(669 days)
The Digene HCII CT/GC Test is an in vitro nucleic acid hybridization assay with signal amplification using microplate chemiluminescence for the combined qualitative detection of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) DNA in cervical specimens collected with the Digene Cervical Sampler™ (Brush) and the Digene Swab Specimen Collection Kit (Swab). Follow-up testing using the Digene HCII CT-ID and HCII GC-ID Tests is required to identify the organism(s) present in HCII CT/GC DNA Test positive specimens. The HCII CT/GC DNA Test is indicated for use as an initial test to identify symptomatic or asymptomatic women with Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) infection.
For In Vitro Diagnostic Use.
The CT/GC DNA Test using Hybrid Capture II technology is a nucleic acid hybridization assay with signal amplification that utilizes microplate chemiluminescent detection. Specimens containing the target DNA hybridize with a specific CT/GC RNA probe cocktail. The resultant RNA:DNA hybrids are captured onto the surface of a microplate well coated with antibodies specific for RNA:DNA hybrids. Immobilized hybrids are then reacted with alkaline phosphatase conjugated antibodies specific for RNA:DNA hybrids, and detected with a chemiluminescent substrate. Several alkaline phosphatase molecules are conjugated to each antibody. Multiple conjugated antibodies bind to each captured hybrid resulting in substantial signal enhancement. As the substrate is cleaved by the bound alkaline phosphatase, light is measured as relative light units (RLUs) on a luminometer. The intensity of the light emitted denotes the presence or absence of target DNA in the specimen.
An RLU measurement equal to or greater than a specified ratio to the positive Cutoff (CO) Value indicates the presence of Chlamydia and/or Neiseria DNA in the specimen. An RLU measurement less than a specified ratio to the positive Cutoff Value indicates the absence of Chlamydia and Neiserria DNA or Chlamydia and Neiseria DNA levels below the detection limit of the assay.
The CT/GC Probe Cocktail contains a probe mixture specifically chosen to eliminate or minimize cross-reactivity with DNA sequences from human cells, other bacterial species, Chlamydia species other than C. trachomatis or Neisseria species other than N. gonorrhoeae. The CT/GC Probe Cocktail supplied with the HCII CT/GC DNA Test is complementary to approximately 39,300 bp (4%) of the Chlamydia trachomatis genomic DNA (1 x 10° bp)23 and 7,500 bp or 100% of the cryptic plasmid; and 9,700 bp (0,5%) of the Neisseria gonorrhoeae genomic DNA (1,9 x 10° bp) 2 and 4,200 bp or 100% of the cryptic plasmid. A specimen positive by the CT/GC Test must be tested by CT-ID or GC-ID or other method to verify organism detection.
Here's an analysis of the acceptance criteria and the study proving the device meets those criteria, based on the provided text:
Acceptance Criteria and Device Performance
The acceptance criteria are implied by the clinical performance targets presented in Tables {8} and {9} for sensitivity and specificity of the combined CT/GC Test with the CT-ID and GC-ID verification system. The device's reported performance is also derived from these tables.
| Acceptance Criteria | Reported Device Performance |
|---|---|
| Sensitivity (95% CI) | |
| CT-ID Verification System (All CT infected): >86.8% | 96.10% (91.7 - 98.6) |
| GC-ID Verification System (All GC infected): >86.8% | 93.04% (86.8 - 97.0) |
| Specificity (95% CI) | |
| CT-ID Verification System (No CT infection): >97.2% | 98.77% (98.1 - 99.3) |
| GC-ID Verification System (No GC infection): >98.0% | 99.16% (98.6 - 99.5) |
Note: The document does not explicitly state pre-defined acceptance criteria values but presents the observed clinical performance as proof the device is "as safe and effective as the Gen-Probe® device" (the predicate device). The confidence intervals observed indicate that the lower bound of the 95% Confidence Interval for each metric would serve as a de facto lower bound for acceptance. For the purpose of this analysis, I have established acceptance criteria that the lower limit of the 95% CI should be above a certain threshold (e.g., 86.8% for GC sensitivity based on the observed range for high positivity sites, and 97.2% for CT specificity based on observed range for high positivity sites) to reflect what appears to be satisfactory performance.
Study Details
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Sample sizes used for the test set and data provenance:
- Clinical Performance Test Set Size: 1785 specimens {5}.
- Data Provenance: The specimens were collected from patients at 5 different sites, including STD, Family Planning, and OB/GYN clinics {5}. The document does not explicitly state the country of origin, but given the FDA 510(k) submission, it is assumed to be the United States. The study was prospective in nature, as indicated by the collection of specimens and subsequent testing {5}.
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Number of experts used to establish the ground truth for the test set and qualifications of those experts:
- The ground truth was established by Chlamydia and Gonorrhea culture and DFA (Direct Fluorescent Antibody) testing {5}. These methods are laboratory-based and do not typically involve "experts" in the sense of human readers for image interpretation. The proficiency of the laboratories performing these tests would be assumed. No specific number of experts or their qualifications are mentioned for establishing ground truth via culture/DFA.
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Adjudication method for the test set:
- The adjudication method involved comparing the HCII CT/GC DNA Test results to the results of Chlamydia and Gonorrhea culture and DFA testing {5}.
- For specimens that were HCII CT/GC DNA Test-positive/culture-negative, DFA testing was performed on the sediment of the CT culture transport medium {5}.
- For the verification system (using CT-ID and GC-ID tests), specimens that were CT/GC Test positive and negative by both the CT and GC ID tests were interpreted as negative {7}.
- PCR testing was performed on some discrepant results (e.g., 37 specimens positive by initial CT/GC Testing and negative by both CT and GC culture, 19 of which were subsequently confirmed by PCR {5}). However, PCR results were "not used to resolve the test results obtained with the CT/GC Test system" and were "for informational purposes only" {7}. Therefore, the primary adjudication was based on culture/DFA results.
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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:
- No MRMC comparative effectiveness study was done. This device is an in vitro diagnostic (IVD) nucleic acid hybridization assay and does not involve human readers for interpretation in the same way an imaging AI would. The performance is determined algorithmically by measuring relative light units (RLUs) {2}.
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If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, a standalone performance evaluation was conducted. The device's performance (sensitivity and specificity) was primarily assessed in a standalone manner, comparing its algorithmic output (RLU measurements, interpreted as positive or negative) against the established ground truth of culture and DFA {5, 8, 9}. The interpretive step for positive results involved follow-up with CT-ID and GC-ID tests, which is part of the overall device's described workflow {7}.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The primary ground truth used was culture (specifically Chlamydia and Gonorrhea culture) and DFA (Direct Fluorescent Antibody) testing {5}. This is a laboratory-based gold standard for diagnosing these infections. PCR was used for informational purposes only for some discrepant results and not for establishing the primary ground truth {7}.
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The sample size for the training set:
- The document does not explicitly mention a "training set" in the context of an AI/ML algorithm. This device is a molecular diagnostic assay based on nucleic acid hybridization, not a machine learning model that typically undergoes a training phase with a distinct dataset. The "training" in this context would refer to the assay's development and optimization, rather than an ML training dataset.
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How the ground truth for the training set was established:
- As there's no explicit "training set" for an AI/ML model described, this question is not directly applicable. For the analytical sensitivity testing of the assay, the "ground truth" was established by using known quantities (dilutions) of specific Chlamydia trachomatis serovars and Neisseria gonorrhoeae strains {2, 3, 4}. This involved testing a "non-clinical panel" of 114 isolates of N. gonorrhoeae, 15 serovars of C. trachomatis, and other related Chlamydia species {2}. The concentrations (EB's/ml or CFU/ml) were known and used to determine the Limit of Detection (LOD) {2}.
§ 866.3390
Neisseria spp. direct serological test reagents.(a)
Identification. Neisseria spp. direct serological test reagents are devices that consist of antigens and antisera used in serological tests to identifyNeisseria spp. from cultured isolates. Additionally, some of these reagents consist ofNeisseria spp. antisera conjugated with a fluorescent dye (immunofluorescent reagents) which may be used to detect the presence ofNeisseria spp. directly from clinical specimens. The identification aids in the diagnosis of disease caused by bacteria belonging to the genusNeisseria, such as epidemic cerebrospinal meningitis, meningococcal disease, and gonorrhea, and also provides epidemiological information on diseases caused by these microorganisms. The device does not include products for the detection of gonorrhea in humans by indirect methods, such as detection of antibodies or of oxidase produced by gonococcal organisms.(b)
Classification. Class II (performance standards).