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The Xpert BCR-ABL Ultra test is an in vitro diagnostic test for the quantitation of BCR-ABL1 and ABL1 mRNA transcripts in peripheral blood specimens of diagnosed t(9;22) positive Chronic Myeloid Leukemia (CML) patients expressing BCR-ABLI fusion transcripts type e13a2 and/or e14a2. The test utilizes automated, quantitative, real-time reverse transcription polymerase chain reaction (RT-qPCR). The Xpert BCR-ABL Ultra test is intended to measure BCR-ABL1 to ABL1 percent ratios on the International Scale (IS), and also expressed as a log molecular reduction (MR value) from a baseline of 100% (IS), in t(9;22) positive CML patients during of treatment with Tyrosine Kinase Inhibitors (TKIs).

The test does not differentiate between e13a2/b2a2 or e14a2/b3a2 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 Xpert BCR-ABL Ultra test is intended for use only on the Cepheid GeneXpert® Dx System and the GeneXpert Infinity System.

The Xpert BCR-ABL Ultra test is an automated in vitro diagnostic test for quantifying the amount of BCR-ABLI (BCR-ABL, hereafter) mRNA transcript as a ratio of BCR-ABL/ABL per the International Scale (IS).

The test is performed on the Cepheid GeneXpert® Dx System and GeneXpert Infinity System (referred to as the GeneXpert systems). The GeneXpert systems require the use of single-use, disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained and specimens never come into contact with working parts of the instrument modules, cross-contamination between samples is minimized. The GeneXpert systems have 1 to 80 randomly accessible modules, depending upon the instrument, that are each capable of performing separate sample preparation and real-time PCR and RT-PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), and a proprietary I-CORE® thermocycler for performing real-time PCR and RT-PCR and detection.

The Xpert BCR-ABL Ultra test includes reagents to detect BCR-ABL fusion genes resulting from two major breakpoints, translocation e13a2/b2a2 and e14a2/b3a2 and the ABL transcript as an endogenous control in peripheral blood specimens. The amount of BCR-ABL transcript in the patient sample is reported as a percent ratio of BCR-ABL/ABL on the International Scale (IS), and also expressed as a log molecular reduction (MR value) from a baseline of 100% (IS), using the GeneXpert software.

There are two controls included in each Xpert BCR-ABL Ultra test, which are the ABL Endogenous Control and the Probe Check Control (PCC). The ABL Endogenous Control normalizes the BCR-ABL target and ensures that sufficient sample is used in the test. The PCC verifies reagent rehydration. PCR tube filling, and that all reaction components, including probes and dyes, are present and functional in the cartridge.

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

Acceptance Criteria and Device Performance for Xpert® BCR-ABL Ultra

Note: The provided document is a 510(k) Summary, which typically focuses on demonstrating substantial equivalence to a predicate device rather than explicitly stating pre-defined "acceptance criteria" in a quantitative, pass/fail manner. For this analysis, I will infer relevant performance metrics from the non-clinical and clinical studies presented as evidence of substantial equivalence. The "Acceptance Criteria" column will represent the demonstrated performance that FDA found acceptable for classification, and the "Reported Device Performance" will be the specific results from the studies.

1. Table of Acceptance Criteria and Reported Device Performance

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

The primary clinical performance study used:

• Total specimens initially enrolled: 266
• Specimens available for analysis: 208 (after exclusions)
• Specimens within quantitative reportable range for both assays: 147
  • Frozen specimens: 117
  • Fresh, prospectively collected specimens: 30

Data Provenance:

• Country of Origin: U.S. (evaluated at four institutions in the U.S. for the clinical study).
• Retrospective/Prospective: The study included both:
  • Prospective: Fresh, prospectively collected EDTA whole blood specimens from CML patients.
  • Retrospective/Archived: Leftover specimens stored as frozen lysates (from the same patient population).

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

The document states that the Xpert BCR-ABL Ultra test performance was compared to an "FDA-cleared molecular assay" (the predicate device). This implies the ground truth for the clinical study was established by the predicate device's results.

• Number of Experts: Not applicable in the sense of human experts reviewing diagnostic images or pathology slides. The ground truth was based on the quantitative results from the predicate molecular assay.
• Qualifications of Experts: Not applicable, as the "ground truth" was an analytical measurement from another device, not human expert consensus.

4. Adjudication Method for the Test Set

Not applicable. The study compares the new device's quantitative results directly against those of an existing FDA-cleared molecular assay. There is no mention of a human adjudication process for discrepancies between the two assays; rather, statistical methods (Deming regression, Bland-Altman) are used to assess agreement and bias.

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

No. An MRMC study is typically performed for diagnostic imaging devices where human readers interpret cases, and AI assistance might improve their performance. This device is an in vitro diagnostic (IVD) based on RT-qPCR, where the result is generated automatically by the instrument, not interpreted by human readers. Therefore, an MRMC study comparing human readers with and without AI assistance is not relevant or applicable for this type of device.

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

Yes, the studies described are standalone performance evaluations of the Xpert BCR-ABL Ultra system. The system performs automated sample preparation, RT-qPCR, and result interpretation without human intervention in the result generation process. The "Non-Clinical Studies" (Linearity, LoD, LoQ, Specificity, Interfering Substances, Carry-Over, Traceability) and the "Clinical Performance" study (comparison to predicate device) all evaluate the device's performance as an automated, standalone system.

7. The Type of Ground Truth Used

The ground truth used for the clinical performance evaluation was the quantitative results obtained from an FDA-cleared molecular assay (the predicate device). The predicate device measures BCR-ABL1 and ABL1 mRNA transcripts using similar RT-qPCR principles.

8. The Sample Size for the Training Set

The document does not explicitly state the sample size for a "training set" for the Xpert BCR-ABL Ultra assay. This is common for IVD assays based on established PCR technology, where the assay design is based on molecular biology principles and analytical validation, rather than machine learning models requiring large datasets for "training." The method is "Reverse transcription, quantitative, polymerase chain reaction (RT-qPCR) based nucleic acid amplification," which is a deterministic analytical method, not an AI/ML algorithm that is "trained" on data in the traditional sense.

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

As noted in point 8, the concept of a "training set" and "ground truth for training" in the context of machine learning (AI/ML) does not directly apply to this device. The development of an IVD assay like Xpert BCR-ABL Ultra involves:

• Assay Design: Primers and probes are designed based on known genetic sequences (BCR-ABL1 and ABL1 mRNA transcripts).
• Analytical Validation: Extensive non-clinical studies (linearity, LoD, LoQ, specificity, interference, etc.) are performed using characterized samples (e.g., CML patient specimens, spiked controls, cell lines, WHO reference panels) to establish the assay's performance characteristics. This is a process of characterizing the assay, not "training" it.

The "ground truth" for these analytical validation steps would be:

• Known concentrations in serially diluted samples.
• Characterized cell lines with specific breakpoints.
• Reference materials (e.g., WHO International Genetic Reference Panel) with assigned values.
• Negative controls (healthy donor blood, non-CML leukemic specimens).

These ground truths are established through laboratory preparation, internationally recognized standards, and biological characterization, rather than human expert consensus on a dataset.

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