(309 days)
The BDProbeTec™ ET Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) Amplified DNA Assays, when tested with the BDProbeTec™ ET System, use Strand Displacement Amplification (SDA) technology for the direct, qualitative detection of Chlamydia trachomatis and Neisseria gonorrhoeae DNA in endocervical swabs, male urethral swabs, and in female and male urine specimens as evidence of infection with C. trachomatis, N. gonorrhoeae, or of co-infection with C. trachomatis and N. gonorrhoeae. Specimens may be from symptomatic or asymptomatic females for the BDProbeTec ET CT and GC Assays, from symptomatic or asymptomatic males for the BDProbeTec ET CT Assay, and from symptomatic males for the BDProbeTec ET GC Assay. A separate Amplification Control is an option for inhibition testing (BDProbeTec ET CT/GC/AC Reagent Pack).
The BDProbeTec™ ET Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) amplified DNA assays utilize homogeneous SDA technology as the amplification method and fluorescent energy transfer (ET) as the detection method to test for the presence of CT and GC in clinical specimens.
For each assay, the SDA reagents are dried in two separate microwell strips. First, the processed sample is added to the Priming Microwell which contains the amplification primers, fluorescent labeled detector probe, and other reagents necessary for amplification. However, because no enzymes are present in the priming microwell strips, no amplification occurs at this step. After incubation, the reaction mixture is transferred to the Amplification Microwell, which contains two enzymes (a DNA polymerase and a restriction endonuclease) necessary for SDA. It is in this latter microwell in which amplification and detection occurs. The Amplification Microwells are sealed to prevent contamination and then incubated in a thermally controlled fluorescent reader which monitors each test well for the generation of amplified products. The presence of CT and GC is determined by relating the BDProbeTec ET MOTA (Method Other Than Acceleration) scores for the sample to pre-determined cutoff values. The MOTA score is a metric used to assess the magnitude of signal generated as a result of the reaction.
If the CT/GC Reagent Pack is used, each sample and control are tested in two discrete microwells: C. trachomatis and N. gonorrhoeae. Results are reported through an algorithm as positive or negative. If the CT/GC/AC Reagent Pack is used, each sample and control are tested in three discrete microwells: C. trachomatis, N. gonorthoeae, and the Amplification Control. The purpose of the Amplification Control is to identify a sample that may inhibit the SDA reaction. Results are reported through an algorithm as positive, negative, or indeterminate.
This document describes the regulatory submission for the BDProbeTec™ ET Chlamydia trachomatis and Neisseria gonorrhoeae Amplified DNA Assays.
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implied by the clinical performance results being deemed "substantially equivalent" to predicate devices by the FDA. The reported device performance is outlined in detail for both C. trachomatis (CT) and N. gonorrhoeae (GC) assays, with sensitivity and specificity values compared to both culture and "patient infected status." The tables below summarize these performances.
Table 1: BDProbeTec™ ET CT Assay Performance (Compared to Patient Infected Status)
| Specimen Type | Symptomatic/Asymptomatic (S/A) | Sensitivity (95% C.I.) | Specificity (95% C.I.) |
|---|---|---|---|
| Female Swab | S | 88.7% (78.1-95.3) | 98.5% (97.1-99.4) |
| A | 96.8% (89.0-99.6) | 97.9% (96.6-98.8) | |
| Total | 92.8% (86.8-96.7) | 98.1% (97.3-98.8) | |
| Female Urine | S | 77.0% (64.5-86.8) | 98.2% (97.0-99.3) |
| A | 83.9% (72.3-92.0) | 98.3% (97.0-99.1) | |
| Total | 80.5% (72.4-87.1) | 98.4% (97.4-99.0) | |
| Male Swab | S | 95.5% (89.7-98.5) | 92.9% (89.9-95.3) |
| A | 89.5% (66.9-98.7) | 97.0% (93.2-99.0) | |
| Total | 94.6% (89.1-97.8) | 94.2% (91.9-96.0) | |
| Male Urine | S | 95.4% (89.6-98.5) | 89.4% (85.9-92.4) |
| A | 89.5% (66.9-98.7) | 95.8% (91.6-98.3) | |
| Total | 94.5% (89.1-97.8) | 91.4% (88.7-93.6) | |
| Overall | 90.7% (87.8-93.1) | 96.6% (95.9-97.1) |
Table 2: BDProbeTec™ ET GC Assay Performance (Compared to Patient Infected Status)
| Specimen Type | Symptomatic/Asymptomatic (S/A) | Sensitivity (95% C.I.) | Specificity (95% C.I.) |
|---|---|---|---|
| Female Swab | S | 96.1% (86.5-99.5) | 99.3% (98.1-99.8) |
| A | 97.4% (86.2-99.9) | 99.6% (98.9-99.9) | |
| Total | 96.6% (90.5-99.3) | 99.5% (98.9-99.8) | |
| Female Urine | S | 83.7% (70.3-92.7) | 99.6% (98.6-100) |
| A | 86.5% (71.2-95.5) | 99.3% (98.4-99.8) | |
| Total | 84.9% (75.5-91.7) | 99.4% (98.8-99.8) | |
| Male Swab | S | 98.4% (95.5-99.7) | 94.8% (91.6-97.0) |
| Male Urine | S | 97.9% (94.7-99.4) | 94.4% (91.2-96.7) |
| Overall | 95.8% (93.8-97.4) | 98.5% (98.2-99.0) |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Test Set: The final data analysis included 4108 C. trachomatis specimens and 4105 N. gonorrhoeae specimens, collected from 2109 patients. Paired specimens (swab and urine) were collected from 2020 of these patients.
- Data Provenance: The data was collected from a multicenter study at seven geographically diverse clinical sites in the United States (implied by the FDA 510(k) submission). The study was prospective in nature, as it involved specimen collection specifically for the evaluation of the new assay.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not explicitly state the number of general medical experts or their specific qualifications (e.g., years of experience) who established the ground truth for the clinical study. However, the ground truth for C. trachomatis was established using:
* Cell culture as a primary reference.
* A "patient infected status" definition.
For N. gonorrhoeae, the ground truth was established using:
* Culture as a primary reference.
* A "patient infected status" definition.
These methods inherently involve expert interpretation (e.g., microbiologists for culture results, potentially infectious disease specialists or clinicians for patient infected status).
4. Adjudication Method for the Test Set
The document describes an adjudication method to define "patient infected status" when the primary culture method was negative but amplification assays were positive:
- For C. trachomatis: A patient was considered infected if (1) the culture was positive, OR (2) positive results were obtained for both AMP1 (a commercially available amplification method, in either swab or urine) and a DFA test (performed from cell culture transport medium), OR (3) AMP1 was positive in both swab and urine paired specimens.
- For N. gonorrhoeae: A patient was considered infected if (1) the culture was positive, OR (2) (in females) if AMP1 was positive in both swab and urine (paired specimens). For males, if AMP1 urine was positive and corresponding swabs were culture negative, a different commercially available amplification assay (AMP2) was performed from culture transport medium for confirmation.
This suggests that an expert consensus or a defined algorithm (rather than a simple 2+1 or 3+1 reader adjudication) was used to establish the "patient infected status" ground truth under specific conditions.
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
The study does not describe a multi-reader, multi-case (MRMC) comparative effectiveness study using a human-in-the-loop AI system. This device is a diagnostic assay, providing a qualitative (positive/negative) result, rather than an imaging or interpretive AI system requiring human reader assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the clinical performance data presented in Tables 1 and 2 represent the standalone performance of the BDProbeTec™ ET assays. The "device performance" columns directly report the sensitivity and specificity of the BDProbeTec™ ET system compared to the established ground truth. There is no indication of human intervention in the interpretation of the assay's MOTA scores (Method Other Than Acceleration) to determine positive or negative results beyond the pre-determined cutoff values.
7. The Type of Ground Truth Used
The ground truth used was a combination of:
- Expert Reference Standard (Culture): C. trachomatis cell culture and N. gonorrhoeae culture were used as primary reference standards.
- Composite Reference Standard ("Patient Infected Status"): For cases where culture was negative but other amplification assays showed positivity, a "patient infected status" was derived using a predefined algorithm involving the predicate amplification assay (AMP1) and, for CT, a Direct Fluorescent Antibody (DFA) test, and for male GC, an additional amplification assay (AMP2). This composite reference standard aims to capture true infections that might be missed by culture alone.
8. The Sample Size for the Training Set
The document does not explicitly state a separate "training set" for the BDProbeTec™ ET assay's algorithm. For in vitro diagnostic devices like this, the "algorithm" (i.e., the cut-off value for the MOTA score) is typically established during analytical validation (including studies like Limit of Detection, reproducibility, and precision) using characterized samples, and then validated with clinical samples.
The analytical studies section describes using several panels for precision, reproducibility, and analytical sensitivity, which could be considered part of the development and optimization (training) process:
- Precision panel: Five-member panel (4 dilutions of CT and GC, and a negative) tested with 6 replicates twice a day for 3 days at 3 sites.
- Reproducibility panels: 30-member swab panels and 30-member urine panels (various seeded levels and unseeded samples) tested across 23 operators.
- Analytical sensitivity: 15 C. trachomatis serovars and 39 N. gonorrhoeae strains diluted and assayed in triplicate.
9. How the Ground Truth for the Training Set Was Established
For the analytical studies that would contribute to establishing optimal parameters or "training" the assay:
- Known Concentrations: Samples were prepared with known concentrations of C. trachomatis (EBs/rxn) and N. gonorrhoeae (cells/rxn) through serial dilutions of quantitated cultures. This provides a clear, quantitative ground truth.
- Uninoculated Samples: Negative controls (sample diluent or unseeded samples) served as a known negative ground truth.
- Known Strains/Serovars: Specific serovars of C. trachomatis and strains of N. gonorrhoeae were used, characterized by standard microbiological methods.
§ 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).