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The Aptima Combo 2® Assay is a target amplification nucleic acid probe test that utilizes target capture for the in vitro qualitative detection and differentiation of ribosomal RNA (rRNA) from Chlamydia trachomatis (CT) and/or Neisseria gonorrhoeae (GC) to aid in the diagnosis of chlamydial and/or gonococcal urogenital disease using the Panther® System as specified.

On the Panther System, the assay may be used to test the following specimens from symptomatic and asymptomatic individuals: clinician-collected endocervical, vaginal and male urethral swab specimens, clinician-collected gynecological specimens collected in the PreservCyt® Solution, patient-collected vaginal swab specimens, 1 and female and male urine specimens.

1 Patient-collected vaginal swab specimens are an option for screening women when a pelvic exam is not otherwise indicated. The vaginal and multitest swab specimen collection kits are not for home use.

Clearance of this pre-market application will add female urine as an acceptable specimen type using the Aptima Combo 2 assay on the Panther system.

The Aptima Combo 2 Assay combines the technologies of target capture, Transcription-Mediated Amplification (TMA), and Dual Kinetic Assay (DKA). Specimens are collected and transferred into their respective specimen transport tubes. The transport solutions in these tubes release the rRNA targets and protect them from degradation during storage. When the Aptima Combo 2 Assay is performed in the laboratory, the target rRNA molecules are isolated from specimens by use of capture oligomers via target capture that utilizes magnetic microparticles. The capture oligomers contain sequences complementary to specific regions of the target molecules as well as a string of deoxyadenosine residues. A separate capture oligomer is used for each target. During the hybridization step, the sequence specific regions of the capture oligomers bind to specific regions of the target molecules. The capture oligomer:target complex is then captured out of solution by decreasing the temperature of the reaction to room temperature. This temperature reduction allows hybridization to occur between the deoxyadenosine region on the capture oligomer and the poly-deoxythymidine molecules that are covalently attached to the magnetic particles. The microparticles, including the captured target molecules bound to them, are pulled to the side of the reaction vessel using magnets and the supernatant is aspirated. The particles are washed to remove residual specimen matrix that may contain amplification reaction inhibitors. After the target capture steps are completed, the specimens are ready for amplification.

Target amplification assays are based on the ability of complementary oligonucleotide primers to specifically anneal and allow enzymatic amplification of the target nucleic acid strands. The Aptima Combo 2 Assay replicates a specific region of the 23S rRNA from CT and a specific region of the 16S rRNA from GC via DNA intermediates. A unique set of primers is used for each target molecule. Detection of the rRNA amplification product sequences (amplicon) is achieved using nucleic acid hybridization. Single-stranded chemiluminescent DNA probes, which are complementary to a region of each target amplicon, are labeled with different acridinium ester molecules. The labeled DNA probes combine with amplicon to form stable RNA:DNA hybrids. The Selection Reagent differentiates hybridized from unhybridized probe, eliminating the generation of signal from unhybridized probe. During the detection step, light emitted from the labeled RNA:DNA hybrids is measured as photon signals in a luminometer, and are reported as Relative Light Units (RLU). In DKA, differences in the kinetic profiles of the CT and GC labeled probes allow for the differentiation of signal; kinetic profiles are derived from measurements of photon output during the detection read time. The chemiluminescent detection for CT signal has very rapid kinetics and has the "flasher" kinetic type. The chemiluminescent detection reaction for GC signal is relatively slower and has the "glower" kinetic type. Assay results are determined by a cut-off based on the total RLU and the kinetic curve type.

The Aptima Combo 2 assay has been designed for and validated on the Panther system. The Panther system is an integrated hardware and software system that together with the Aptima Combo 2 assay fully automates all the steps necessary to perform the assay from sample preparation through amplification of nucleic acid, detection, data reduction and amplicon inactivation.

Here's an analysis of the provided text regarding the Aptima Combo 2 Assay (Panther System), focusing on acceptance criteria and the supporting study:

The provided document describes a 510(k) premarket notification for the Aptima Combo 2 Assay (Panther System) to add female urine as an acceptable specimen type. The study aimed to demonstrate substantial equivalence to the predicate device, which already included other specimen types.

1. Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a table format with numerical targets. Instead, it presents the Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) of the device compared to a Composite Comparator Algorithm (CCA) for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) in female urine samples. For regulatory clearance, these performance metrics are implicitly the acceptance criteria; the observed performance must be deemed sufficient for the intended use and comparable to similar marketed devices.

Based on the performance tables provided, here's a summary of the reported device performance, which likely served as the basis for acceptance:

Reported Performance of Aptima Combo 2 Assay (Panther System) for Female Urine

Note: The confidence intervals provide the range within which the true PPA/NPA is likely to fall. For asymptomatic GC, the PPA has a wider confidence interval due to a smaller number of positive cases.

2. Sample Size and Data Provenance

• Sample Size for Test Set:
  • Total subjects initially enrolled: 2640
  • Subjects with valid Aptima Combo 2 Assay results on Panther System: 2581
  • Evaluable subjects for performance (conclusive CCA status): 2580
  • Final Sample Size for CT performance: 2572 (1379 symptomatic, 1193 asymptomatic) after accounting for equivocal results and non-evaluable subjects.
  • Final Sample Size for GC performance: 2579 (1383 symptomatic, 1196 asymptomatic) after accounting for equivocal results and non-evaluable subjects.
• Data Provenance: Retrospective study.
  • Specimens originated from women enrolled in a previously completed prospective study.
  • The study participants (women) were enrolled from 17 geographically and ethnically diverse US clinical sites, including family planning, academic centers, and public health clinics.

3. Number of Experts and Qualifications for Ground Truth

The document does not specify the number of experts used to establish the ground truth or their qualifications. The ground truth (Composite Comparator Algorithm, CCA) was established using multiple FDA-cleared NAATs, not directly by human experts adjudicating individual cases based on clinical information or pathology.

4. Adjudication Method for the Test Set

The adjudication method used to establish the Composite Comparator Algorithm (CCA) for the ground truth was:

• 2 out of 3 rule: When 2 out of 3 FDA-cleared CT/GC NAATs were positive, the CCA was considered positive. When 2 out of 3 NAATs were negative, the CCA was considered negative.
• Tie-breaker: If the results from the initial two comparator NAATs did not determine the CCA, a third FDA-cleared CT/GC NAAT was performed using remnant urine samples to determine the CCA.

This is a form of consensus-based ground truth, but using other diagnostic tests rather than direct clinical expert consensus.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was done. This study evaluated the standalone performance of a diagnostic assay (Aptima Combo 2 Assay) against a reference standard (CCA), not the effect of AI assistance on human readers.

6. Standalone Performance

Yes, a standalone performance study was done. The entire clinical study described evaluates the performance of the Aptima Combo 2 assay on the Panther System (the algorithm/device itself) directly against the Composite Comparator Algorithm (CCA) without human interpretation as part of the primary outcome measure. The PPA and NPA values reported are the standalone performance metrics.

7. Type of Ground Truth Used

The ground truth used was a Composite Comparator Algorithm (CCA), which was derived from the results of multiple (up to 3) FDA-cleared nucleic acid amplification tests (NAATs). While this is a common method for establishing a "gold standard" in diagnostic test evaluations, it is not direct pathology, clinical outcomes data, or expert consensus in the traditional sense of clinicians reviewing patient records or images. It establishes the "truth" based on a highly sensitive and specific panel of existing diagnostic tools.

8. Sample Size for the Training Set

The document does not provide information on the sample size for a training set. This is a diagnostic assay (a lab test), not an AI/machine learning model in the typical sense that would require a separate, explicit "training set" for model parameters. The "development" or "training" of such an assay involves reagent formulation, assay protocol optimization, and establishing cut-offs, typically done using characterized samples, but not usually reported with a distinct "training set" size in the same manner as an AI algorithm. The study described is a clinical validation or "test set" evaluation.

9. How the Ground Truth for the Training Set was Established

As mentioned above, there is no explicit "training set" described in the context of this 510(k) submission. The performance study evaluated the device against a CCA, as detailed in point 4 and 7.

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