(89 days)
cobas TV/MG on the cobas 6800/8800 Systems is an automated, qualitative in vitro nucleic acid diagnostic test that utilizes real-time polymerase chain reaction (PCR), for the direct detection of Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG) DNA in male or female urine, self-collected vaginal swab specimens (collected in a clinical setting), clinician-collected vaginal swab specimens, and endocervical specimens, all collected in cobas PCR Media (Roche Molecular Systems, Inc.). cobas TV/MG also detects TV DNA in cervical specimens collected in PreservCyt solution and MG DNA in self-collected meatal swab specimens (collected in a clinical setting) and clinician-collected meatal swab specimens. This test is intended as an aid in the diagnosis of TV and MG infections in individuals suspected to have TV or MG infection.
A vaginal swab (self-collected or clinician-collected) is the preferred specimen type for MG testing in females due to higher sensitivity compared to endocervical swabs and urine. For males, urine is the preferred specimen type due to higher sensitivity compared to meatal swabs. If vaginal swab or male urine is not used and MG testing, is negative, further testing with the preferred specimen type may be indicated if M. genitalium infection is strongly suspected.
cobas® TV/MG on the cobas® 6800/8800 Systems is an automated, qualitative in vitro nucleic acid diagnostic test for the direct detection of Trichomonas vaginalis (TV) and Mycoplasma genitalium (MG) DNA in male or female urine, self-collected vaginal swab specimens (collected in a clinical setting), clinician-collected vaginal swab specimens, and endocervical specimens collected in cobas® PCR Media (Roche Molecular Systems, Inc.). cobas® TV/MG also detects TV DNA in cervical specimens collected in PreservCyt® Solution and MG DNA in self-collected meatal swab specimens (collected in a clinical setting) and clinician-collected meatal swab specimens. The DNA Internal Control, used to monitor the entire sample preparation and PCR amplification process, is introduced into each specimen during sample processing. In addition, the test utilizes external controls (low titer positive control and a negative control).
cobas® TV/MG is based on fully automated sample preparation (nucleic acid extraction and purification) followed by PCR amplification and detection. The cobas® 6800/8800 Systems consist of the sample supply module, the transfer module, the processing module, and the analytic module. Automated data management is performed by the cobas® 6800/8800 software which assigns test results for all tests as positive, negative or invalid. Results can be reviewed directly on the system screen, exported, or printed as a report.
Nucleic acid from patient samples and added internal control DNA (DNA-IC) molecules are simultaneously extracted. In summary, nucleic acid is released by addition of proteinase and lysis reagent to the sample. The released nucleic acid binds to the silica surface of the added magnetic glass particles. Unbound substances and impurities, such as denatured protein, cellular debris and potential PCR inhibitors are removed with subsequent wash steps and purified nucleic acid is eluted from the magnetic glass particles with elution buffer at elevated temperature. External controls (positive and negative) are processed in the same way with each cobas® TV/MG run.
Selective amplification of target nucleic acid from the sample is achieved by the use of targetspecific forward and reverse primers for TV and MG which are selected from highly-conserved regions within the respective target organism. TV is detected by one selective set of primers and a probe, while MG is detected by using two sets targeting separate regions (dual-target). Selective amplification of DNA IC is achieved by the use of sequence-specific forward and reverse primers which are selected to have no homology with either the TV or MG target regions. A thermostable DNA polymerase enzyme is used for PCR amplification. The target and DNA-IC sequences are amplified simultaneously utilizing a universal PCR amplification profile with predefined temperature steps and number of cycles. The master mix includes deoxyuridine triphosphate (dUTP), instead of deoxythymidine triphosphate (dTTP), which is incorporated into the newly synthesized DNA (amplicon). Any contaminating amplicon from previous PCR runs is eliminated by the AmpErase enzyme, which is included in the PCR master mix, during the first thermal cycling step. However, newly formed amplicons are not eliminated since the AmpErase enzyme is inactivated once exposed to temperatures above 55°C.
The cobas® TV/MG master mix contains one detection probe specific for the TV target sequence, two detection probes specific for the MG target sequences and one for the DNA-IC. The probes are labeled with target specific fluorescent reporter dyes allowing simultaneous detection of TV target, MG targets and DNA-IC in three different target channels. When not bound to the target sequence, the fluorescent signal of the intact probes is suppressed by a quencher dye. During the PCR amplification step, hybridization of the probes to the specific single-stranded DNA template results in cleavage of the 5' to 3' exonuclease activity of the DNA polymerase resulting in separation of the reporter and quencher dyes and the generation of a fluorescent signal. With each PCR cycle, increasing amounts of cleaved probes are generated and the cumulative signal of the reporter dye increases concomitantly. Real-time detection and discrimination of PCR products is accomplished by measuring the fluorescence of the released reporter dyes for the TV and MG targets and DNA-IC, respectively.
Here's an analysis of the acceptance criteria and study that proves the device meets the acceptance criteria, based on the provided text:
Device: cobas TV/MG for use on cobas 6800/8800 systems
Acceptance Criteria and Reported Device Performance (Summary derived from Clinical Performance Evaluation):
The acceptance criteria are implicitly defined by the reported sensitivity and specificity values necessary for the device to be considered "substantially equivalent" to predicate devices and acceptable for aiding diagnosis. The tables below show the detailed performance for various specimen types and patient populations.
1. Table of Acceptance Criteria and Reported Device Performance:
| Metric / Specimen Type | Female Urine (Overall) | Female Vaginal Swab (Overall) | Female PreservCyt® (Overall) | Female Endocervical Swab (Overall) | Male Urine (Overall) | Male Meatal Swab (Overall) |
|---|---|---|---|---|---|---|
| TV Sensitivity (95% CI) | 97.7% (94.1%, 99.1%) | 99.4% (96.8%, 99.9%) | 94.7% (90.2%, 97.2%) | 97.6% (94.1%, 99.1%) | 100.0% (85.7%, 100.0%) | N/A (TV not tested) |
| TV Specificity (95% CI) | 98.7% (97.7%, 99.2%) | 96.8% (95.4%, 97.8%) | 98.9% (98.0%, 99.4%) | 98.1% (97.0%, 98.8%) | 98.4% (97.4%, 99.1%) | N/A (TV not tested) |
| MG Sensitivity (95% CI) | 86.4% (75.5%, 93.0%) | 96.6% (88.5%, 99.1%) | 83.1% (71.5%, 90.5%) | 83.1% (71.5%, 90.5%) | 100.0% (94.0%, 100.0%) | 85.0% (73.9%, 91.9%) |
| MG Specificity (95% CI) | 97.0% (95.8%, 97.9%) | 97.0% (95.8%, 97.9%) | 98.4% (97.4%, 99.0%) | 98.4% (97.4%, 99.0%) | 97.6% (96.4%, 98.4%) | 97.9% (96.7%, 98.6%) |
Note: The document implies these performance characteristics are the acceptance criteria by evaluating the device against them for substantial equivalence.
2. Sample Size and Data Provenance:
- Test Set (Clinical Study):
- Total subjects enrolled: 2,194 (1,108 females and 1,046 males evaluable for TV and/or MG analyses).
- Total samples tested: 6,807 (with 5,285 TV results and 5,382 MG results across all specimen types from evaluable subjects).
- Data Provenance: Multi-site, prospective study from 10 geographically diverse sites in the US.
3. Number of Experts and Qualifications for Ground Truth:
- Number of Experts: Not explicitly stated as human experts in the context of adjudication for the clinical study. The ground truth (Patient Infected Status - PIS) was established using a combination of FDA-cleared and laboratory-developed tests, not through expert consensus on images or clinical assessments by a panel of medical professionals in an adjudication process.
- Qualifications of Experts: Not applicable in the traditional sense of human readers adjudicating data. The "experts" are the established reference methods (FDA-cleared TV NAATs, TV culture, and 3 laboratory developed MG NAATs).
4. Adjudication Method for the Test Set:
- Trichomonas vaginalis (TV) PIS:
- Combination of FDA-cleared TV NAATs and TV culture.
- If Culture (+) or FDA-Cleared NAAT (+), then PIS = Infected.
- If both Culture (-) and FDA-Cleared NAAT (-), then PIS = Non-Infected.
- If either is invalid and the other is positive, PIS = Infected. If the valid test is negative with an invalid, PIS = Indeterminate.
- Mycoplasma genitalium (MG) PIS:
- A combination of 3 laboratory developed MG NAATs.
- "Any 2 positive tests out of the 3 MG reference NAATs used" determined as composite reference standard for positivity. (This implicitly means 2/3 or 3/3 positive for infected, and likely 0/3 or 1/3 positive for non-infected, though not explicitly detailed for all negative scenarios).
- For the specimen-specific agreement section (Table 41), the ground truth for MG was defined as an "anatomic site-specific composite reference standard" with "any 2 positive tests out of the 3 MG reference NAATs used."
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:
- No MRMC comparative effectiveness study was done. This study is for an in vitro diagnostic (IVD) device, not an AI imaging or clinical decision support system that would typically involve human readers. The performance evaluation is against a defined gold standard (PIS), not a comparison of human reader performance with and without AI assistance.
6. Standalone (Algorithm Only) Performance:
- Yes, a standalone performance was done. The entire study is a standalone (device only) performance study, as the cobas TV/MG system is "an automated, qualitative in vitro nucleic acid diagnostic test." Its performance is evaluated directly against the Patient Infected Status (PIS), without human interpretation in the loop.
7. Type of Ground Truth Used:
- Composite Reference Standard (CRS) / Patient Infected Status (PIS).
- For TV: Combination of FDA-cleared TV NAATs and TV culture.
- For MG: Combination of 3 laboratory-developed MG NAATs (specifically, any 2 of 3 positive).
8. Sample Size for the Training Set:
- Not Applicable / Not Provided. This document describes a PMA (premarket approval) or 510(k) submission for a diagnostic test. For such devices, while methods are developed and validated, a distinct "training set" for an AI algorithm is not typically detailed in these regulatory summaries in the same way it would be for an AI/ML-based device. The analytical studies (LoD, inclusivity, precision, specificity, interference) serve as a comprehensive "training" and "validation" of the assay's chemical and molecular components. The "clinical study" acts as the independent test set for regulatory submission.
9. How the Ground Truth for the Training Set was Established:
- Not Applicable / Not Provided. As noted above, typical diagnostic assays do not have a "training set" in the common AI/ML sense with explicitly defined ground truth established for it. The development and optimization of the assay's chemistry and PCR targets would involve internal studies and potentially reference materials to achieve performance targets, but these are part of the overall assay design process rather than a distinct "training set with ground truth."
§ 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.