(73 days)
The Xpert Xpress Strep A Assay, performed on the GeneXpert Instrument Systems, is a rapid, qualitative in vitro diagnostic test for the detection of Streptoccus pyogenes (Group A beta-hemolytic Strep A) in throat swab specimens from patients with signs and symptoms of pharyngitis.
The Xpert Xpress Strep A Assay utilizes an automated real-time polymerase chain reaction (PCR) to detect Streptococcus pyogenes DNA.
The Xpert Xpress Strep A Assay is an automated real-time polymerase chain reaction (PCR) in vitro diagnostic test for qualitative detection of Streptococcus pyogenes from throat swab specimens from patients with signs and symptoms of pharyngitis.
The Xpert Xpress Strep A Assay is performed on the Cepheid GeneXpert® Instrument Systems (GeneXpert Dx, GeneXpert Infinity-48s, and GeneXpert Infinity-80 systems). The GeneXpert Instrument System platform automates sample preparation, amplification and real-time detection.
The GeneXpert Instrument Systems require the use of single-use, disposable cartridges (the Xpert Xpress Strep A 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 Xpress Strep A Assay includes primers and probes for the simultaneous detection and differentiation of a targeted sequence of the S. pyogenes genome allowing detection of Strep A directly from throat swab specimens collected from patients with signs and symptoms of pharyngitis. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are internal controls utilized by the GeneXpert Instrument System platform. The SPC is present to control for adequate processing of the target bacteria and to monitor for the presence of inhibitor(s) in the PCR assay to avoid false-negative results. The Probe Check Control verifies reagent rehydration, real-time PCR tube filling in the cartridge, probe integrity, and dye stability.
The single-use, multi-chambered fluidic cartridges are designed to complete sample preparation and real-time PCR for the detection of genomic DNA S. pyogenes in ~24 minutes or less. The GeneXpert Instrument Systems, comprised of the GeneXpert Dx Systems and the GeneXpert Infinity 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), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and RT-PCR and detection.
Throat swab specimens are collected using the ESwab collection device and transported to the GeneXpert area and prepared according to package insert instructions. After mixing the specimen, the liquid sample is transferred to the Xpert Xpress Strep A Assay cartridge. The user initiates a test from the system user interface and places the cartridge into the GeneXpert instrument platform, which performs hands-off real-time, multiplex PCR for detection of DNA. The results are automatically generated at the end of the process in a report that can be viewed and printed.
Here's an analysis of the provided text to extract the acceptance criteria and study details:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria for performance are not explicitly stated in a dedicated section with pre-defined numerical targets. However, based on the clinical study results and comparisons to the predicate, we can infer the demonstrated performance. The key performance metrics are Sensitivity, Specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) relative to culture and latex agglutination.
Inferred Acceptance Criteria (Based on demonstrating substantial equivalence to predicate) and Reported Device Performance (Combined First and Second Swab Data):
| Performance Metric | Implied Acceptance Criterion (Likely for Substantial Equivalence) | Reported Device Performance | Comments |
|---|---|---|---|
| Sensitivity | High (e.g., comparable to or better than predicate) | 100.0% (95% CI: 97.3-100.0) | Excellent sensitivity. |
| Specificity | High (e.g., comparable to or better than predicate) | 94.1% (95% CI: 91.5-95.9) | Good specificity. |
| PPV | High (e.g., comparable to or better than predicate) | 84.1% (95% CI: 77.8-88.9) | |
| NPV | High (e.g., comparable to or better than predicate) | 100.0% (95% CI: 99.1-100.0) | Excellent negative predictive value. |
| Indeterminate Rate | Low (e.g., 95%) | 98.6% (142/144) agreement | |
| Reproducibility (Moderate Positive) | 100% agreement expected | 100% (144/144) agreement |
Study Proving Acceptance Criteria (Clinical Performance):
- Study Design: A multi-site clinical study that collected throat ESwab specimens from patients with signs and symptoms of pharyngitis. The study combined data from two approaches:
- One study collected a second prospective throat swab after a standard of care (SOC) swab.
- Another study used leftover excess SOC throat swab specimens.
2. Sample Sizes and Data Provenance for the Test Set:
- Initial Enrolled Specimens: 844
- Excluded Specimens: 261 (due to inclusion criteria failure, reference culture procedural error, delay in reference culture inoculation, delay in shipment, or labeling error).
- Specimens Included in Performance Analysis (Test Set): 583
- Successful on initial test: 565/583 (96.9%)
- Valid results after retest (overall): 577/583 (99.0%)
- Data Provenance: Geographically diverse regions within the United States. The study was conducted between December 2016 and March 2017, suggesting it was a prospective or mixed (prospective and retrospective for leftover samples) collection. The text states "one study enrolled consented subjects from whom a second prospective throat swab specimen was collected" and "another study tested specimens from subjects for which leftover excess standard of care (SOC) throat swab specimens were available."
3. Number of Experts and Qualifications for Ground Truth for the Test Set:
- The document does not specify the number of experts or their qualifications for establishing the initial ground truth (culture and latex agglutination). These are standard laboratory procedures, but details about expert reviewers for discordant results are mentioned.
4. Adjudication Method for the Test Set:
- Discordant results between the Xpert Xpress Strep A Assay and the reference method (culture) were investigated.
- Method: An alternative PCR/bidirectional sequencing assay was used for adjudication. The results of this alternative PCR were footnoted in the performance tables (e.g., for 26 discrepant samples in Table 8-7, 21 were confirmed positive by alternative PCR, 4 negative, and 1 not tested). This indicates an independent molecular method was used to resolve discrepancies.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No, a MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay, not an imaging device or one that involves human "readers" interpreting results in a variable way that MRMC studies are designed for. Its performance is evaluated biochemically against a reference standard.
6. Standalone Performance Study (Algorithm only without human-in-the-loop):
- Yes, a standalone study was performed. The clinical performance data presented (Sensitivity, Specificity, PPV, NPV) represents the performance of the Xpert Xpress Strep A Assay (the "algorithm/device") functioning independently relative to a microbiological reference method (culture). The results are automatically generated by the GeneXpert Instrument Systems.
7. Type of Ground Truth Used:
- For the clinical performance study (test set), the primary ground truth reference method was culture and latex agglutination for Strep A typing.
- For resolving discordant results, an alternative PCR/bidirectional sequencing assay was used.
8. Sample Size for the Training Set:
- The document does not specify the sample size for a "training set" in the context of an algorithm. For IVDs, the development process typically involves various internal testing and optimization (which could be considered analogous to training) but not usually a distinct "training set" of patient specimens in the same way an AI model would have. The document focuses on analytical and clinical validation studies.
9. How Ground Truth for the Training Set Was Established:
- As a training set is not explicitly defined in the context of this IVD device's approval process in this document, the method for establishing its ground truth is not applicable/not provided. The analytical and clinical validation studies use established reference methods as ground truth.
§ 866.2680
Streptococcus spp. nucleic acid-based assay.(a)
Identification. AStreptococcus spp. nucleic acid-based assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify variousStreptococcus spp. nucleic acids extracted directly from clinical specimens. The device detects specific nucleic acid sequences for organism identification. The identification aids in the diagnosis of diseases caused by bacteria belonging to the genusStreptococcus and provides epidemiological information on these diseases. Pathogenic streptococci are associated with infections, such as sore throat, impetigo (an infection characterized by small pustules on the skin), urinary tract infections, rheumatic fever, and kidney disease.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include detailed device description documentation, including the device components, ancillary reagents required but not provided, and a detailed explanation of the methodology including primer/probe sequence, design, and rationale for sequence selection.
(2) Premarket notification submissions must include detailed documentation from the following analytical and clinical performance studies: Analytical sensitivity (Limit of Detection), reactivity, inclusivity, precision, reproducibility, interference, cross reactivity, carry-over, and cross contamination.
(3) Premarket notification submissions must include detailed documentation from a clinical study. The study, performed on a study population consistent with the intended use population, must compare the device performance to results obtained from well-accepted reference methods.
(4) Premarket notification submissions must include detailed documentation for device software, including, but not limited to, software applications and hardware-based devices that incorporate software.
(5) Premarket notification submissions must include database implementation methodology, construction parameters, and quality assurance protocols, as appropriate.
(6) The device labeling must include limitations regarding the need for culture confirmation of negative specimens, as appropriate.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling.
(8) Premarket notification submissions must include details on an end user device training program that will be offered while marketing the device, as appropriate.