(773 days)
For In Vitro Diagnostic Use.
The Rheonix STI TriPlex™ Assay, as performed on the Rheonix Encompass MDx® Workstation, is an automated DNA extraction and multiplex PCR amplification test system intended for the direct, qualitative detection of DNA from Chlamydia trachomatis (CT), and/or Neisseria gonorrhoeae (NG), and/or Trichomonas vaginalis (TV) in male urine specimens collected with the Rheonix Urine Specimen Collection Kit. The test is indicated to aid in the diagnosis of chlamydial urogenital disease, gonococcal urogenital disease and trichomoniasis in asymptomatic male individuals.
The Rheonix Encompass MDx® Workstation and the Rheonix STT TriPlex™ Assay are comprised of an instrument with associated hardware and accessories, disposable microfluidic CARD cartridges, master mixes and reagent components used to extract, amplify, and detect DNA using end point PCR. In addition, all male urine specimens in this system must be collected using the Rheonix Urine Specimen Collection Kit. The process is fully automated with the user intervention required only for loading and unloading the samples and disposable assay components. The Rheonix Encompass MDx Workstation's software automatically interprets test results which may be called as POS (positive), NEG (negative), or IND (indeterminate) for each of the assay's three targets. In addition, if the instrument encounters an error during the performance of the assay, it will report an ERR code. If either an IND or ERR code results, the same specimen should be reanalyzed for the presence of the target for which the indeterminate or error code occurred. Each assay has a built-in process control that assures that the individual steps of the entire process occurred properly. The user may also include external positive and/or negative controls to monitor the assay performance.
The Rheonix STI TriPlex Assay, performed on the Rheonix Encompass MDx Workstation, is an automated DNA extraction and multiplex PCR amplification test system for the direct, qualitative detection of DNA from Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) in male urine specimens.
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance:
The document describes the clinical performance (sensitivity and specificity) against a Patient Infection Status (PIS) derived from FDA-cleared Nucleic Acid Amplification Tests (NAATs). While explicit "acceptance criteria" are not listed as pass/fail values, the reported performance metrics serve as the demonstration that the device is fit for its intended use. For the purpose of this response, I will list the observed clinical performance as the "reported device performance," which implicitly met the FDA's criteria for substantial equivalence.
| Acceptance Criterion (Implicit) | Reported Device Performance (95% CI) |
|---|---|
| Chlamydia trachomatis (CT) | |
| Sensitivity for CT Detection (All Male Urine) | 96.9% (93.0% - 98.7%) |
| Specificity for CT Detection (All Male Urine) | 100.0% (99.7% - 100.0%) |
| Neisseria gonorrhoeae (NG) | |
| Sensitivity for NG Detection (All Male Urine) | 99.1% (95.2% - 99.8%) |
| Specificity for NG Detection (All Male Urine) | 100.0% (99.7% - 100.0%) |
| Trichomonas vaginalis (TV) | |
| Sensitivity for TV Detection (All Male Urine) | 97.1% (85.5% - 99.5%) |
| Specificity for TV Detection (All Male Urine) | 99.9% (99.6% - 100.0%) |
| Rate of Non-Reportable Results (Initial Combined IND & ERR) | |
| CT | 1.3% (0.8% - 1.9%) |
| NG | 1.0% (0.6% - 1.6%) |
| TV | 1.5% (1.0% - 2.2%) |
| Rate of Unresolved Non-Reportable Results | |
| CT | 0.0% (0.0% - 0.2%) |
| NG | 0.0% (0.0% - 0.2%) |
| TV | 0.1% (0.0% - 0.04%) for TV (representing 1 out of 1585 evaluated subjects, with all other initially failed runs yielding valid, interpretable results upon repeat testing) |
| Analytical Performance (Based on LoD, ≥95% positivity) | |
| CT LoD (Serovar D / H) | 19 IFU/ml / 26 IFU/ml (achieved ≥95% positivity at LoD) Others tested at 3xLoD or lower, or higher for L1 (8.1xLoD) and Ba (5.8xLoD), with ≥95% positivity. |
| NG LoD (ATCC 49226 / 19424) | 180 CFU/ml / 110 CFU/ml (achieved ≥95% positivity at LoD) All 30 additional strains detected at ≥95% positive rate at 110 CFU/mL. |
| TV LoD (ATCC 30236 / 50143) | 4 Trophozoites/ml / 5 Trophozoites/ml (achieved ≥95% positivity at LoD) All six additional strains detected at ≥95% positive rate at 4 trophozoites/mL. |
| Carry-over/Cross-contamination | No carry-over or cross-contamination observed between high positive and negative samples. |
| Analytical Specificity | Of 156 non-target organisms tested, 154 gave negative results for all three replicates. Two organisms (Herpes Simplex Virus, Type I for TV; Neisseria meningitides serogroup D for NG) initially showed one positive result out of three, but retesting in triplicate yielded all negative results, indicating no cross-reactivity. |
| Interfering Substances | None of the 26 tested substances yielded interference at medically relevant concentrations. |
| Mixed Infection/Competitive Interference | No interference observed when CT, NG, or TV were tested at low target concentrations in the presence of exceedingly high concentrations of the other two targets. |
2. Sample size used for the test set and the data provenance:
- Test Set Sample Size:
- CT and NG: 1606 evaluable male subjects.
- TV: 1585 evaluable male subjects (out of 1586, one excluded due to invalid test result).
- Data Provenance:
- Country of Origin: United States. Specimens were collected at 8 geographically distinct sites in the US.
- Retrospective or Prospective: Prospective. The study enrolled both symptomatic and asymptomatic subjects, and one first-catch urine specimen was collected from each subject.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
The ground truth, referred to as "Patient Infection Status (PIS)," was established by multiple FDA-cleared Nucleic Acid Amplification Tests (NAATs), not individual human experts. The document does not specify the number or qualifications of experts involved in running these comparator NAATs or interpreting their results beyond the described adjudication method. It implies that these were standard laboratory procedures using cleared devices.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:
The adjudication method used to establish the Patient Infection Status (PIS) for the test set was a 2+1 method:
- For each target (CT, NG, TV), up to three different FDA cleared NAATs were used.
- If the first two NAATs yielded concordant results (both positive or both negative), the PIS was defined accordingly.
- If the first two NAATs were not concordant, a third "tie-breaker" test was used. The PIS was then determined based on the majority rule (2 out of 3 results being either positive or negative).
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:
This device is an automated in vitro diagnostic (IVD) assay for nucleic acid detection, not an AI-assisted imaging device that involves human "readers." Therefore, an MRMC comparative effectiveness study involving human readers and AI assistance was not applicable and not performed. The device itself provides an automated interpretation (Positive, Negative, Indeterminate, or Error).
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
Yes, a standalone performance study was done. The entire premise of the clinical performance evaluation (Tables 15-17) is a direct comparison of the Rheonix STI TriPlex Assay's automated results (Positive, Negative) against the established Patient Infection Status (PIS). There is no mention of a human-in-the-loop component for the Rheonix system's result interpretation. The workstation's software automatically interprets test results.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
The ground truth used was molecular diagnostic consensus derived from multiple FDA-cleared Nucleic Acid Amplification Tests (NAATs). This is a common and accepted method for establishing ground truth in diagnostic studies for infectious diseases, as NAATs are highly sensitive and specific.
8. The sample size for the training set:
The document does not explicitly specify a "training set" for the clinical performance evaluation in the context of device clearance. Instead, it describes analytical and clinical performance studies demonstrating the device's capability. For an IVD like this, "training" typically refers to the development and optimization phase using internal validation data rather than a distinct, reported "training set" from a pivotal clinical trial. No sample size for a separate training set is provided in this submission summary.
9. How the ground truth for the training set was established:
As noted above, a distinct "training set" with ground truth established in the same manner as a clinical test set is not typically described for IVD device submissions in this way. The analytical performance characteristics (e.g., Limit of Detection, Inclusivity, Specificity, Interference, Carry-over) are established using contrived samples with known concentrations of target organisms and potential interfering substances, which serve as a form of "ground truth" for ensuring the assay's fundamental analytical capabilities during its development and internal validation. The clinical study then validates these capabilities in real-world patient samples against the PIS.
§ 866.3393 Device to detect nucleic acids from non-viral microorganism(s) causing sexually transmitted infections and associated resistance marker(s).
(a)
Identification. A device to detect nucleic acids from non-viral microorganism(s) causing sexually transmitted infections and associated resistance marker(s) is an in vitro diagnostic device intended for the detection and identification of nucleic acids from non-viral microorganism(s) and their associated resistance markers in clinical specimens collected from patients suspected of sexually transmitted infections. The device is intended to aid in the diagnosis of non-viral sexually transmitted infections in conjunction with other clinical and laboratory data. These devices do not provide confirmation of antibiotic susceptibility since mechanisms of resistance may exist that are not detected by the device.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The intended use for the labeling required under § 809.10 of this chapter must include a detailed description of targets the device detects, the results provided to the user, the clinical indications appropriate for test use, and the specific population(s) for which the device is intended.
(2) Any sample collection device used must be FDA-cleared, -approved, or -classified as 510(k) exempt (standalone or as part of a test system) for the collection of specimen types claimed by this device; alternatively, the sample collection device must be cleared in a premarket submission as a part of this device.
(3) The labeling required under § 809.10(b) of this chapter must include:
(i) A detailed device description, including reagents, instruments, ancillary materials, all control elements, and a detailed explanation of the methodology, including all pre-analytical methods for processing of specimens;
(ii) Detailed discussion of the performance characteristics of the device for all claimed specimen types based on analytical studies, including Limit of Detection, inclusivity, cross-reactivity, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate;
(iii) Detailed descriptions of the test procedure, the interpretation of test results for clinical specimens, and acceptance criteria for any quality control testing;
(iv) Limiting statements indicating that:
(A) A negative test result does not preclude the possibility of infection;
(B) The test results should be interpreted in conjunction with other clinical and laboratory data available to the clinician;
(C) Reliable results are dependent on adequate specimen collection, transport, storage, and processing. Failure to observe proper procedures in any one of these steps can lead to incorrect results; and
(D) If appropriate (
e.g., recommended by the Centers for Disease Control and Prevention, by current well-accepted clinical guidelines, or by published peer reviewed research), that the clinical performance is inferior in a specific clinical subpopulation or for a specific claimed specimen type; and(v) If the device is intended to detect antimicrobial resistance markers, limiting statements, as appropriate, indicating that:
(A) Negative results for claimed resistance markers do not indicate susceptibility of detected microorganisms, as resistance markers not measured by the assay or other potential mechanisms of antibiotic resistance may be present;
(B) Detection of resistance markers cannot be definitively linked to specific microorganisms and the source of a detected resistance marker may be an organism not detected by the assay, including colonizing flora;
(C) Detection of antibiotic resistance markers may not correlate with phenotypic gene expression; and
(D) Therapeutic failure or success cannot be determined based on the assay results, since nucleic acid may persist following appropriate antimicrobial therapy.
(4) Design verification and validation must include:
(i) Detailed device description documentation, including methodology from obtaining sample to result, design of primer/probe sequences, rationale for target sequence selection, and computational path from collected raw data to reported result (
e.g., how collected raw signals are converted into a reported result).(ii) Detailed documentation of analytical studies, including, Limit of Detection, inclusivity, cross-reactivity, microbial interference, interfering substances, competitive inhibition, carryover/cross contamination, specimen stability, within lab precision, and reproducibility, as appropriate.
(iii) Detailed documentation and performance results from a clinical study that includes prospective (sequential) samples for each claimed specimen type and, when determined to be appropriate by FDA, additional characterized clinical samples. The study must be performed on a study population consistent with the intended use population and compare the device performance to results obtained from FDA accepted comparator methods. Documentation from the clinical studies must include the clinical study protocol (including a predefined statistical analysis plan) study report, testing results, and results of all statistical analyses.
(iv) A detailed description of the impact of any software, including software applications and hardware-based devices that incorporate software, on the device's functions.