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The Bio-Rad VARIANT™ II Hemoglobin A Ic Program is intended for the percent determination of hemoglobin A Ic in human whole blood using ion-exchange high-performance liquid chromatography (HPLC). The Bio-Rad VARIANT II Hemoglobin Alc Program is intended for Professional Use Only. For in vitro diagnostic use. Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.

The VARIANT™ II ß-thalassemia Short Program is intended for the separation and area percent determinations of hemoglobins A2 and F, and as an aid in the identification of abnormal hemoglobins in whole blood using ion-exchange high-performance liquid chromatography (HPLC). The Bio-Rad VARIANT II ß-thalassemia Short Program is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use. Measurement of the percent hemoglobin A2 and F are effective in screening of ß-thalassemia (i.e., hereditary hemolytic anemias characterized by decreased synthesis or more types of abnormal hemoglobin polypeptide chains).

The VARIANT II Hemoglobin Testing System is a fully automated, highthroughput hemoglobin analyzer. The VARIANT II Hemoglobin Testing System provides an integrated method for sample preparation, separation and determination of the relative percent of specific hemoglobin in whole blood. It consists of two modules - the VARIANT II Chromatographic Station (VCS) and the VARIANT II Sampling Station (VSS). In addition, a personal computer is used to control the VARIANT System using Clinical Data Management (CDM) Software.

A personal computer (PC) is used to control the VARIANT II Hemoglobin Testing System using Clinical Data Management (CDM™) software. The CDM software supports import of sample information from and export of patient results to a Laboratory Information System (LIS). Control results are displayed on Levy-Jennings Charts and are exportable to Unity Real Time™.

This K130860 submission is a Special 510(k) for a device modification, meaning the changes are to existing predicate devices (VARIANT II Hemoglobin A1c Program and VARIANT II ß-thalassemia Short Program) and aim to demonstrate substantial equivalence without impacting the core performance specifications, intended use, or operating principles. The modifications primarily involve software and firmware updates, along with a PC Board replacement.

Therefore, the study focuses on verification and validation (V&V) testing to ensure the modified device remains safe, effective, and substantially equivalent to its predicate. It does not present new performance data against specific acceptance criteria for diagnostic accuracy as would be expected for a novel device or a device with significant performance changes. Instead, it asserts that the changes do not affect the previously established performance claims.

Here's an analysis based on the provided text, focusing on how the device meets acceptance criteria related to its modifications:

1. Table of Acceptance Criteria and Reported Device Performance

Since this is a device modification submission where the performance specifications are stated to be unchanged from the predicate, the acceptance criteria are implicitly that the modified device's performance is at least as good as the predicate device and that the modifications do not introduce new risks or degrade existing performance. The "performance" reported is the outcome of the verification/validation and risk management processes.

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

The document does not specify a numerical sample size for a "test set" in the traditional sense of a clinical or analytical performance study. Given the nature of a Special 510(k) for software/firmware/hardware changes, the "test set" would refer to the data and scenarios used during verification and validation (V&V) testing.

• Sample Size: Not explicitly stated as a number of patient samples. The V&V efforts would likely involve testing various functionalities, defect fixes using specific test cases, and potentially a range of instrument data (already available or specifically generated for V&V).
• Data Provenance: Not explicitly stated. For "defect corrections," the data likely originated from "customer feedback" and scenarios that caused the identified defects. For general V&V, it would involve internal testing data. It's implied to be retrospective, as it addresses "customer feedback" and "defects" from prior versions, but specific details are absent.

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

This type of information is not applicable or not provided for this submission. The ground truth in this context is typically related to diagnostic accuracy, which is not being re-evaluated because performance claims are "transferred from predicate device."

For defect fixes, the "ground truth" would be whether the defect is successfully resolved and the intended functionality works as designed. This is assessed by engineering and quality assurance teams during V&V. The document mentions "a trained risk assessment team" for FMEA, but not "experts" establishing a diagnostic ground truth for a test set.

4. Adjudication Method for the Test Set

Not applicable/not provided. No "adjudication method" for interpreting results from a test set is mentioned because the submission directly states that performance specifications and claims are unchanged and transferred from the predicate. The "ground truth" for V&V testing of software/firmware changes is based on successful execution of tests and resolution of identified bugs, not on expert consensus interpretation of diagnostic output.

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 device is an automated in vitro diagnostic (HPLC system) for measuring specific hemoglobin levels, not an AI-assisted diagnostic imaging or interpretation tool that involves human readers. Therefore, an MRMC study is not relevant to this submission.

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

The device itself (VARIANT II Hemoglobin Testing System with CDM Software) operates as a standalone automated system for measurement. The changes are to its software/firmware. The V&V testing would assess the functionality of this automated system in its modified state. So, the testing effectively evaluates the "standalone" performance of the modified system, but it's not a new standalone study; it's a re-validation of the existing standalone system after modifications. The performance claims are asserted to be the same as the predicate (which was a standalone device).

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

For the original predicate devices, the ground truth for establishing performance (e.g., accuracy of HbA1c or HbA2/F measurements) would have been based on comparison to reference methods or clinical outcomes.

For this specific submission (device modification):

• For defect corrections: The "ground truth" is the successful elimination of the defect and the proper functioning of the software features (e.g., CDM not crashing, calibrator reassignment working). This is validated through internal software testing.
• For performance: The submission directly states "No change or impact, claims transferred from predicate device." This means the ground truth for performance measures (precision, accuracy, linearity, etc.) was established during the original predicate device's clearance and is implicitly inherited rather than re-established in detail for this modification. The V&V here confirmed that the modifications did not degrade the ability to achieve those previously established performance characteristics.

8. The Sample Size for the Training Set

Not applicable/not provided. This device is not described as involving a machine learning algorithm that requires a "training set." The software and firmware updates are for controlling the HPLC system and managing data, not for learning from data in the way an AI algorithm would.

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

Not applicable. As no training set for a machine learning algorithm is involved, this question is not relevant to the submission.

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The Bio-Rad VARIANT II Hemoglobin A1c Program is intended for the percent determination of hemoglobin A1c in human whole blood using ion-exchange highperformance liquid chromatography (HPLC).
The Bio-Rad VARIANT II Hemoglobin A1c Program is intended for Professional Use Only.
Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.

The VARIANT II Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II Hemoglobin A1c Program is based on chromatographic separation of Hemoglobin A1c on a cation exchange cartridge.

Here's a breakdown of the acceptance criteria and the study details for the Bio-Rad VARIANT™ II Hemoglobin A1c Program, based on the provided text:

Acceptance Criteria and Reported Device Performance

The provided document describes a substantial equivalence study comparing a new device (VARIANT™ II Hemoglobin A1c Program (270-2101NU)) to a predicate device (VARIANT™ II Hemoglobin A1c Program (270-2101)). Therefore, the acceptance criteria are implicitly defined by the demonstration that the new device performs equivalently to the predicate device across various metrics. The study aims to show that the new device is "substantially equivalent" rather than meeting specific numerical performance targets against a predefined standard.

Table of Acceptance Criteria (Implied by Predicate Equivalence) and Reported Device Performance:

• Low Patient (n=240, Mean 5.5%): Within run %CV = 0.9, Within Device %CV = 1.60
• High Patient (n=160, Mean 8.8%): Within run %CV = 0.6, Within Device %CV = 1.38
  Predicate Device (270-2101):
• Low Patient (n=80, Mean 5.4%): Within run %CV = 1.46, Total Precision %CV = 2.14
• High Patient (n=80, Mean 13.7%): Within run %CV = 0.65, Total Precision %CV = 1.68
  Conclusion: "the precision results...are equivalent." |
  | Linearity (Linear Range) | The linear measuring range of the new device should be comparable to the predicate device. | New Device (270-2101NU): 3.1 - 18.5 % HbA1c
  Predicate Device (270-2101): 1.3 - 18.9 % HbA1c
  (Interpretation: Ranges are similar, supporting substantial equivalence.) |
  | Interfering Substances | The new device should demonstrate similar resistance to common interfering substances at comparable concentrations. | New Device (270-2101NU) & Predicate (270-2101):
• Bilirubin: No interference up to 20 mg/dL
• Lipids (Triglycerides): No interference up to 6000 mg/dL
• EDTA: No interference up to 11X EDTA
• Hemoglobin F: 10% (New), 15% (Predicate)
  (Interpretation: Generally similar, with a slight difference in HbF tolerance for the new device which isn't explicitly flagged as non-equivalent.) |

Study Details:

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

   • Accuracy (Method Correlation):
     • Sample Size: 42 EDTA whole blood patient samples.
     • Data Provenance: Not explicitly stated, but the samples are described as "patient samples," implying human origin. Country of origin and whether retrospective or prospective are not mentioned.
   • Precision:
     • New Device (270-2101NU): 240 samples for "Low Patient" and 160 samples for "High Patient."
     • Predicate Device (270-2101): 80 samples for "Low Patient" and 80 samples for "High Patient."
     • Data Provenance: "EDTA whole blood patient samples." Country of origin and whether retrospective or prospective are not mentioned, but the samples were analyzed at "three Bio-Rad sites" for the new device and on "one VARIANT II Hemoglobin Testing System" for the predicate.

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

   • The study is a method correlation and precision study for an in vitro diagnostic device, not an AI or imaging device requiring expert interpretation of results.
   • No human experts are mentioned as establishing ground truth in the context of diagnostic performance for this type of device. The ground truth for HbA1c values would be considered the measured value obtained from the method itself (or a reference method if specified).
   • The study compares the new device's measurements to the predicate device's measurements, implying the predicate device's results serve as a form of reference for comparison, and the predicate itself is standardized "Traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC. Certified via the National Glycohemoglobin Standardization Program (NGSP)."

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

   • This concept of "adjudication" is typically relevant for studies where human interpretation or labeling is involved, such as in image analysis or clinical trials with subjective endpoints.
   • For this in vitro diagnostic device study, the outputs are quantitative measurements of HbA1c. Therefore, no adjudication method in the traditional sense was used or needed for the test set.

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, an MRMC comparative effectiveness study was not done.
   • This study is for an in vitro diagnostic (IVD) device, specifically an automated assay, which does not involve human readers interpreting AI outputs. The device directly measures a biomarker (HbA1c).

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

   • Yes, a standalone performance evaluation was done. The entire study assessed the performance of the Bio-Rad VARIANT™ II Hemoglobin A1c Program (an automated analytical instrument) in generating HbA1c measurements, without human intervention in the result generation itself. The "algorithm" here refers to the instrument's internal processes for chromatographic separation and calculation, not an AI algorithm in the contemporary sense.

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

   • The "ground truth" for the performance evaluation is established through comparison to a legally marketed predicate device (Bio-Rad VARIANT™ II Hemoglobin A1c Program (270-2101)).
   • Both the new and predicate devices are stated to be "Traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC. Certified via the National Glycohemoglobin Standardization Program (NGSP)." This indicates that the measurements themselves are standardized against established reference methods, which serve as the ultimate "ground truth" for HbA1c values.

7. The sample size for the training set:

   • This is a study for an IVD device, not an AI/machine learning model. Therefore, the concept of a "training set" for an algorithm is not applicable. The device's operational parameters are based on its physical and chemical design, calibrated using established standards, not trained on a dataset.

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

   • As explained above, there is no training set in the AI sense for this device. The device operates based on principles of high-performance liquid chromatography calibrated against reference methods (DCCT, IFCC, NGSP).

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This software submission covers three assays with three different intended uses:

Hemoglobin A1c:
The VARIANT II Hemoglobin A1c Program is intended for the percent determination of hemoglobin A1c in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).
The VARIANT II Hemoglobin Alc Program is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.

Beta-thalassemia:
The VARIANT II Beta thalassemia Short Program is intended for the separation and area percent determinations of hemoglobin A2 and F, and as an aid in the identification of abnormal hemoglobins in human whole blood using ionexchange high-performance liquid chromatography (HPLC).
The VARIANT II Beta-thalassemia Short Program is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.

Total GHb:
The VARIANT II Total GHb Program is intended for the separation and area percent determination of total glycated hemoglobin (GHb) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).
The VARIANT II Total GHb Program with is intended for use only with the Bio-Rad VARIANT II Hemoglobin Testing System. For in vitro diagnostic use.

Indications for Use:
This software submission covers three assays and has two different Indications for Use:

HbA1c & GHb: Measurement of percent hemoglobin A1c is effective in monitoring long-term glucose control in individuals with diabetes mellitus.
HbA2 and HbF: Measurement of the percent hemoglobin A2 and F are effective in screening of β-thalassemia (i.e. hereditary hemolytic anemias characterized by decreased synthesis of one or more types of abnormal hemoglobin polypeptide chains).

The VARIANT II Hemoglobin Testing System uses the principles of high performance liquid chromatography (HPLC). The VARIANT II Hemoglobin A1c and Beta-thalassemia Short Program are based on chromatographic separation of hemoglobins on a cation exchange cartridge. The Total GHb Program is based on principles of boronate affinity high pressure liquid chromatography to separate glycated hemoglobin from non-glycated hemoglobin.

The new feature in this submission is the upgrade in CDM software. The current software (3.5) requires Windows NT and Object Store N.T. These products are nearing the end of their lifecycle. CDM 4.0 software is needed to transfer the CDM software to Microsoft XP Operating System and Object Store version 4.0.

Here's an analysis of the provided text regarding the acceptance criteria and study for the Bio-Rad VARIANTT II Hemoglobin Testing System with CDM 4.0.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria in this submission are implicit, established by demonstrating substantial equivalence to predicate devices (CDM 3.5 versions of the programs). The key performance metrics evaluated are accuracy (method correlation) and precision.

Here's the table:

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

• Hemoglobin A1c Program (Accuracy): 40 EDTA whole blood samples.
• Beta thalassemia Short Program (Accuracy): 40 EDTA whole blood samples.
• Total GHb Program (Accuracy): 40 EDTA whole blood samples.
• Precision Studies (all programs): Although specific sample numbers are sometimes noted as n=40 or n=80 for the combined precision data, it's important to note these refer to the number of individual measurements or patient samples, not necessarily distinct patients. The studies involved analyzing "duplicate aliquots of normal HbA1c and diabetic HbA1c patient samples and controls" over several days.
• Data Provenance: The document states "EDTA whole blood samples" and "patient samples and controls." It does not specify the country of origin or if the data was retrospective or prospective. Given the context of method correlation and precision, it's likely these were carefully selected samples to cover the analytical range, and are prospective in nature for the purpose of the study.

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

This submission is for an in vitro diagnostic device (IVD) that measures specific biomarkers (HbA1c, HbA2, HbF, GHb) using analytical techniques (HPLC). The "ground truth" for such devices is typically established through a reference method or a highly accurate existing method.

In this case, the device's performance is compared against its predicate device (the older CDM 3.5 version of the same program). The predicate device itself would have been validated against a reference method.

• No external human experts were explicitly used to establish "ground truth" for the test set in this particular comparative study. The ground truth is the measurement obtained from the predicate device (CDM 3.5).
• The standardization for HbA1c and GHb is stated as "Traceable to the Diabetes Control and Complications Trial (DCCT) reference method and IFCC. Certified via the National Glycohemoglobin Standardization Program (NGSP) for HbA1c." This indicates that the values obtained by both the new and predicate devices are ultimately traceable to established clinical reference standards, which is how the "ground truth" of the concentration values is ensured.

4. Adjudication Method for the Test Set

Not applicable. This is not a study involving human interpretation of images or data that would require adjudication. It's a quantitative measurement device, and the comparison is statistical (regression and precision).

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

No. This is an in vitro diagnostic device for quantitative measurement, not an AI or imaging device requiring human reader interpretation or MRMC studies.

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

Yes, the studies presented are standalone performance evaluations of the device (system including software) in terms of its analytical accuracy and precision. There is no human-in-the-loop aspect being evaluated here, as the device is designed for automated measurement.

7. The Type of Ground Truth Used

The "ground truth" for the performance evaluation in this 510(k) submission is the measurements obtained from the predicate device (the Bio-Rad VARIANT II Hemoglobin Testing System running CDM 3.5). The new device (CDM 4.0) is compared directly to the predicate to demonstrate substantial equivalence, meaning it performs similarly.

Underlying this, the initial "ground truth" for quantitative values for HbA1c is linked to reference methods (DCCT and IFCC) and certification (NGSP). For HbA2 and HbF, the ground truth is also tied to established quantitative analysis using HPLC.

8. The Sample Size for the Training Set

The document does not describe a "training set" in the context of machine learning or AI. This device is an analytical instrument with associated software. The software (CDM 4.0) is an upgrade to manage the data and system on a new operating system, not a machine learning algorithm that is "trained."

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

Not applicable, as there is no "training set" in the machine learning sense for this device. The software update primarily concerns operating system compatibility and database management, not the underlying analytical algorithm itself.

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The VARIANT™ II Hemoglobin A1c Program is intended for the determination of hemoglobin A1c in human whole blood using ion-exchange high performance liquid chromatography (HPLC).

The VARIANT™ II Hemoglobin A1c Program is intended for use only with the Bio-Rad VARIANT™ II Hemoglobin Testing System.

For in vitro diagnostic use only.

The VARIANT™ II Hemoglobin A1c Program is based on chromatographic separation of HbA1c on a cation exchange cartridge. The analytical system of instrument and reagent kit provides a means of measuring Hemoglobin A1c, formed by the non-enzymatic attachment of circulating blood glucose to the N terminal valine of the B-chain of the hemoglobin molecule (HbAo). Attachment of glucose to hemoglobin is achieved in a two step process. The first step is the formation of an unstable aldimine (Schiff base, labile, or pre-A1c), a reversible reaction between the carbonyl group of glucose and the N terminal valine of the ß-chain of hemoglobin. The amount of Schiff base formed is directly proportional to the blood glucose concentration. The second step is the much slower and irreversible conversion of the Schiff base intermediate to the stable "ketoamine" product (Hemoglobin A1c). The percentage of Hemoglobin A1c in whole blood is dependent on the level of sustained blood glucose and indicative of mean blood glucose over the lifetime of red blood cells (~ 120 days).

The VARIANT™ II HbA1c Program has added front end automation and Clinical Data Management Software capabilities. The front end automation allows sampling from primary sample tubes. The predicate used a hemolysis reagent during sample preparation to remove Schiff base. The VARIANT™ II HbA1c Program separates Schiff base from HbA1c in the analysis step.

Here's a breakdown of the acceptance criteria and study information for the Bio-Rad VARIANT™ II HbA1c Program, based on the provided text:

Acceptance Criteria and Device Performance

Study Information:

1. Sample Size Used for the Test Set and Data Provenance:

   • Precision Study: Low, medium, and high patient whole blood samples were used. The exact number of samples or runs is not specified, but the study implies multiple measurements for within-run and between-run variability.
   • Correlation Study: The document does not specify the exact sample size for the correlation study against the VARIANT™ HbA1c Program.
   • Data Provenance: Not specified, but generally, clinical validations for these types of devices in the US would use samples from the US or a similar regulatory environment. The document is for a US FDA submission.

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

   • This device is an in vitro diagnostic (IVD) for quantitative measurement of HbA1c. The "ground truth" for such devices is typically established through reference methods or comparison to a predicate device, rather than expert consensus on image interpretation or similar qualitative assessments. For the precision studies, the device measures the HbA1c values directly. For accuracy, it's compared to another device. Therefore, no "experts" in the sense of clinical reviewers are explicitly mentioned for establishing ground truth.

3. Adjudication Method:

   • Not applicable as the "ground truth" for this quantitative IVD is based on direct measurement or comparison to a predicate device, not qualitative assessments requiring adjudication.

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

   • No. This is an In Vitro Diagnostic (IVD) device that performs a biochemical assay. MRMC studies are typically for imaging devices where human readers interpret results, often with and without AI assistance. This device provides a quantitative numerical output, not an image for human interpretation.

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

   • Yes, implicitly. The performance data presented (precision, correlation) are measurements of the device's analytical performance on its own, without direct human intervention in the result generation beyond operating the instrument and loading samples.

6. Type of Ground Truth Used:

   • For precision, the ground truth is the inherent variability of the assay itself when measuring known samples (low, medium, high patient whole blood).
   • For accuracy/correlation, the ground truth is considered to be the results obtained from the predicate device, VARIANT™ HbA1c Program (K926469).

7. Sample Size for the Training Set:

   • This is an IVD device, not a machine learning algorithm in the typical sense that would have a "training set" for model development. The "training" for this device involves analytical method development and optimization, and subsequent validation using characterized samples. No specific "training set" relevant to AI/ML is mentioned or applicable here.

8. How the Ground Truth for the Training Set was Established:

   • As explained above, the concept of a "training set" and its ground truth in the context of AI/ML does not directly apply to this traditional IVD device. The development process would involve extensive analytical testing and optimization using characterized biological samples and controls, but this is distinct from the training of a machine learning model.

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