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The BCR-ABL1 (p210) %IS Kit (Digital PCR Method) 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 t (9;22) positive Chronic Myeloid Leukemia (CML) adult patients expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2. The BCR-ABL1 (p210) %IS Kit (Digital PCR Method) is a reverse transcription-quantitative PCR performed on the Sniper Digital PCR All-in-One 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 t (9:22) positive CML patients during monitoring of treatment with Tyrosine Kinase Inhibitors (TKIs).

The BCR-ABL1 (p210) %IS Kit (Digital PCR Method) is intended for use only on the Sniper Digital PCR All-in-One 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 BCR-ABL1 (p210) %IS Kit (Digital PCR Method) is designed for detection of the BCR-ABL1 fusion gene (p210) and ABL1 gene, with specific primers and specific fluorescence probes. The test process includes three parts. The first part is to extract ribonucleic acid (RNA) from peripheral blood of CML patients. The second part is to detect BCR-ABL1 fusion gene (p210) and ABL1 internal reference gene in RNA samples by RT-dPCR (Reverse Transcription-Droplet PCR) reaction solution using the Sniper Digital PCR All-in-One System (DQ24-Dx). The third part is to analyze the results.

The Sniper Digital PCR All-in-One System consists of one instrument, which can be used together with it's supporting consumables and BCR-ABL1 (p210) %IS Kit (Digital PCR Method) to complete the detection of samples.

The Sniper Digital PCR All-in-One System divides the sample into about 20000 droplets and carries out PCR amplification, read the number of positive and negative droplets through fluorescent signals, and then calculate the concentration of nucleic acid quantitatively according to the volume of the droplets and the principle of Poisson Distribution.

DQ24-Dx-Sight Software (v1.0.2) is used to control the system and analyze test results. This software is embedded in the Sniper Digital PCR All-in-One System.

Here's a breakdown of the acceptance criteria and study detailed in the provided document:

Acceptance Criteria and Device Performance

Study Details

1. A table of acceptance criteria and the reported device performance: See table above.

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

   • Precision/Reproducibility (Multi-site): 5 positive pools (3 variants, 5 different MR concentrations). 36 replicates per sample (2 replicates/run, 2 runs/day, 3 days, 3 sites). Total 540 observations.
   • Precision between batches: 2 positive pools (2 variants, 4 different MR concentrations). 108 replicates per sample (3 replicates/run, 2 runs/day, 3 days, 1 site with 2 instruments, 3 reagent lots). Total 864 observations.
   • RNA Extraction Method: 3 positive pools (3 variants, 5 different MR concentrations) each derived from multiple positive peripheral blood samples (6 e13a2, 7 e14a2) or K562 cells. Total of 180 results (samples extracted 2 times by 2 operators/day for 3 days).
   • Linearity/Assay reportable range: 2 positive pools (2 variants, 10 different MR concentrations). 4 replicates per sample.
   • Limit of Blank: 144 negative samples.
   • Limit of Detection/Limit of Quantitation: 2 positive pools (2 variants, 3 different MR concentrations). 20 replicates per day for 3 days with 2 reagent lots. Total 120 replicates.
   • Analytical Specificity (Interference): 1 sample pool (MR ~3.0). 2 replicate extractions, each tested in 3 replicates (6 tests per sample type). Potential interfering substances evaluated.
   • Primer Specificity: 4 positive samples (p190, p230, p210 e13a2, p210 e14a2) at 4 different concentrations. 4 replicates per sample.
   • Carryover Contamination: 1 high positive pool and 1 negative pool. 64 total test samples (32 high positive wells and 32 negative wells).
   • RNA Input: 2 positive pools (2 variants, 4 different MR concentrations). 3-5 replicates per run across 6 different RNA input amounts.
   • Real-Time Stability: 1 positive pool (1 variant, 3 different MR concentrations). 3 lots tested across 7 time points (T0, T3, T6, T9, T11, T12, T13).
   • Freeze-thaw Stability: Same samples as real-time stability. 1 lot tested with 3, 5, and 6 freeze-thaw cycles.
   • Specimen Stability: 3 fresh peripheral blood samples (1 variant, 3 different MR values). RNA extracted on Day 0, 1, 2. Each RNA sample tested 6-8 replicates.
   • Method Comparison with Predicate Device: 112 clinical samples (retrospective) collected from 2 hospitals. All samples were from patients diagnosed with t(9;22) positive CML with MR values distributed between 0.32 and 4.47.
   • Data Provenance: The document explicitly mentions that for the Method Comparison Study, clinical samples were collected from 2 hospitals and were retrospective. Other analytical studies used various types of prepared RNA samples or pools. The specific country of origin is not explicitly stated for all samples, but the submitting company is Suzhou Sniper Medical Technologies Co., Ltd. from China, suggesting the data collection likely occurred there.

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

   • Ground Truth Type: For the analytical studies, the ground truth was established by known concentrations/MR values of prepared RNA samples or specific variants (e.g., in linearity, LOD/LOQ, primer specificity). For the method comparison study, the ground truth was the result from the predicate device, the QXDx BCR-ABL %IS Kit.
   • Experts: The document does not explicitly state the use of external "experts" (e.g., radiologists, pathologists) to establish ground truth for this in vitro diagnostic (IVD) kit. The ground truth for analytical performance was based on the physical properties of the prepared samples (e.g., known dilutions, concentrations). For the clinical comparison, the predicate device served as the reference.

4. Adjudication method for the test set:

   • Not applicable. As this is an IVD kit for quantitative measurement and not an image-based AI device requiring human interpretation, there is no mention of an adjudication method like 2+1 or 3+1 for establishing ground truth. Raw data from instrument readings are compared against predefined analytical or clinical reference methods/values.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • Not applicable. This is an in vitro diagnostic device, not an imaging AI device involving human interpretation/readers. Therefore, an MRMC study with human readers and AI assistance is not relevant or described.

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

   • The study primarily details the standalone performance of the device (BCR-ABL1 (p210) %IS Kit on the Sniper Digital PCR All-in-One System) itself, without direct human-in-the-loop interaction for result interpretation beyond running the assay and reviewing the automatically generated results. The device "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." The "results are interpreted automatically by the embedded Software DQ24-Dx-Sight from measured droplet counts, fluorescent signals, and embedded calculation algorithms." This indicates a standalone algorithmic performance.

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

   • For the analytical performance section, the ground truth was based on known concentrations/values of prepared RNA samples and comparisons to the 1st WHO International Genetic Reference Panel for BCR-ABL translocation quantitation.
   • For the method comparison study, the ground truth was established by the results from the legally marketed predicate device (QXDx BCR-ABL %IS Kit).

8. The sample size for the training set:

   • The document describes the analytical and method comparison studies for validation of the device. It does not mention a separate "training set" in the context of machine learning, as this is a digital PCR assay kit and not an AI/ML-based diagnostic system that typically requires distinct training, validation, and test sets.

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

   • Not applicable, as no "training set" is described for an AI/ML context.

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