(177 days)
The Xpert Xpress Strep A test, performed on the GeneXpert Xpress System, is a rapid, qualitative in vitro diagnostic test for the detection of Streptococcus pyogenes (Group A B-hemolytic Strep A) in throat swab specimens from patients with signs and symptoms of pharyngitis. The Xpert Xpress Strep A test can be used as an aid in the diagnosis of Group A Streptococcal pharvngitis. The assay is not intended to monitor treatment for Group A Streptococus infections.
The Xpert Xpress Strep A test 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 test is performed on the Cepheid GeneXpert® Xpress System. The GeneXpert Xpress System platform automates sample preparation, amplification and real-time detection.
The GeneXpert Xpress System requires 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 test includes primers and probes for the detection 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 Xpress 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 Xpress System, comprised of the GeneXpert Xpress II and GeneXpert Xpress IV, is capable of performing separate sample preparation and realtime 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 cartridge. The user initiates a test from the system user interface and places the cartridge into the GeneXpert Xpress 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 a breakdown of the acceptance criteria and the study details for the Cepheid Xpert Xpress Strep A device, based on the provided FDA 510(k) summary:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined "acceptance criteria" in a bulleted or numbered list with pass/fail thresholds. Instead, it presents the results of various studies and concludes substantial equivalence to a predicate device. For the purpose of this request, I will infer the acceptance criteria from the reported performance of the predicate device and the general regulatory expectations for such assays, then juxtapose it with the Xpert Xpress Strep A's performance.
| Acceptance Criterion (Inferred) | Xpert Xpress Strep A Reported Performance |
|---|---|
| Clinical Performance: | |
| Sensitivity (relative to culture) | 99.4% (95% CI: 96.5-99.9) |
| Specificity (relative to culture) | 94.1% (95% CI: 91.6-95.9) |
| Positive Predictive Value (PPV) | 85.3% (95% CI: 79.5-89.7) |
| Negative Predictive Value (NPV) | 99.8% (95% CI: 98.7-100.0) |
| Accuracy | 95.5% (95% CI: 93.5-96.8) |
| Indeterminate Rate (initial) | 5.3% (33/623) |
| Indeterminate Rate (after retest) | 0.8% (5/623) |
| Analytical Performance: | |
| Limit of Detection (LoD) - ATCC BAA-946 | 9 CFU/mL (3 CFU/test) |
| Limit of Detection (LoD) - ATCC 19615 | 18 CFU/mL (6 CFU/test) |
| Analytical Reactivity (Inclusivity) | 100% (24 S. pyogenes strains correctly detected at 3X LoD) |
| Analytical Specificity (Exclusivity) | 100% (70 potentially cross-reactive microorganisms reported as "Strep A NOT DETECTED") |
| Microbial Interference | No interference observed from 27 commensal microorganisms (with Strep A at 3X LoD) |
| Interfering Substances | No assay interference from 10 potentially interfering substances (e.g., blood, mucus, saliva) |
| Carry-Over Contamination | 0% (All 42 negative samples correctly reported as "Strep A NOT DETECTED" after high positive samples) |
| Reproducibility: | |
| Total Agreement (Negative) | 100% (90/90) |
| Total Agreement (Strep A High Neg) | 91% (82/90) |
| Total Agreement (Strep A Low Pos) | 97% (87/90) |
| Total Agreement (Strep A Moderate Pos) | 100% (90/90) |
| Initial Indeterminate Rate (reproducibility study) | 3.6% (13/360) (all resolved upon retesting) |
2. Sample Size and Data Provenance
- Clinical Study Test Set Sample Size: 618 specimens were included in the final analysis (initially 666, with 43 excluded).
- Data Provenance: The clinical study was a prospective, multi-center investigational study conducted at nine clinical sites in geographically diverse regions within the United States between January 2017 and May 2017.
3. Number of Experts and Qualifications for Ground Truth (Clinical Study)
The document specifies that the Xpert Xpress Strep A clinical performance was established relative to culture and latex agglutination for Strep A typing. It also mentions "an alternative PCR/bidirectional sequencing assay" used to investigate discordant results.
- Number of Experts: Not explicitly stated for establishing the primary ground truth (culture and latex agglutination). These methods are standard laboratory procedures typically performed by trained medical technologists or microbiologists.
- Qualifications of Experts: Not explicitly described. However, the use of standard microbiology lab techniques implies performance by qualified laboratory personnel. The "alternative PCR/bidirectional sequencing assay" would also be performed by trained molecular diagnosticians or researchers.
4. Adjudication Method (Clinical Study)
- Primary Adjudication: The primary ground truth for the clinical study was established by culture and latex agglutination for Strep A typing. This acts as the "gold standard" against which the device was compared.
- Discordant Analysis: For specimens where the Xpert Xpress Strep A result differed from the culture result, an "alternative PCR/bidirectional sequencing assay" was used to investigate the discrepancy. This serves as a secondary adjudication method to verify the true status of discordant samples.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not done. The Xpert Xpress Strep A is an automated in vitro diagnostic (IVD) test, not an AI system designed to assist human readers in image interpretation or similar tasks. Its performance is evaluated independently against a reference method (culture).
6. Standalone Performance
- Yes, a standalone performance study was done. The entire clinical study, analytical sensitivity, specificity, interference, and reproducibility studies assess the performance of the algorithm and instrument (Xpert Xpress Strep A test on the GeneXpert Xpress System) directly against various reference standards and controlled conditions, without human interpretation of the final result. The device provides a "Strep A DETECTED" or "Strep A NOT DETECTED" result automatically.
7. Type of Ground Truth Used (Clinical Study)
- The primary ground truth used for the clinical study was bacterial culture and latex agglutination for Strep A typing.
- For discordant sample resolution, an alternative PCR/bidirectional sequencing assay was used.
8. Sample Size for the Training Set
The document describes pre-market validation studies typically conducted for IVD devices, not machine learning model development. Therefore, there is no explicit "training set" sample size mentioned as would be the case for an AI/ML device. The device's underlying PCR assay design and algorithm are developed based on established scientific principles and analytical verification, rather than being "trained" on a large dataset in the AI sense.
9. How Ground Truth for the Training Set Was Established
As mentioned above, the concept of a "training set" and its "ground truth" in the AI/ML context is not directly applicable here. The device is a PCR assay with a defined molecular target and detection algorithm. The closest analogue to "ground truth establishment" during development would be:
- Analytical Validation: Extensive analytical studies (e.g., Limit of Detection, Inclusivity, Exclusivity, Interference) using well-characterized bacterial strains, spiked samples, and clinical matrices to ensure the assay correctly identifies the target organism and differentiates it from non-targets under various conditions. These studies confirm the assay's fundamental ability to detect S. pyogenes DNA.
- Assay Design and Optimization: The design of the primers and probes for the S. pyogenes genome target would be based on known genetic sequences, and optimized empirically to ensure specificity and sensitivity.
§ 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.