for monitoring the long-term glycemic control of persons with diabetes. The A1c and total hemoglobin (tHb) values generated as part of the HbA1cN and HbA1cI results are intended for use in the calculation of the A1c / total hemoglobin ratio, and must not be used individually for diagnostic purposes.

*Note: HbA1cN reports HbA1c in % and HbA1cI reports HbA1c in mmol/mol

The ADVIA® Chemistry A1c Calibrators are for in vitro diagnostic use in the calibration of the A1c and total hemoglobin methods (Automated and Manual Pretreatment) on the ADVIA Chemistry Systems.

The concentration of A1c and the concentration of total hemoglobin are measured and the ratio is reported (either as % or mmol/mol).

There are two different sample pretreatment methods available on the ADVIA Chemistry System. The first method is an Automated Pretreatment that uses 4 reagents: A1c Denaturant Reagent, Total Hemoglobin Reagent (tHb 2), A1c Agglutinator Reagent (R1) and A1c Antibody Reagent (R2). In this Automated Pretreatment step, the whole blood sample is mixed with the A1c Denaturant Readent. The red blood cells are lysed and the hemoglobin chains are hydrolyzed by the protease present in the reagent.

The second method is a Manual Pretreatment that uses the same reagents as the first method except that the A1c Denaturant Reagent is replaced with the Hemoglobin Denaturant Reagent. For this method, there is an off-line pretreatment that is followed bv a 10 minute incubation.

For the measurement of total hemoglobin, the Total Hemoglobin Reagent is used. The method is based on the conversion of all hemoglobin derivatives into alkaline hematin in an alkaline solution of a nonionic detergent

A latex agglutination inhibition method is used for the measurement of specific A1c. The A1c present in the sample competes with the agglutinator (synthetic latex containing multiple copies of the immunoreactive portion of A1c) for the anti-A1c antibody; thereby reducing the rate of agglutination. A concentration curve is obtained by monitoring the change in scattered light as a change of absorbance. The actual change in absorbance is inversely proportional to the concentration of A1c in the sample. The HbA1cN NGSP result (%) or the HbA1cl IFCC result (mmol/mol) is calculated using the A1c and total hemoglobin values.

The ADVIA® Chemistry A1c Calibrators are used to calibrate the methods. The calibrators consist of four (4) levels of lyophilized whole blood containing varying concentrations of HbA1c and total hemoglobin. There is a single level calibration for total hemoglobin (Cal 1) and a multi-level calibration (six levels) for A1c. Four calibrator levels (designated Cal 1 - 4) are provided in a single kit and each level is 0.5 g/vial. The other two levels consist of Saline (Cal 0) and Cal 5 (prepared by the system from Cal 4 using 1.4 times the volume used for Cal 4).

The target value of each calibrator (calibration) level is:

• Calibration Level 1 (Cal 0): 0.00 umol/L A1c, 0.0 g/dL Total Hemoglobin ●
• Calibration Level 2 (Cal 1): 2.30 µmol/L A1c, 11.0 g/dL Total Hemoglobin .
• Calibration Level 3 (Cal 2): 3.65 umol/L A1c .
• Calibration Level 4 (Cal 3): 5.15 umol/L A1c .
• Calibration Level 5 (Cal 4): 6.80 umol/L A1c .
• Calibration Level 6 (Cal 5): 8.20 umol/L A1c

The Siemens Healthcare Diagnostics ADVIA® Chemistry Hemoglobin A1c Assay and Calibrators were evaluated for substantial equivalence to predicates. The study demonstrated performance through various tests, including imprecision, method comparison, interfering substances, matrix equivalency, and analytical range.

1. Acceptance Criteria and Reported Device Performance

The provided document does not explicitly state pre-defined acceptance criteria for the performance characteristics. Instead, it presents the results of these performance studies and concludes that they are "acceptable results compared to the Predicate Device" and "support that the ADVIA Chemistry Hemoglobin A1c assay... is substantially equivalent to the Tosoh G7 HPLC Hemoglobin A1c method." However, based on the provided data, we can infer implied acceptance around certain metrics. The performance metrics are reported in comparison to the predicate device or a reference method.

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

• Sample Size for Method Comparison (Test Set): 80 samples for both Automated and Manual Pretreatment methods.
• Data Provenance: Not explicitly stated (e.g., country of origin). The data appears to be from internal studies conducted by Siemens Healthcare Diagnostics. It is retrospective in the sense that samples were likely collected and then tested, but not explicitly labeled as prospective.

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

Not applicable. This device is an in vitro diagnostic (IVD) assay measuring a biochemical marker (HbA1c). The "ground truth" for the test set in this context is established by a reference method or a predicate device, not by expert interpretation of images or other subjective assessments.

4. Adjudication Method for the Test Set

Not applicable. As this is an IVD assay, ground truth is established by an objective, traceable reference method (NGSP Reference Method, specifically Tosoh G7 in this case), not through expert consensus requiring adjudication.

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

Not applicable. This is an in vitro diagnostic device, not an imaging device or AI-assisted diagnostic tool that involves human readers interpreting cases. Therefore, an MRMC study and the concept of human reader improvement with AI assistance are not relevant to this submission.

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

Yes, the studies presented (imprecision, method comparison, interfering substances, analytical range) demonstrate the standalone performance of the ADVIA Chemistry Hemoglobin A1c Assay. The device directly measures HbA1c concentrations and calculates the ratio, functioning independently of human interpretation of the final measurement.

7. Type of Ground Truth Used

The ground truth used for the method comparison study was established using the NGSP Reference Method (Tosoh G7 Automated HPLC Analyzer - HbA1c Variant Analysis Mode). The document states that the Tosoh G7 is certified by NGSP and used as a reference method for establishing traceable results to the Diabetes Control and Complications Trial (DCCT). This indicates a highly standardized and traceable method for establishing the true HbA1c values.

8. Sample Size for the Training Set

Not explicitly stated. The document focuses on the performance studies (validation) of the finished device. For IVD assays, "training sets" are usually involved in the initial assay development and optimization, rather than being a distinct, reported phase like in AI/ML device development. The calibrators themselves are used to "train" or calibrate the instrument on an ongoing basis.

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

For IVD assays like this, the "ground truth" for calibrators is typically established through a process of assigning traceable values. The ADVIA® Chemistry A1c Calibrators are stated to be "Traceable to NGSP*** and Traceable to IFCC by Master Equation." This means the assigned values for the calibrators are determined through rigorous analytical methods that link them back to internationally recognized standardization programs (NGSP and IFCC), ensuring accuracy and consistency across different laboratories and instruments. This would involve a hierarchy of reference methods and materials.

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