(254 days)
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
| Acceptance Criteria (Inferred) | Reported Device Performance (Xpert® BCR-ABL Ultra) |
|---|---|
| Linearity/Dynamic Range: |
- Linear regression R² for
e13a2/b2a2breakpoint. - Linear regression R² for
e14a2/b3a2breakpoint. - Maximum Standard Deviation (SD) within reportable range. | -
e13a2/b2a2: R² = 0.98304 e14a2/b3a2: R² = 0.9788- Maximum SD = 0.26 (within reportable range of MR0.26 to MR4.52) |
| Analytical Sensitivity (LoD): - LoD for
e13a2/b2a2breakpoint (target 95% positivity). - LoD for
e14a2/b3a2breakpoint (target 95% positivity). - Overall LoD claimed for both breakpoints. | -
e13a2/b2a2: 0.0030% (IS)/MR4.52 (95.74% positivity at this level) e14a2/b3a2: 0.0029% (IS)/MR4.55 (96.04% positivity at this level)- Overall LoD: 0.0030% (IS)/MR4.52 |
| Analytical Sensitivity (LoQ): - Equivalence to LoD.
- MR Standard Deviation for
e13a2/b2a2ande14a2/b3a2within defined limits (e.g.,
§ 866.6060 BCR-ABL quantitation test.
(a)
Identification. A BCR-ABL quantitation test is identified as a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) test for the quantitation of BCR-ABL1 expressed on the International Scale (IS) and control transcripts in total RNA from whole blood of diagnosed t(9;22) positive chronic myeloid leukemia (CML) patients during monitoring of treatment with tyrosine kinase inhibitors. This test is not intended for the diagnosis of CML.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the following information:
(i) The indication for use must indicate the variant(s) for which the assay was designed and validated, for example BCR-ABL e13a2 and/or e14a2.
(ii) A detailed description of all components in the test, including the following:
(A) A detailed description of the test components, all required reagents, instrumentation and equipment, including illustrations or photographs of non-standard equipment or methods;
(B) Detailed documentation of the device software including, but not limited to, standalone software applications and hardware-based devices that incorporate software;
(C) Methodology and protocols for control procedures for the assay to allow reporting on the International Scale;
(D) A description of the result outputs, analytical sensitivity of the assay, and the range of values that will be reported; and
(E) A description of appropriate internal and external controls that are recommended or provided. The description must identify those control elements that are incorporated into the testing procedure.
(iii) Information that demonstrates the performance characteristics of the test, including:
(A) For indications for use based on a threshold established in a predicate device of this generic type, device performance data from either a method comparison study to the predicate device or through a clinical study demonstrating clinical validity using well-characterized prospectively or retrospectively obtained clinical specimens, as appropriate, representative of the intended use population;
(B) For indications for use based on a threshold not established in a predicate device of this generic type, device performance data from a clinical study demonstrating clinical validity using well-characterized prospectively or retrospectively obtained clinical specimens, as appropriate, representative of the intended use population;
(C) Device reproducibility data generated, using a minimum of three sites, of which at least two sites must be external sites, with two operators at each site. Each site must conduct a minimum of three runs per operator over non-consecutive days evaluating a minimum of five different BCR-ABL concentrations that span and are well distributed over the measuring range and include MR3 (0.1 percent IS). Results shall be reported as the standard deviation and percentage coefficient of variation for each level tested. Prespecified acceptance criteria must be provided and followed;
(D) Device precision data using clinical samples to evaluate the within-lot, between-lot, within-run, between run, and total variation;
(E) Device linearity data using a dilution panel created from clinical samples;
(F) Device analytic sensitivity data, including limit of blank, limit of detection, and limit of quantification;
(G) Device specificity data, including interference and cross-contamination; and
(H) Device stability data, including real-time stability of samples under various storage times, temperatures, and freeze-thaw conditions.
(iv) Identification of risk mitigation elements used by your device, including a detailed description of all additional procedures, methods, and practices incorporated into the instructions for use that mitigate risks associated with testing using your device.
(2) Your 21 CFR 809.10 compliant labeling must include the following:
(i) The intended use in your 21 CFR 809.10(a)(2) and (b)(2) complaint labeling must include an indication for use statement that reads “This test is not intended for the diagnosis of CML”; and
(ii) A detailed description of the performance studies conducted to comply with paragraph (b)(1)(iii) of this section and a summary of the results.
(3) Your device output must include results on the International Scale (IS) and your assay must include multipoint calibration controls traceable to a relevant international reference panel (
e.g., the World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA).