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The QXDx™ BCR-ABL %IS Kit is an in vitro nucleic acid amplification test for the quantitation of BCR-ABL1 and ABL1 transcripts in total RNA from whole blood of diagnosed (9;22) positive Chronic Myeloid Leukemia (CML) patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2. The QXDx BCR-ABL %IS Kit is a reverse transcription-quantitative PCR performed on the Bio-Rad QXDx™ AutoDG™ ddPCR System and is intended to measure BCR-ABL1 to ABL1, expressed as a log molecular reduction (MR value) from a baseline of 100% on the International Scale, in (9;22) positive CML patients during monitoring of treatment with Tyrosine Kinase Inhibitors (TKIs).

The QXDx BCR-ABL %IS Kit is intended for use only on the Bio-Rad QXDx AutoDG ddPCR System.

The test does not differentiate between e13a2 or e14a2 fusion transcripts and does not monitor other rare fusion transcripts resulting from t(9;22). This test is not intended for the diagnosis of CML.

The QXDx AutoDG ddPCR System consists of two instruments, the QXDx Automated Droplet Generator and the QXDx Droplet Reader, and their associated consumables. The QXDx Automated Droplet Generator partitions samples into approximately 20,000 nanoliter-sized droplets and, after PCR on a thermal cycler, droplets from each sample are analyzed individually on the QXDx Droplet Reader. PCR-positive and PCR-negative droplets are counted to provide direct quantification of nucleic acid in digital form. Results are analyzed on QXDx Software running on a Windows based computer.

The QXDx AutoDG ddPCR System contains:

• QXDx Automated Droplet Generator ●
• QXDx Droplet Reader ●
• Laptop Computer with QXDx Software .
• Accessory components: ●
  • o ddPCR Dx AutoDG Consumable Pack
    • Automated Droplet Generation Oil for Probes ■
    • DG32 Cartridges w/ Gaskets ■
    • ddPCR Pipet Tips
    • . ddPCR 96 Well Plates
    • . ddPCR Pierceable Foil Seals
  • o ddPCR Dx AutoDG Droplet Reader Oil Pack

Components of the kit QXDx BCR-ABL %IS KIT:

• QXDXTM BCR-ABL primers & probes
• QXDXTM Nuclease Free Water
• QXDXTM iScript Advanced Reverse Transcriptase
• QXDXTM 5x iScript Select Reaction Mix
• QXDXTM RT Primers
• QXDXTM 2X ddPCRTM Supermix
• QXDXTM BCR-ABL ~0.1%IS
• QXDXTM BCR-ABL ~10%IS
• QXDXTM BCR-ABL Neg-CTRL
• QXDXTM BCR-ABL H-CTRL
• QXDXTM BCR-ABL L-CTRL

The provided document details the analytical and clinical performance of the QXDx BCR-ABL %IS Kit for use on the QXDx AutoDG ddPCR System. This device is an in vitro nucleic acid amplification test for the quantitation of BCR-ABL and ABL1 transcripts in total RNA from whole blood of diagnosed Chronic Myeloid Leukemia (CML) patients.

The document does not describe the acceptance criteria and study for an AI/ML powered medical device, but rather for an in vitro diagnostic (IVD) kit. Therefore, many of the typical acceptance criteria and study elements associated with AI/ML devices (e.g., human-in-the-loop performance, expert consensus for ground truth on images, MRMC studies) are not applicable.

Below is a breakdown of the acceptance criteria and study details provided for this IVD kit, adapted to the requested format where possible, and noting where specific requested information (relevant to AI/ML devices) is not available for this type of device.

Acceptance Criteria and Reported Device Performance

The core acceptance criteria are related to the analytical performance of the kit, primarily precision, reproducibility, cross-reactivity, interference, linearity, and detection capability. The performance is consistently reported in terms of Molecular Reduction (MR) value or %International Scale (%IS), which are standardized measures for BCR-ABL levels.

Table 1: Acceptance Criteria of the QXDx BCR-ABL %IS Kit and Reported Performance

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The Hemoglobin Variants System is intended as a qualitative screen for the presence of hemoglobins F, A, S, D, C and E in eluates of neonatal blood collected on filter paper by high-performance liquid chromatography (HPLC). The Hemoglobin Variants System is intended for Professional Use Only. For in vitro diagnostic use. The Hemoglobin Variants System is for use only with the Newborn Hemoglobin System (NHS).

This device, consisting of the reagents, controls, apparatus, HPLC instrumentation, software is indicated for professional laboratory IVD use to isolate and identify inherently determined abnormal (S, D, C, E) and normal (F, A) hemoqlobin types in neonatal blood samples.

The instrument, Newborn Hemoglobin System (NHS) utilizes same principles of ionexchange high-performance liguid chromatography (HPLC). The NHS instrument is a fully automated, high-throughput hemoglobin analyzer. It utilizes principles of ion-exchange highperformance liquid chromatography (HPLC). The NHS provides an integrated method for the separation and determination of relative percent of specific hemoglobins of dried blood spots. The dried blood spot collected from neonatal heel stick is punched and eluted with deionized water. The punched disc is removed and eluted sample is transferred into microplate well. The eluted sample is analyzed to identify specific inherently abnormal (S, D, C, E) as well as normal (F, A) hemoglobins through the system.

The NHS consists of two modules — the Newborn Chromatographic Station (NCS) and the Newborn Auto Sampler (NAS). NCS module delivers buffer solutions (See table 4 for kit components) to the Hemoglobin Variants System CE Mini-Columns and the detector. The NAS module through automatic injection introduces eluted sample from microplate wells. Each sample is processed individually. The mini-column contains a cation exchange gel, and the analyzer makes use of a continuous pre-programmed gradient system. The preprogrammed gradient is designed to have the hemoglobins of interest elute from the minicolumn with retention times that fall within pre-determined windows characteristic of known normal and abnormal hemoglobins. The ionic strength of two phosphate buffers passing through the mini-column is changed over three minutes. The eluted hemoglobins introduced through automatic injection are sequentially detected with a dual-wavelength filter photometer. which monitors hemoglobin absorbance at 415 nm and corrects for any gradient induced absorbance changes at 690 nm. Detection is performed at two wavelengths (415 nm and 690 nm) to ensure a stable baseline. Sample of water immediately following a newborn or quality control sample prevents carryover.

A workstation is used to control the Newborn Hemoglobin System using Genetic Disease Management (GDM) software. The GDM software is designed to execute the assay protocol on the NHS instrument using the Hemoglobin Variants System reagent kit components. The software processed HPLC data is outputted in a printed report that contains: 1) sample identification, 2) date and time of analysis, 3) report data (i.e., peak names, retention times, area, relative percent), and 4) chromatogram. Also system assigns a presumptive phenotype "pattern" to each sample result. The pattern is calculated by applying a set of "rules" to the peaks identified in the peak table. The purpose of the pattern rules is to eliminate minor peaks from the pattern, identify system or sample problems, and to focus the operator on the samples that may require further investigation. The pattern rules used by the GDM software were derived from those generated by the Genetic Diseases Laboratory for the state of California, USA, after analysis of 2.5 million newborns by HPLC over a four year period (Eastman, et al., 1996)'. Laboratories using the Newborn Hemoglobin System pattern rules and assignment should perform an internal validation study to confirm the performance of the system for their application. 1.Eastman, J. W.; Wong, R.; Liao, C. L.; Morales, D. R. Automated HPLC Screening of Newborns for Sickle Cell Anemia and Other Hemoglobinopathies. Clin. Chem. 1996, 42 (5), 704—710.

The HbReview Software is to support the review of transmitted result and release of an approved result for each neonate sample analyzed on Hemoglobin Variants System with Newborn Hemoglobin System. A screening site using Newborn Hemoglobin Systems (NHS) transmits results from the Genetic Disease Management (GDM) software to the central site. The central site uses HbReview software to review results, identify samples for retesting, add comments and release results to the reporting site. Features are provided to assist Reviewers and Approvers in their tasks of examining results from the Hemoglobin Newborn Screening test.

The HbReview software is a Client-Server design. The Review process provides a user interface (client) to a relational database, which is located on a separate computer (the server). The Client software permits an authorized user to make changes to the data maintained on the Server.

This submission describes the Bio-Rad Hemoglobin Variants System on Newborn Hemoglobin System with GDM and HbReview Software. This device is intended as a qualitative screen for the presence of hemoglobins F, A, S, D, C and E in eluates of neonatal blood collected on filter paper by high-performance liquid chromatography (HPLC).

Here's an analysis of the provided information:

1. Table of acceptance criteria and the reported device performance:

The document does not explicitly state acceptance criteria or provide a table of performance metrics (like sensitivity, specificity, accuracy) from a validation study for the Hemoglobin Variants System. It focuses on demonstrating substantial equivalence to a predicate device (Bio-Rad VARIANT™nbs Sickle Cell Program).

However, the "Indications for Use" section states: "This device...is indicated for professional laboratory IVD use to isolate and identify inherently determined abnormal (S, D, C, E) and normal (F, A) hemoglobin types in neonatal blood samples." This implies that the device must accurately identify these hemoglobin types.

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

The document does not provide information on the sample size used for a test set or the data provenance (country of origin, retrospective/prospective) for a performance study of the modified device.

It mentions that the "pattern rules used by the GDM software were derived from those generated by the Genetic Diseases Laboratory for the state of California, USA, after analysis of 2.5 million newborns by HPLC over a four year period (Eastman, et al., 1996)." This refers to the historical data used to establish the rules for the GDM software, not a specific test set for the current device's performance validation. It also suggests that laboratories using the system should perform an internal validation.

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

The document does not explicitly state the number or qualifications of experts used to establish ground truth for a specific test set for the modified device. The reference to the Genetic Diseases Laboratory in California for establishing GDM pattern rules implies expert involvement in the development of those rules, but not necessarily in evaluating a specific test set for the current submission.

4. Adjudication method for the test set:

The document does not describe an adjudication method for a test set.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done:

No, the document does not mention an MRMC comparative effectiveness study for the modified device. The focus is on demonstrating substantial equivalence, not on quantifying the improvement of human readers with AI assistance.

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

The device described is a system that combines instrumentation, reagents, and software for analysis. While the GDM and HbReview software play a role, the system is designed for in vitro diagnostic use by professional laboratories. The HbReview software aids in the review and release of results by human operators. Therefore, it's not a standalone "algorithm only without human-in-the-loop" performance in the context of typical AI device submissions. The "pattern rules" in GDM are an automated algorithmic component, but the overall system involves human oversight for result review and release.

7. The type of ground truth used:

The document implies that the ground truth for identifying hemoglobin types (F, A, S, D, C, E) would be established through laboratory methods that definitively identify these hemoglobins. For the historical data used to derive GDM pattern rules, it was based on HPLC analysis with extensive validation as referenced (Eastman, et al., 1996). For the current device, a robust laboratory gold standard (e.g., confirmatory biochemical or genetic testing) for hemoglobin types would be expected to serve as ground truth in any validation studies.

8. The sample size for the training set:

The document does not explicitly state a sample size for a training set for the modified device.

However, it states that the GDM software's pattern rules were derived from "analysis of 2.5 million newborns by HPLC over a four-year period (Eastman, et al., 1996)" by the Genetic Diseases Laboratory for the state of California. This large dataset effectively served as the "training data" for formulating those rules.

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

For the 2.5 million newborns analyzed that informed the GDM pattern rules, the ground truth was established through HPLC analysis (ion-exchange high-performance liquid chromatography). This method is a standard laboratory technique for identifying and quantifying hemoglobin variants. The implied ground truth relies on the established accuracy and reliability of this HPLC method, likely supported by expert interpretation and potentially confirmatory testing in ambiguous cases over the four-year period mentioned.

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The D-10™ Hemoglobin A1c Program is intended for the quantitative determination of hemoglobin A1c (IFCC mmol/ mol and NGSP %) in human whole blood using ion- exchange high-performance liquid chromatography (HPLC) on the D-10TM Hemoglobin Testing System.

Hemoglobin Alc measurements are 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 D-10™ Hemoglobin A1c Program is intended for professional in vitro diagnostic use only.

The D-10™ Hemoglobin Testing System utilizes the principles of ion-exchange highperformance liquid chromatography (HPLC). A dual-piston, low pulsation HPLC pump and a proportioning value deliver the buffer solution to an analytical cartridge and detector. Whole blood samples undergo an automatic two step dilution process and then introduced into the analytical flow path. Pre-diluted samples are aspirated directly and introduced into the analytical flow path. Between sample injections, the sample probe is rinsed with Wash/Diluent Solution to minimize sample carryover.

A programmed buffer gradient of increasing ionic strength delivers the sample to the analytical cartridge where the hemoglobin species are separated based upon their ionic interactions with the cartridge material and the buffer gradient. The separated hemoglobin species then pass through the photometer flow cell where changes in the absorbance are measured at 415 nm and recorded as a digital chromatogram.

The software performs a reduction of raw data collected from each analysis that may indicate use of a calibration factor. A samples report and chromatogram are generated for each sample.

The D-10™ Hemoglobin A1c Program is designed to be used on the D-10™ Hemoglobin Testing System with or without a D-10 Rack Loader.

The provided text describes a 510(k) premarket notification for the D-10 Hemoglobin A1c Program. This device is an in vitro diagnostic (IVD) used for the quantitative determination of hemoglobin A1c (HbA1c) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC).

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

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" in a single table, but rather presents performance characteristics derived from various studies. Based on the "Summary of Nonclinical Performance Data" and the conclusion that "The performance criteria as stipulated by the Special Controls requirements for HbA1c systems that diagnose diabetes have clearly been met," we can infer the acceptance criteria from the reported results. The critical performance metrics for an HbA1c assay for diabetes diagnosis typically include precision (CV%), linearity, and method comparison (bias).

2. Sample Sizes Used for the Test Set and Data Provenance:

• Precision/Reproducibility: Four EDTA whole blood samples at target HbA1c concentrations (~5%, ~6.5%, ~8%, ~12%) and five quality control materials were used. Each sample/control was run in duplicate, in 2 runs per day, on 3 instruments for 20 days, and repeated with 3 different kit lots, yielding a total of 720 results per sample over 60 days. The data provenance is not explicitly stated (e.g., country of origin, retrospective/prospective clinical samples), but it implies prospective collection for the study.
• Linearity: Low (3.9% HbA1c) and high (18.8% HbA1c) EDTA whole blood patient samples were mixed in varying ratios to create 11 sample pools. The exact number of individual patient samples generating the pools is not specified.
• Method Comparison: 128 variant-free whole blood K3 EDTA samples were evaluated. The range of HbA1c was from 3.9% to approximately 19.0% (19 to 184 mmol/mol). Data provenance is not explicitly stated for these samples, but they are referred to as "patient samples."
• Endogenous/Drug Interference & Hemoglobin Derivatives Interference: Two EDTA whole blood sample pools (low level ~6.5% HbA1c and high level ~8.0% HbA1c) were used for spiking experiments. Ten replicates of each pool with interferent and control were analyzed. The specific number of individual patient samples that formed these pools is not detailed.
• Hemoglobin Variant Study: A panel of normal and diabetic whole blood EDTA patent variant samples for HbS (n=22), HbC (n=20), HbD (n=22), HbE (n=23), HbA2 (n=20), and HbF (n=24) were used. These are patient samples with known variants.

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

• For Method Comparison: The D-10™ Hemoglobin A1c Program results were compared to "testing performed at a secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay." The NGSP SRL (National Glycohemoglobin Standardization Program Secondary Reference Lab) is itself a highly qualified reference standard, implying expert oversight and standardized methods for ground truth determination, though specific human experts are not named or qualified in this document.
• For Hemoglobin Variant Study: Comparison was made to a "NGSP reference method that has been demonstrated to be free from the hemoglobin interferent." Similar to the method comparison, this relies on a standardized reference method rather than individual expert adjudication for each sample.

4. Adjudication Method for the Test Set:

Not applicable in the traditional sense of image or clinical outcome adjudication by multiple experts. The ground truth for the method comparison and variant studies was established by comparison to a standardized NGSP reference method, which inherently provides a highly controlled and validated "truth" for HbA1c measurements.

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

No, a MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) for laboratory use, not typically subject to 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 described are all standalone performance evaluations of the D-10™ Hemoglobin A1c Program device. The tests, such as precision, linearity, method comparison, and interference studies, assess the analytical performance of the algorithm and hardware without human interpretation in the loop determining the HbA1c value.

7. The Type of Ground Truth Used:

The ground truth for the performance studies primarily relies on:

• Reference Methods: For method comparison and variant studies, the ground truth was established by a "secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay" and an "NGSP reference method."
• Expected Values/Spiking: For precision, linearity, and interference studies, ground truth was based on preparing samples with known concentrations or by comparing to control samples without interferents.
• Consensus/Certification: The general standardization is traced to IFCC reference calibrators and NGSP certification.

8. The Sample Size for the Training Set:

This document describes premarket notification studies for an in vitro diagnostic device, not a machine learning algorithm. Therefore, there is no explicit "training set" in the context of machine learning model development. The device relies on established chemical and physical principles (ion-exchange HPLC) with programmed parameters, rather than learning from a large dataset. Calibration of the instrument is performed using calibrator materials, but this is distinct from a machine learning training set.

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

As there is no machine learning-based training set, this question is not applicable. The device's operational parameters and calibration are based on established analytical chemistry principles and reference materials. The value assignment for the calibrator materials "were previously reviewed under 510(k) submission K031043," indicating their ground truth was established through a separate, regulated process.

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The D-100™ HbA1c test is intended for the quantitative determination of hemoglobin A1c (IFCC mmol/mol and NGSP %) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC) on the D-100 Hemoglobin Testing System.

Hemoglobin A1c measurements are used as an aid in diagnosis of diabetes mellitus, 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 D-100TM HbA1c test is intended for Professional Use Only.

Calibrators:

The D-100™ HbA1c Calibrator Pack is for the calibration of the D-100 Hemoglobin Testing System used for the quantitative determination of hemoglobin A1c(HbA1c) in human whole blood.

The Bio-Rad D-100™ HbA1c utilizes principles of ion-exchange high-performance liquid chromatography (HPLC). A high-pressure pumping system delivers a buffer solution to an analytical cartridge and detector. Whole blood samples undergo an automatic hemolysis and dilution process before being introduced into the analytical flow path. Prediluted samples are identified based upon the use of a microvial adapter in the sample rack, and the automatic dilution step is omitted.

A programmed buffer gradient of increasing ionic strength delivers the sample to the analytical cartridge where the hemoglobin species are separated based upon their ionic interactions with the cartridge material and the buffer gradient. The separated hemoglobin species then pass through the flow cell where changes in the absorbance are measured at 415 nm and recorded as a digital chromatogram.

The software performs an analysis of the hemoglobin peaks in the chromatogram, recording information including retention time, peak area, and relative are percent. Any peaks that are identified as the target analyte(s) are calibrated before generating a sample report and chromatogram for each sample. The software includes an optional feature (Advisor) that compares the sample report against a set of rules that are programmed to take user-specified actions.

The D-100™ HbA1c test is designed to be used on the D-100™ Hemoglobin Testing System.

This document describes the D-100™ HbA1c test and D-100™ HbA1c Calibrator Pack, intended for the quantitative determination of hemoglobin A1c (HbA1c) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC) on the D-100™ Hemoglobin Testing System. The test is used as an aid in diagnosing diabetes mellitus, identifying individuals at risk for diabetes, and monitoring long-term blood glucose control in diabetic patients. The calibrators are used for the calibration of the system.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implied through the study designs, particularly the "significant interference" threshold for analytical specificity and the performance demonstrated in linearity and precision studies. For the purpose of this summary, the relevant performance metrics are extracted and presented.

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The VARIANT™ II TURBO HbA1c Kit- 2.0 is intended for the quantitative determination of hemoglobin A1c (IFCC mmol/mol and NGSP %) in human whole blood using ion-exchange high-performance liquid chromatography (HPLC) on the VARIANT II TURBO Hemoglobin Testing System and VARIANT II TURBO Link Hemoglobin Testing System.

This test is to be used as an aid in diagnosis of diabetes and as an aid in identifying patients who may be at risk for developing diabetes.

The VARIANT II TURBO HbA1c Kit- 2.0 is intended for Professional Use Only.

The Hemoglobin Capillary Collection System (HCCS) is intended for the collection of human whole blood for the percent determination of hemoglobin A1c using Bio-Rad HPLC methods.

The VARIANT™ II TURBO HbA1c Kit - 2.0 utilizes principles of ion-exchange highperformance liquid chromatography (HPLC). The samples are automatically diluted on the VARIANT™ II TURBO Sampling Station (VSS) and injected into the analytical cartridge. The VARIANT™ II TURBO Chromatographic Station (VCS) dual pumps deliver a programmed buffer gradient of increasing ionic strength to the cartridge, where the hemoglobins are separated based on their ionic interactions with the cartridge material. The separated hemoglobins then pass through the flow cell of the filter photometer, where changes in the absorbance at 415 nm are measured. An additional filter at 690 nm corrects for background absorbance.

The VARIANT™ II TURBO Clinical Data Management (CDM™) software performs reduction of raw data collected from each analysis. Two-level calibration is used for adjustment of the calculated HbA1c values. A sample report, including retention times of detected peaks and a chromatogram, is generated by the CDM for each sample. The A1c peak is shaded for ease of identification. The area is calculated using an exponentially modified Gaussian (EMG) algorithm and the result printed in either mmol/mol or % HbA1c format as selected by the user.

The VARIANT™ II TURBO HbA1c Kit – 2.0 is designed to be used on the standalone VARIANT™ II TURBO and the VARIANT™ II TURBO Link Hemoglobin Testing Systems. VARIANT™ II TURBO and the VARIANT™ II TURBO Link Hemoglobin Testing Systems are identical with respect to all operational and system components. Physically, the VARIANT™ II TURBO Link VSS outer case is modified for compatibility with a track Functionality of the VARIANT™ II TURBO Link has not changed, just the system. physical orientation to accommodate sample tube management on a track system.

This document describes the performance of the VARIANT™ II TURBO HbA1c Kit - 2.0, an in vitro diagnostic device used for quantitative determination of hemoglobin A1c.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are derived from the "Special Controls Requirements for HbA1c for Diabetes Diagnosis" as outlined in Table 17 of the document (though it's mislabeled and actually on page 14 of the PDF). The device performance is reported in various sections of the "Summary of Performance Data."

Detailed Study Information:

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

• Precision/Reproducibility Study:
  • Sample Size: 4 EDTA whole blood samples (at ~5%, ~6.5%, ~8%, and ~12% HbA1c) and 5 quality control materials. Each sample had 720 measurements (run in duplicate, 2 runs/day, for 20 days across 3 instruments).
  • Data Provenance: Not explicitly stated regarding country of origin, but it involves patient samples and quality control materials, which are typically retrospective or derived from clinical settings.
• Method Comparison Study:
  • Sample Size: 130 variant-free whole blood EDTA samples.
  • Data Provenance: Not explicitly stated regarding country of origin. The samples ranged from 3.4% to 20.0% HbA1c, suggesting prospective collection covering a diagnostic range. It mentions comparison to a "secondary NGSP SRL reference laboratory," implying real-world clinical samples.
• Linearity Study:
  • Sample Size: Low (3.4%HbA1c) and high (20.6%HbA1c) EDTA whole blood patient samples mixed at varying ratios, creating 11 distinct levels (Level 1 to Level 11).
  • Data Provenance: Patient samples, likely retrospective.
• Analytical Specificity (Interference) Studies:
  • Endogenous Interference: Two EDTA whole blood sample pools (~6.5%HbA1c and ~8.0%HbA1c) were used. 10 replicates of each pool with test and control samples.
  • Drug Interference: Two EDTA whole blood sample pools (~6.5%HbA1c and ~8.0%HbA1c) were used. 10 replicates of each drug with test and control samples.
  • Hemoglobin Derivatives Interference: Low (~6.5%HbA1c) and high (~8.0%HbA1c) whole blood EDTA samples. Ten replicates each.
  • Hemoglobin Variant Study: Specific variant samples (HbS, HbC, HbD, HbE, HbA2, HbF), with n=21-29 for each variant (e.g., 26 for HbS, 25 for HbC). Tested in duplicate.
  • Data Provenance: Not explicitly stated regarding country of origin. "Patient samples" were used for some, and pure substances/serum samples for others.

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

• The document does not explicitly state the number or qualifications of experts for establishing ground truth.
• For the Method Comparison Study, the device's results were compared to a "secondary NGSP SRL reference laboratory using a cleared HPLC-based HbA1c assay." The NGSP (National Glycohemoglobin Standardization Program) provides certification for laboratories and methods to ensure traceability to the DCCT (Diabetes Control and Complications Trial) reference method. This implies the ground truth is established by a highly standardized and validated reference method in an accredited laboratory, rather than by individual experts' consensus.
• For the Hemoglobin Variant Study, the comparison was against "a NGSP reference method that has been demonstrated to be free from the hemoglobin interferent," again pointing to a high-standard reference method as the ground truth.

4. Adjudication Method for the Test Set

• No explicit adjudication method (like 2+1 or 3+1 consensus) is described. The ground truth relies on established reference methods (NGSP-certified HPLC for HbA1c, and specialized NGSP reference methods for variant studies) as opposed to human adjudication of ambiguous cases. This is typical for quantitative analytical devices where a measurable reference standard exists.

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

• No, an MRMC comparative effectiveness study was not done. This type of study typically evaluates the effectiveness of a diagnostic aid (like AI) on physician performance in interpreting medical images or making diagnoses. The VARIANT™ II TURBO HbA1c Kit - 2.0 is an automated in vitro diagnostic device for quantitative chemical analysis, not an image interpretation or diagnostic aid that involves human "readers." Its performance is measured directly against reference methods and statistical criteria.

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

• Yes, the studies evaluate the standalone (algorithm only) performance. The device is an automated system (ion-exchange HPLC) that processes samples and produces quantitative HbA1c results. The performance data presented (precision, linearity, method comparison, interference studies) directly assesses the accuracy and reliability of this automated system in determining HbA1c values, without human intervention in the interpretative step. The "Human-in-the-loop" aspect would primarily involve sample collection and loading the instrument, not interpretation of the results themselves.

7. The Type of Ground Truth Used

• Primarily reference method comparison, traceable to international standards.
  • For HbA1c quantification, the ground truth is established by comparison to NGSP-certified reference methods, which are themselves traceable to the DCCT (Diabetes Control and Complications Trial) reference method and IFCC (International Federation of Clinical Chemistry and Laboratory Medicine) units. This is stated under "Traceability" (Section 8.d) and in the method comparison and variant studies.
  • For interference studies, the ground truth is based on the expected values of spiked samples without the interferent, as measured by the device itself or a control.

8. The Sample Size for the Training Set

• The document does not explicitly mention a "training set" in the context of machine learning or algorithm development. This device is based on established HPLC principles and data reduction algorithms, which are typically designed and validated, rather than "trained" in the machine learning sense. The performance studies described serve as validation/verification of the final device.

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

• As a traditional in vitro diagnostic device based on HPLC, there isn't a "training set" in the machine learning paradigm. The device's underlying principles (ion-exchange chromatography, spectrophotometry, and specific algorithms for peak detection and calculation) are built upon scientific understanding and engineering. The "ground truth" for developing and calibrating such systems would come from well-characterized reference materials and methods, likely through extensive internal R&D and calibration procedures following international standards, but this is not detailed as a "training set" in the document.

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The Bio-Rad VARIANT II TURBO Link Hemoglobin Alc 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 TURBO Link Hemoglobin A Ic Program is for use with the VARIANT II TURBO Link Hemoglobin Testing System interfaced with an automated sample transport system.

The Bio-Rad VARIANT II TURBO Link Hemoglobin AIc Program is Professional Use Only. Measurement of hemoglobin A Ic is effective in monitoring long-term glycemic control in individuals with diabetes mellitus.

The VARIANT II TURBO Link Hemoglobin Testing System is the next generation Instrument VARIANT II TURBO Hemoglobin Testing System. It integrates the VARIANT II TURBO with the Sysmex HST-N (Hematology Sample Transportation)/XN-9000 TLA systems to allow management of patient sample tubes with A 1c order on the same platform. The VARIANT II TURBO Link system communicates with the Sysmex HST-N/XN-9000 TLA hardware and software in order to receive, identify, inject, and analyze samples with an A 1 c order.

The VARIANT II TURBO Link Hemoglobin Testing System is a fully automated, highthroughput hemoglobin analyzer. It consists of three modules - the VARIANT II TURBO Link Chromatographic Station (VCS), the VARIANT II TURBO Link Sampling Station (VSS), and the Reagent Reservoir Module. In addition, a personal computer (PC) is used to control the VARIANT II TURBO Link system using Clinical Data Management (CDM™) software.

Here's an analysis of the acceptance criteria and study information for the Bio-Rad VARIANT™ II TURBO Link Hemoglobin A1c Program, based on the provided text:

Premarket Notification (510(k)) Summary: K140801

It is important to note that this 510(k) pertains to a device modification (specifically, software and firmware updates) of an already cleared device, the VARIANT™ II TURBO Link Hemoglobin A1c Program (K070819). The document explicitly states: "When compared to the predicate device, there are no changes to the performance specifications, intended or indications for use, or operating principles. Moreover, Risk Analysis and Verification/Validation testing results demonstrate that the changes do not affect product safety, effectiveness, and substantial equivalency claims." Therefore, the "acceptance criteria" for the modified device are primarily centered on demonstrating that the changes do not degrade the performance of the predicate device. The performance claims for the modified device are directly transferred from the predicate.

1. Table of Acceptance Criteria and Reported Device Performance

As this is a modification to an already cleared device and the document states "No change, claims transferred from predicate device" for performance, specific numerical acceptance criteria and reported performance for the modified device itself are not explicitly presented as a new performance study. Instead, the acceptance is based on demonstrating that the software and firmware updates do not negatively impact the performance validated for the predicate device.

The main acceptance criteria for this specific 510(k) effectively become:

• The modified device (with updated software and firmware) performs as safely and effectively as the predicate device.
• Risk mitigations, hazard controls, and residual risks are as safe and effective as the predicate device.
• Design verification/validation tests met established acceptance criteria (which implicitly refer to the predicate's performance).

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

The document does not explicitly provide details on a test set sample size or data provenance in the context of a new clinical or performance study for the modified device. The studies conducted were primarily an engineering verification and validation to affirm that the software and firmware changes did not degrade performance.

The studies mentioned are:

• Risk Analysis (FMEA): Identified and mitigated risks associated with modifications.
• Verification and Validation Testing: Evaluated the modified product against acceptance criteria to ensure safety, effectiveness, and substantial equivalence to the predicate.

Since the performance claims are transferred from the predicate device (K070819), any "test set" for performance evaluation would have been part of the original predicate's clearance. This submission indicates that existing product risk tables and customer complaints were reviewed, suggesting that real-world operational data (retrospective, ongoing) might have informed the risk analysis process.

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

This document does not describe the use of experts to establish a "ground truth" for a test set in the conventional sense of a diagnostic performance study. The focus is on demonstrating that software and firmware changes do not compromise the previously established performance.

The "ground truth" for the original HbA1c measurement performance (predicate device) is stated as being certified by the NGSP as traceable to the Diabetes Control and Complications Trial (DCCT) Reference method. This is an external, highly standardized, and internationally recognized reference method, not established by individual experts for this specific submission.

The risk analysis process involved a "trained risk assessment team," but their qualifications and exact number are not specified, nor were they establishing clinical ground truth.

4. Adjudication Method for the Test Set

No adjudication method for a test set is mentioned, as this submission focuses on verification/validation of software/firmware changes and demonstrating substantial equivalence to a predicate device, rather than a new primary diagnostic performance study requiring expert adjudication of 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

No MRMC study was performed or described. This device is an automated, high-throughput hemoglobin analyzer, not a diagnostic imaging AI tool requiring human "readers" or "assistance."

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

Yes, the device (both predicate and modified) is inherently a standalone algorithm (or automated system) without human-in-the-loop performance influencing the primary measurement. It's a fully automated analyzer that performs ion-exchange high-performance liquid chromatography. The "algorithm" is integral to its operation, but it's not a separate software AI algorithm in the contemporary sense of providing diagnostic interpretations to a human. The updated software and firmware control the instrument itself.

The verification and validation "determined whether risk mitigations, hazard controls, and residual risks were as safe and effective as the predicate device," which implies standalone performance of the modified system.

7. The Type of Ground Truth Used

The "ground truth" for the overall performance of the HbA1c measurement method (which is unchanged from the predicate) is traceable to the Diabetes Control and Complications Trial (DCCT) Reference method, as certified by the NGSP (National Glycohemoglobin Standardization Program). This is a highly standardized and validated reference method for HbA1c.

8. The Sample Size for the Training Set

No training set is mentioned. This is not an AI/Machine Learning device that undergoes a "training" phase with a dataset. It's an analytical instrument.

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

Not applicable, as no training set was used.

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The BioPlex 2200 Celiac IgA kit is an in vitro multiplex flow immunoassay intended for the semi-quantitative detection of IgA autoantibodies to deamidated gliadin peptide (DGP) and tissue Transglutaminase (tTG) in human serum. In conjunction with clinical findings and other diagnostic tests, the test system is used as an aid in the diagnosis of Celiac Disease (gluten-sensitive enteropathy). The BioPlex 2200 Celiac IgA kit is intended for use with the Bio-Rad BioPlex 2200 System.

The BioPlex 2200 Celiac IgG kit is an in vitro multiplex flow immunoassay intended for the semi-quantitative detection of IgG autoantibodies to deamidated gliadin peptide (DGP) and tissue Transglutaminase (tTG) in human serum. In conjunction with clinical findings and other diagnostic tests, the test system is used as an aid in the diagnosis of Celiac Disease (gluten-sensitive enteropathy). The BioPlex 2200 Celiac IgG kit is intended for use with the Bio-Rad BioPlex 2200 System.

The BioPlex 2200 Celiac IgA Calibrator Set is intended for the calibration of the BioPlex 2200 Celiac IgA Reagent Pack.

The BioPlex 2200 Celiac IgG Calibrator Set is intended for the calibration of the BioPlex 2200 Celiac IgG Reagent Pack.

The BioPlex 2200 Celiac IgA Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex 2200 Celiac IgA Reagent Pack in the clinical laboratory. The performance of the BioPlex Celiac IgA Control Set has not been established with any other antitissue Transglutaminase (tTG) and anti-Deamidated Gliadin Peptide IgA assays.

The BioPlex 2200 Celiac IgG Control Set is intended for use as an assayed quality control to monitor the overall performance of the BioPlex 2200 Instrument and BioPlex 2200 Celiac IgG Reagent Pack in the clinical laboratory. The performance of the BioPlex Celiac IgG Control Set has not been established with any other antitissue Transglutaminase (tTG) and anti-Deamidated Gliadin Peptide IgG assays.

BioPlex® 2200 Celiac IgA and IgG kits include the following components:
One (1) 10 mL vial of Bead Set, containing dyed beads coated with recombinant antigens; an Internal Standard bead (ISB), a Serum Verification bead (SVB) and IgA Verification Bead (AVB) (in Celiac IgA only), in MOPS (3-[N-Morpholino] propanesulfonic acid) buffer supplemented with Glycerol and protein stabilizer (bovine and porcine). ProClin 300 (≤ 0.3%), sodium benzoate (≤ 0.1%) and sodium azide (

Here's an analysis of the acceptance criteria and study findings for the BioPlex® 2200 Celiac IgA and IgG kits, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state numerical acceptance criteria in a dedicated section with pass/fail thresholds. Instead, it presents performance characteristics from various studies. For this table, I will present the reported performance, which implicitly serves as the evidence that the device meets acceptable levels for these metrics. The "Target Performance" column will reflect typical expectations for such assays or the performance shown by the predicate devices where applicable.

Performance Characteristics for BioPlex® 2200 Celiac IgA and IgG Kits

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

• Precision/Reproducibility:

  • CLSI EP5-A2: 24 samples (serum panel consisting of samples spanning the measuring range), tested in replicate twice daily over 20 days (n=80 replicates per sample type).
  • CLSI EP15-A2: 12 samples (serum panel consisting of samples spanning the measuring range), tested in 4 replicates per run, one run per day over 5 days (n=20 replicates per sample type).
  • Lot-to-lot Reproducibility: Unspecified number of serum samples covering the assay range, tested with three reagent lots on three instruments, 10 replicates for two runs per lot (60 points per sample ID for calculation).

• Linearity/Reportable Range: 3 low positive and 3 high positive patient serum samples for each antibody (anti-tTG IgA/IgG, anti-DGP IgA/IgG).

• Analytical Specificity (Interference): Test substances (e.g., Hemolysate, Bilirubin, Triglycerides). No specific number of samples given for the interference study, but the substances were tested at specified concentrations.

• Analytical Specificity (Cross-Reactivity): 244 samples from individuals with various disease states (e.g., Chronic Active Hepatitis, Crohn's Disease, Diabetes Mellitus Type 1, Rheumatoid Arthritis). The number of samples for each disease state ranged from 6 to 30.

• Assay Cut-off Determination: 123 samples from patients with diagnosed celiac disease and 112 from non-celiac/rheumatic disease control donors. Confirmed with 298 samples from apparently healthy donors.

• Method Comparison with Predicate Device:

  • All samples: 156 patients with celiac disease, 163 patients with other rheumatic or non-CD disease control, 11 celiac IgA deficient patients, and 16 Dermatitis Herpetiformis (DH) patients. Total: 346-347 samples (1 sample excluded in some analyses).
  • Samples within measuring range (and 10% diluted): Varying totals per assay, e.g., anti-tTG IgA (211), anti-DGP IgA (310), anti-tTG IgG (288), anti-DGP IgG (248).

• Clinical Studies (Sensitivity and Specificity): 319 serum specimens, including 163 non-Celiac disease control patients and 156 diagnosed Celiac disease patients.

• Expected Values/Reference Range: 300 serum samples from apparently healthy donors (139 males, 161 females, age

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The Bio-Rad VARIANT™ II TURBO HbA Ic Kit - 2.0 is intended for the quantitative determination of hemoglobin Alc in human whole blood using ion-exchange high performance liquid chromatography (HPLC) on the VARIANT II TURBO Hemoglobin Testing System. Measurement of hemoglobin Alc is effective in monitoring long term glycemic control in individuals with diabetes mellitus. The Bio-Rad VARIANT II TURBO HbAlc Kit - 2.0 is intended for professional Use.

The VARIANT II TURBO Hemoglobin Testing System is the next generation HPLC system with higher volume capability when compared to the VARIANT II testing system. The VARIANT II TURBO Hemoglobin Testing System provides an integrated method for sample preparation, separation, and determination of specific hemoglobin in whole blood. It is a fully automated, high-throughput system. It consists of 2 modules: the VARIANT II TURBO Sampling Station (VSS) and the VARIANT II TURBO Chromatographic Station (VCS). A personal computer (PC) is used to control the VARIANT II TURBO 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™.

The provided text describes a Special 510(k) Summary for a Device Modification related to the Bio-Rad VARIANT™ II TURBO HbA1c Kit - 2.0. This type of submission is for modifications to a legally marketed device that do not significantly alter its performance specifications, intended use, or operating principles.

Crucially, the document explicitly states:

• "When compared to the predicate device, there are no changes to the performance specifications, intended or indications for use, or operating principles."
• "Performance Claims: No change, claims transferred from predicate device."

Therefore, this specific submission does not present new acceptance criteria or a new study to prove device performance, as the performance claims are directly transferred from the predicate device (K122472). The modifications described are primarily software and firmware updates, customer-requested features, and defect fixes.

The document focuses on demonstrating that these changes do not affect product safety, effectiveness, and substantial equivalency claims to the predicate device. This is achieved through a risk management process, review of modifications, and design verification/validation tests.

Based on the provided text, I cannot extract the specific acceptance criteria and a study proving those criteria were met for this modified device because the submission relies on the established performance of its predicate.

However, I can describe what the document does provide in relation to an implicit "acceptance" or validation of the modifications:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not provide a table of new acceptance criteria for performance, nor new reported device performance data, because the performance claims are stated to be unchanged from the predicate device.

Instead, the "acceptance criteria" for the modifications themselves relate to successful verification and validation (V&V) testing.

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

The document details "design verification/validation tests" and a risk management process, but does not specify sample sizes for these tests. It also does not explicitly mention the country of origin or whether the data was retrospective or prospective, as the focus is on the software and firmware changes and their impact on safety and effectiveness, rather than a clinical performance study.

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

The document states: "For each identified risk, a Failure Mode and Effects Analysis (FMEA) was conducted. This was performed in a systematic manner by a trained risk assessment team until consensus was reached that an adequate analysis had been performed."

• Number of Experts: Not explicitly stated, but implies a "team" (more than one).
• Qualifications of Experts: Described as a "trained risk assessment team." No further specific qualifications (e.g., radiologist with X years of experience) are provided, which is typical for device engineering and risk management teams.

4. Adjudication Method for the Test Set

The FMEA process involved a "trained risk assessment team until consensus was reached," suggesting a form of group adjudication, but no specific method like "2+1" or "3+1" is detailed. It implies a collaborative decision-making process to reach agreement on risk identification and mitigation.

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

No, an MRMC comparative effectiveness study was not done. This type of study is typically used for diagnostic devices that involve human interpretation of results, where the AI might assist or replace that interpretation. This device is an automated in vitro diagnostic system for measuring HbA1c, and its modifications are software/firmware related, not involving human interpretation of clinical images or data in a way that would necessitate an MRMC study.

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

The device itself is an automated system. The "design verification/validation tests" would have evaluated the performance of the modified software and firmware in a standalone manner, integrated into the instrument, to ensure it met its functional and safety requirements. However, the document doesn't provide details on the specific "standalone" tests conducted beyond stating they "met established acceptance criteria" for the modifications.

7. The Type of Ground Truth Used

For the modifications, the "ground truth" was established based on:

• Identified potential risks and hazards (from reviewing modifications, design inputs, existing risk tables, customer complaints, and IEC 62304:2009 requirements).
• Predicate device claims and performance established during its initial clearance (K122472), against which the modified device's safety, effectiveness, and substantial equivalency were assessed.

For the predicate device's original performance claims (which are transferred), the ground truth for HbA1c measurement is based on:

• Certification by the NGSP as traceable to the Diabetes Control and Complications Trial (DCCT) Reference method.
• Certification by the IFCC as traceable to the IFCC Reference Measurement Procedure.

8. The Sample Size for the Training Set

Not applicable. This submission is for modifications to an existing in vitro diagnostic device, not a new algorithm that requires a "training set" in the context of machine learning. The software and firmware updates "include customer requested features, whereas both software and firmware include specific defect fixes," implying development rather than a machine learning training process.

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

Not applicable, as there is no mention of a machine learning "training set" in this context.

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Liquichek Pediatric Control is intended for use as an assayed quality control serum to monitor the precision of laboratory testing procedures for the analytes listed in this package insert.

Liquichek Pediatric Control is prepared from bovine serum with added chemicals. therapeutic drugs, preservatives and stabilizers. The control is provided in liquid form for convenience.

Here's an analysis of the provided text regarding the acceptance criteria and supporting studies for the Liquichek Pediatric Control device:

The provided K130963 document is a 510(k) Premarket Notification for a quality control material, not a diagnostic device that performs clinical measurements or generates diagnoses. Therefore, the typical acceptance criteria and study designs (like standalone performance, MRMC studies, expert ground truth for clinical decision-making, large training sets, etc.) for AI/ML-driven diagnostic devices are not applicable.

This document describes a substantial equivalence claim for a laboratory control. The "performance" being evaluated is its stability and its ability to serve as a reliable control material over time.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria here are implicitly related to the stability claims, ensuring the control material remains consistent and effective for its stated duration. The "performance" is the successful demonstration of these stability periods.

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

The document mentions "replicate analyses" and "representative sampling of this lot of product" for value assignment and stability studies. However, specific sample sizes (number of vials, number of runs, etc.) for the stability studies are NOT provided in this public summary.

• Data Provenance: Not explicitly stated regarding country of origin, but the testing was performed by "the manufacturer and/or independent laboratories." The studies are prospective in nature, as they are "real-time stability studies" and "accelerated stability studies" specifically conducted to establish the claims.

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

• Not applicable in the typical sense for a diagnostic device. For this quality control material, the "ground truth" for analytes is established through value assignment and stability testing using validated analytical methods. This involves laboratory instruments and established chemical/biological testing procedures, not interpretation by human clinical experts. The "experts" would be analytical chemists or clinical laboratory scientists operating the testing equipment.

4. Adjudication Method for the Test Set

• Not applicable. This isn't a scenario requiring adjudication between human readers or algorithms in a diagnostic context. The "adjudication" would be based on the established analytical methods meeting predefined laboratory performance criteria for stability, precision, and accuracy compared to the predicate and internal specifications.

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

• No such study was done. MRMC studies are used for diagnostic devices where human interpretation is involved, often to assess the impact of AI assistance. This device is a quality control material and does not involve human readers making clinical interpretations.

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

• Not applicable in the typical sense. This device is a material used within laboratory testing procedures, not a standalone algorithm. The "performance" is its physical and chemical stability over time, as assessed by analytical instruments, not an AI algorithm's output.

7. Type of Ground Truth Used

• The "ground truth" for this device relates to the assigned values for the analytes and the stability of these values over time under various storage conditions. This is established through:
  • Validated analytical methods: The analytes' concentrations are determined using standard laboratory instruments and assays.
  • Reference materials/calibrators: Primary calibrators or reference materials would be used to ensure the accuracy of the assigned values.
  • Stability protocols: Real-time and accelerated stability studies are conducted according to predefined protocols to determine how long the analyte values remain within acceptable limits.

8. Sample Size for the Training Set

• Not applicable. This device is a quality control material, not an AI/ML algorithm that requires a training set.

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

• Not applicable. As there is no AI/ML algorithm and no training set, this question is not relevant to the provided submission.

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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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