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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

Study Details for the QXDx BCR-ABL %IS Kit

As this is an in vitro diagnostic (IVD) kit and not an AI/ML powered device, several of the requested sections are not applicable.

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

   • Precision and Multisite Reproducibility: 36 replicates per sample (2 reps x 2 runs x 3 days x 3 sites x 1 reagent lot). Two panels of eight test samples each (six contrived, two controls).
   • Lot to Lot Reproducibility: 108 data points per sample (3 replicates x 2 operators x 3 days x 3 lots x 2 instruments). Sixteen (16) BCR-ABL1 negative and one hundred (100) BCR-ABL1 positive RNA samples (pooled).
   • Cross Reactivity: Each dilution tested with 4 or 8 replicates (N). Two prepared samples (p190, p230 variants).
   • Interference: Ten (10) tests per sample type (5 replicate extractions x 2 tests per extraction). Various interferents tested.
   • Assay Linearity: Not explicitly stated, but typically involves multiple dilutions. Two positive BCR-ABL RNA patient pools (E13a2, E14a2) and one negative RNA pool.
   • Detection Capability (LoD): 160 replicates per sample (20 replicates x 4 days x 2 lots x 1 instrument) for two contrived samples (e13a2, e14a2 variants).
   • Kit, Calibrator and Control Stability: 3 kit lots at various time points (T0, T1, T2.5, T5, T11, T12, T19, T25 months). Freeze-thaw: 4 kits from one lot tested through several cycles.
   • Specimen Stability (Whole Blood Stability): Positive blood sample and 3 negative blood samples. Dilutions tested with 4 or 11 replicate extractions.
   • WHO Standard Quantification: 7 kit lots. Four (4) levels of WHO primary standards tested in four (4) replicates per lot.
   • Carryover Contamination: 288 initial replicate tests; 286 valid replicates (from 2 plates, tested on 3 instruments).
   • Clinical Performance (Method Comparison): 139 samples. Samples acquired from at least two geographically distinct regions. Samples were de-identified leftover RNA samples, previously collected. The study was conducted at a single testing lab.
   • Data Provenance (Retrospective/Prospective, Country): For the clinical method comparison study, samples were "de-identified leftover RNA samples that have been previously collected from a minimum of two (2) sites." This indicates a retrospective data collection approach. The country of origin is not explicitly stated, but the submission is to the US FDA, so it's likely from the US or a region with compliant medical standards.

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

   • Not Applicable. For this IVD device, the "ground truth" is established by the known concentrations/compositions of the samples (e.g., contrived samples with specific BCR-ABL:ABL ratios, WHO primary reference standards with assigned values, or comparison to a legally marketed predicate device). There are no human experts "reading" or annotating images or clinical data to establish ground truth in the way described for AI/ML devices.

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

   • Not Applicable. As there are no human expert readings of the test set requiring adjudication. The ground truth refers to the biochemical composition or an independent, established reference assay.

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:

   • Not Applicable. This is an in vitro diagnostic device, not an AI-powered system designed to assist human readers (e.g., radiologists interpreting images). The "method comparison" study compares the device's analytical performance against a predicate device, not human performance.

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

   • This entire document describes the standalone performance of the IVD kit and its associated system (QXDx AutoDG ddPCR System). The output is a quantitative MR value or %IS, which is then used by clinicians for patient management. There is no "human-in-the-loop performance" for the device's operation itself, beyond standard laboratory procedures and interpretation of the quantitative results.

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

   • The ground truth extensively used in the analytical studies is based on:
     • Contrived samples: Samples prepared by mixing known concentrations of BCR-ABL positive and negative RNA, allowing for precise control of target ratios.
     • Reference materials: Specific WHO International Standards (WHO-IS primaries) with assigned values used for calibration and verification.
     • Predicate device comparison: The Asuragen Quantidex qPCR BCR-ABL IS Kit (IVD) served as the comparator in the clinical method comparison study, establishing a "ground truth" for comparative performance.
     • Known sample characteristics: E.g., for cross-reactivity and interference studies, samples with known absence of target or presence of interfering substances are used.

7. The sample size for the training set:

   • Not applicable in the usual AI/ML sense. This is an IVD kit involving biochemical reactions and a detection system, not a machine learning algorithm that undergoes 'training' on a dataset in the same way. The development and optimization of the kit's components and parameters would be based on internal R&D, but there isn't a "training set" in the context of typical AI/ML submissions.

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

   • Not Applicable. As above, there's no "training set" in the AI/ML sense. The ground truth for the analytical studies (which could be considered analogous to validation/testing stages for IVDs) was established by carefully prepared samples with known concentrations/compositions or recognized international standards.

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