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The CAPI 3 Hb A1c kit is intended for separation and quantification of the HbA1c glycated fraction of hemoglobin (in IFCC unit (mmol/mol) and NGSP unit (%)) in venous whole human blood, by capillary electrophoresis in alkaline buffer with the CAPILLARYS 3 TERA instrument of hemoglobin A1c is used as an aid in diagnosis of diabetes, as an aid to identify patients who may be at risk for developing diabetes mellitus, and for the monitoring of long-term blood glucose control in individuals with diabetes mellitus. The CAPI 3 Hb A1c kit is intended for in vitro Diagnostic Use Only.

The CAPILLARYS 3 TERA instrument uses the principle of capillary electrophoresis in free solution. With this technique, charged molecules are separated by their electrophoretic mobility in an alkaline buffer with a specific pH. Separation occurs according to the electrolyte pH and electroosmotic flow. The CAPILLARYS 3 TERA instrument has silica capillaries functioning in parallel allowing 12 simultaneous analyses of HbA1c quantification in a whole blood sample. A sample dilution with hemolysing solution is prepared and injected by aspiration at the anodic end of the capillary. A high voltage protein separation is then performed and direct detection of the hemoglobins is made at the cathodic end of the capillary at 415 nm, which is the absorbance wave length specific to hemoglobins. Before each run, the capillaries are washed with a wash solution and prepared for the next analysis with buffer. Direct detection provides accurate relative quantification of individual hemoglobin A1c fraction. In addition, the high resolution of CAPI 3 Hb A1c procedure allows the quantification of HbA1c even in the presence of labile HbA1c. carbamylated and acetylated hemoglobins, and major hemoqlobin variants. By using an alkaline pH buffer, normal and abnormal (or variant) hemoglobins are detected in the following order, from cathode to anode: A2/C, E, S/D, F, A0, other Hb (including minor Hb A1) and then A1c. The HbA1c concentrations are standardized and indicated in %HbA1c (DCCT/NGSP) and in mmol/mol (IFCC) units.

The provided text describes the 510(k) premarket notification for the CAPI 3 Hb A1c kit, a device used for measuring hemoglobin A1c levels. The document outlines the device's indications for use, technological characteristics, and performance data to demonstrate substantial equivalence to a legally marketed predicate device.

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

1. Table of Acceptance Criteria and Reported Device Performance

The "Special Controls for Diabetes Diagnosis Claim" section (Section 6) explicitly lists the acceptance criteria set by the FDA for devices of this type, along with how the device's performance data addresses these. While the document doesn't present a direct "acceptance criteria vs. reported performance" table, I can synthesize one from Section 6 and the preceding "Performance Data" (Section 5).

Acceptance Criteria and Reported Device Performance for CAPI 3 Hb A1c

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

• Precision/Reproducibility Study (Section 5a):

  • Sample Size: Four different whole blood samples at specific targeted HbA1c concentrations (~5%, ~6.5%, ~8%, ~12%) were used. These were analyzed in duplicate on two capillaries per run on 3 instruments. The study used three lots of kits over 24 days, resulting in a total of 1728 individual results.
  • Data Provenance: The document does not explicitly state the country of origin for these samples. It implies they are clinical samples used in a laboratory setting for reproducibility testing within the manufacturer's or contracted facility. The study design (CLSI guidelines EP05-A3) suggests a prospective, experimentally controlled setup.

• Comparison Studies (Accuracy) (Section 5e):

  • Sample Size: 152 variant-free whole blood samples.
  • Data Provenance: The samples covered the measuring range and spanned decision points for diabetes diagnosis. The comparison was against results from an NGSP reference laboratory using a cleared HPLC HbA1c method. The specific origin (e.g., country) or whether these were retrospectively or prospectively collected is not stated, but the nature of a comparison study with a reference method implies a real-world clinical sample set.

• Interference Studies (Section 5g):

  • Sample Size: Two different whole blood samples (one near cut-off, one with elevated HbA1c) were used for endogenous and drug interference testing. For hemoglobin variant interference, a number of specific samples were used (e.g., 20 Hb A2 samples, 19 Hb F samples, 24 each for Hb S, C, D, and E samples).
  • Data Provenance: Not explicitly stated regarding country or retrospective/prospective. The description suggests these were specific, characterized samples obtained for interference testing, likely in a controlled laboratory environment.

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

• For this in-vitro diagnostic device (HbA1c measurement), "ground truth" is typically established by reference methods or standardized laboratory procedures, not by expert consensus in the way imaging AI models are.
• Comparison Study (Section 5e): The ground truth for the 152 samples was established by "testing performed at a NGSP reference laboratory using the cleared HPLC HbA1c method (Automated Glycohemoglobin Analyzer HLC-712G8)." This is the gold standard for HbA1c measurement and implies the highest level of analytical accuracy for the measured values.
• The document does not mention human experts establishing ground truth or their qualifications; it relies on a technical reference standard.

4. Adjudication Method for the Test Set

• Adjudication methods (like 2+1, 3+1) are typically used in subjective interpretation tasks (e.g., radiology image reading) where multiple human readers contribute to a consensus ground truth.
• For quantitative lab tests like HbA1c, adjudication is not applicable in the same sense. The "ground truth" is the result obtained from a single, highly accurate, standardized reference method, which is considered definitive. Any comparison is statistical, typically regressing one device's results against the reference method's results.

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

• No, an MRMC comparative effectiveness study was not done.
• MRMC studies are relevant for medical imaging devices where human readers interpret images, and the AI system is an "assistant" in that interpretive task.
• This device is an automated in-vitro diagnostic assay, meaning it directly measures a biomarker. It's not an AI system designed to assist human interpretation of complex visual data. Therefore, the concept of "human readers improving with AI vs. without AI assistance" does not apply here.

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

• Yes, the primary performance shown is "standalone" performance.
• The CAPI 3 Hb A1c kit, when run on the CAPILLARYS 3 TERA instrument, provides a direct quantitative measurement. The performance data presented (precision, linearity, comparison, total error, interferences) are all reflective of the device's analytical performance on its own, without human real-time intervention for result calculation or interpretation beyond standard laboratory procedures for operating the instrument and reporting results.
• The output is a numerical value (%HbA1c or mmol/mol), not an image or diagnosis requiring human interpretation in the loop with an AI algorithm.

7. Type of Ground Truth Used

• The ground truth for the comparison studies (accuracy) was established by a standardized reference method (HPLC HbA1c) run at an NGSP reference laboratory.
• This is a form of analytical reference standard, considered the most accurate and reliable method for determining true HbA1c concentrations in the samples.
• For precision and interference studies, the "ground truth" is inherent to the specific sample concentrations being tested, often prepared or characterized against
  these same reference methodologies.

8. Sample Size for the Training Set

• This information is not provided because this is not an AI/ML (Artificial Intelligence/Machine Learning) device requiring a "training set."
• The CAPI 3 Hb A1c kit is an in-vitro diagnostic device based on the principle of capillary electrophoresis, a well-established analytical chemistry technique. Its "performance" is governed by its chemical reagents, instrument design, and physical principles, not by a learned algorithm from data.
• Therefore, there is no "training set" in the context of machine learning. The development and validation of such a device involve optimization of reagents, hardware, and software parameters, followed by rigorous analytical performance validation studies (as detailed in Section 5).

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

• Not applicable, as there is no "training set" for this type of device (see point 8 above).

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The CAPI 3 Hb A1c kit is designed for separation and quantification of the HbA1c glycated fraction of hemoglobin in venous whole human blood, by capillary electrophoresis in alkaline buffer (pH 9.4) with the CAPILLARYS 3 TERA instrument. Measurement of hemoglobin A1c is effective in monitoring long-term glycemic control in individuals with diabetes mellitus. This test is not for screening or diabetes. The CAPI 3 Hb A1c kit is designed for Professional Use Only.

The Multi-system Hb A1c CAPILLARY Controls (2) are designed for the migration control and quality control of human glycated hemoglobin Alc quantification with SEBIA capillary electrophoresis procedures:

• CAPILLARYS Hb A1c performed with the CAPILLARYS 2 FLEX-PIERCING automated instrument,
• CAPI 3 Hb Alc performed with the CAPILLARYS 3 TERA automated instrument and,
• MINICAP Hb A1c performed with the MINICAP FLEX-PIERCING automated instrument.
  The Hb Alc CAPILLARY Controls are designed for Professional Use Only.
  For In Vitro Use.

The CAPILLARYS 3 TERA instrument uses the principle of capillary electrophoresis in free solution. With this technique, charged molecules are separated by their electrophoretic mobility in an alkaline buffer with a specific pH. Separation occurs according to the electrolyte pH and electroosmotic flow.
The CAPILLARYS 3 TERA instrument has silica capillaries functioning in parallel allowing 12 simultaneous analyses of HbA1c quantification in a whole blood sample. A sample dilution with hemolysing solution is prepared and injected by aspiration at the anodic end of the capillary. A high voltage protein separation is then performed and direct detection of the hemoglobins is made at the cathodic end of the capillary at 415 nm, which is the absorbance wave length specific to hemoglobins. Before each run, the capillaries are washed with a wash solution and prepared for the next analysis with buffer.
Direct detection provides accurate relative quantification of individual hemoglobin A1c fraction. In addition, the high resolution of CAPI 3 Hb A1c procedure allows the quantification of HbA1c even in the presence of labile HbA1c, carbamylated and acetylated hemoglobins, and major hemoglobin variants.
By using an alkaline pH buffer, normal and abnormal (or variant) hemoglobins are detected in the following order, from cathode to anode: A2/C, E, S/D, F, A0, other Hb (including minor Hb A1) and then A1c.

The provided document describes the Sebia CAPI 3 Hb A1c kit and the MULTI-SYSTEM Hb A1c CAPILLARY Controls (2), which are devices used for the separation and quantification of the HbA1c glycated fraction of hemoglobin. The document presents performance data primarily related to analytical precision and accuracy, rather than a clinical study with human readers or ground truth established by experts in a diagnostic context.

Here's an analysis based on the categories requested:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria mentioned are implicitly derived from the reported performance, as specific quantitative criteria are not explicitly stated for all aspects (e.g., a target CV for precision). However, the study aims to demonstrate that the device performs within acceptable analytical limits for precision and accuracy.

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

• Precision Test Set: 8 different blood samples (3 normal HbA1c, 1 near cut-off, 4 elevated HbA1c). These samples were run extensively: each in duplicate on two capillaries per run, two runs per day over six days per lot of CAPI 3 Hb A1c kit, using three lots, yielding a total of 432 results per sample over 18 days. The provenance of these blood samples (e.g., country of origin, retrospective/prospective) is not specified in the provided text.
• Linearity Test Set:
  • Mixture of 2 different blood samples (normal and elevated HbA1c) in different proportions, analyzed in triplicate.
  • Dilution of 4 different blood samples (1 normal, 1 near cut-off, 2 elevated HbA1c), serially diluted.
    Provenance not specified.
• Accuracy (Internal Correlation) Test Set: 100 blood samples (normal and elevated HbA1c levels). Provenance not specified.
• Accuracy (External Correlation - Study 1) Test Set: 175 blood samples (normal and elevated HbA1c levels). Provenance not specified.
• Accuracy (External Correlation - Study 2) Test Set: 117 blood samples (normal and elevated HbA1c levels). Provenance not specified.
• Combined Accuracy Study Set: 392 whole blood samples (100 internal + 175 external study 1 + 117 external study 2). Provenance not specified, but the studies were likely conducted internally or by contract labs in the company's operational regions (e.g., France, USA given the submitter and manufacturer locations). Retrospective vs. prospective is not explicitly stated, but blood samples were used for testing the device's performance retrospectively to their collection.

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

Not applicable in the context of this device. This device is an in vitro diagnostic (IVD) for quantitative measurement of HbA1c. The "ground truth" for the test set is established by a "commercially available capillary electrophoresis technique for HbA1c quantification that is NGSP standardized," which serves as the reference method. There were no human experts adjudicating diagnostic outcomes based on the device's output.

4. Adjudication Method for the Test Set

Not applicable. As this is a quantitative analytical device, the comparison is against a reference measurement method directly, not through expert adjudication of images or clinical cases.

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 automated quantitative measurement, not an AI-powered diagnostic imaging or decision support tool that involves human readers.

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

Yes, the studies reported are standalone performance studies of the CAPI 3 Hb A1c procedure (kit + CAPILLARYS 3 TERA instrument). It measures HbA1c levels automatically without human interpretation of the measurement itself, beyond loading samples and reviewing the quantitative results.

7. The Type of Ground Truth Used

The ground truth for the accuracy studies was established by a "commercially available capillary electrophoresis technique for HbA1c quantification that is NGSP standardized." This is a reference method, not expert consensus, pathology, or outcomes data in the usual sense of clinical diagnostic studies. NGSP (National Glycohemoglobin Standardization Program) standardization indicates traceability to the Diabetes Control and Complications Trial (DCCT) reference method.

8. The Sample Size for the Training Set

The provided document describes performance evaluation studies (precision, linearity, accuracy, interference) for a finished diagnostic device. It does not mention a "training set" in the context of machine learning or AI algorithm development because the device is a laboratory instrument based on an electrokinetic separation technique (capillary electrophoresis), not a machine learning model that requires training data. Therefore, the concept of a training set as typically understood in AI/ML is not applicable here.

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

Not applicable, as there is no "training set" in the context of this device's analytical methodology.

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