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The Aptima® SARS-CoV-2 Assay is a nucleic acid amplification in vitro diagnostic test intended for the qualitative detection of RNA from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated and purified from nasopharyngeal (NP) swab and anterior nasal (AN) swab specimens obtained from patients with signs and symptoms of COVID-19.

Positive results are indicative of the presence of SARS-CoV-2 RNA. The Aptima SARS-CoV-2 Assay is intended for use as an aid in the diagnosis of COVID-19 if used in conjunction with other clinical, epidemiological, and laboratory findings. Clinical correlation with patient history and other diagnostic information is necessary to determine patient infection status. Positive results do not rule out bacterial infection or co-infection with other viruses.

Negative results do not preclude SARS-CoV-2 infection and should not be used as the sole basis for patient management decisions. Negative results must be combined with clinical observations, patient history, and epidemiological information.

The Aptima SARS-CoV-2 Assay is a nucleic acid amplification in vitro diagnostic test developed for use on the fully automated Panther/Panther Fusion system to detect RNA from SARS-CoV-2 isolated and purified from nasopharyngeal and anterior nasal swab specimens collected into UTM/VTM or with the RespDirect Collection Kit.

The Aptima SARS-CoV-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 RNA target and protect them from degradation during storage. When the Aptima SARS-CoV-2 Assay is performed in the laboratory, the target RNA 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 SARS-CoV-2 Assay replicates specific regions of the RNA from SARS-CoV-2 virus. Detection of the RNA amplification product sequences (amplicon) is achieved using nucleic acid hybridization. Single-stranded chemiluminescent nucleic acid probes, which are unique and complementary to a region of each target amplicon and Internal Control (IC) amplicon, are labeled with different acridinium ester (AE) molecules. The AE-labeled probes combine with the amplicon to form stable hybrids. The Selection Reagent differentiates hybridized from unhybridized probe, eliminating the generation of signal from the unhybridized probe. During the detection step, light emitted from the labeled 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 labeled probes allow for the differentiation of signal; kinetic profiles are derived from measurements of photon output during the detection read time.

The Aptima SARS-CoV-2 Assay amplifies and detects 2 conserved regions of the ORF1ab gene in the same reaction, using the "glower" kinetic type. The 2 regions are not differentiated and amplification of either or both regions lead to RLU signal. The assay results are determined by a cut-off based on the total RLU and the kinetic curve type.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the performance metrics presented as evidence of substantial equivalence to the predicate device. The key metrics are Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA). While explicit numerical acceptance thresholds are not provided in the document, the reported performance demonstrates "comparable" results to the predicate device.

Study Details:

1. Sample Sizes Used for the Test Set and Data Provenance:

   • Clinical Study 1 (NP Swab Specimens):
     • Total Enrolled: 1646 specimens
     • Evaluable (Final Data Set): 1495 NP swab specimens (1195 fresh, 300 frozen)
     • Provenance: Prospective multicenter study from four participating US pediatric/adolescent, private and/or university hospitals. Specimens collected between June-July 2020 and January-April 2023. Remnant specimens.
   • Clinical Study 2 (Anterior Nasal Swab Specimens):
     • Total Enrolled Subjects: 2301
     • Evaluable Subjects: 2177 individuals (1159 with evaluable anterior nasal swab specimens in UTM/VTM, and 1018 with evaluable nasal swab specimens in eSTM).
     • Provenance: Prospective, multicenter clinical study at nine geographically and ethnically diverse US sites during the 2022-2023 respiratory season.

2. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications:

   • The document does not specify the number or qualifications of experts directly establishing the clinical ground truth. Instead, it relies on a Composite Comparator Algorithm (CCA). The CCA consists of "two highly sensitive US FDA EUA SARS-CoV-2 molecular tests" and a "validated PCR followed by bi-directional sequencing (PCR/BDS) assay." This implies that the 'expertise' comes from the validation and regulatory clearance of these comparator assays, rather than individual human experts adjudicating each case.

3. Adjudication Method for the Test Set:

   • Composite Comparator Algorithm (CCA): "A final CCA result was assigned when two of the three comparator assay results were in concordance." This serves as the adjudication method for determining the true positive/negative status of the clinical samples.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done:

   • No. This type of study (MRMC) is typically performed for diagnostic imaging devices where human readers interpret images with and without AI assistance. The Aptima SARS-CoV-2 Assay is an in vitro diagnostic (IVD), a laboratory test that detects nucleic acids, not an imaging device requiring human interpretation of visual data. Therefore, an MRMC study is not applicable here.

5. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:

   • Yes, this is effectively a standalone performance study. The Aptima SARS-CoV-2 Assay is an automated nucleic acid amplification test run on the Panther/Panther Fusion system. Its performance is directly compared to the CCA, without human intervention in the interpretation of the device's results.

6. The Type of Ground Truth Used:

   • Clinical Studies: Composite Comparator Algorithm (CCA) based on the concordance of results from two highly sensitive FDA EUA SARS-CoV-2 molecular tests and a validated PCR/BDS assay. This is a form of reference standard derived from established and highly sensitive laboratory methods.
   • Analytical Studies (e.g., LoD, Reactivity, Specificity): The ground truth was established by known concentrations of SARS-CoV-2 virus strains or other microorganisms/interfering substances, prepared in controlled laboratory settings (e.g., "spiked with inactivated cultured SARS-CoV-2 virus").

7. The Sample Size for the Training Set:

   • The document describes performance evaluation studies (analytical and clinical) for market clearance. It does not provide information on the specific training set size used for the development or training of the assay's internal algorithms (e.g., for the kinetic curve analysis or cut-off determination). This information would typically be part of the assay development and validation, not necessarily detailed in a 510(k) summary unless it significantly changed or impacted performance during the clearance process for the specific assay rather than the underlying platform. The focus here is on the performance of the final, already "trained" device.

8. How the Ground Truth for the Training Set Was Established:

   • As noted above, details regarding the training set's ground truth establishment are not provided in this 510(k) summary. For IVD devices, ground truth for training internal algorithms typically involves using characterized positive and negative clinical samples, spiked samples with known viral loads, and potentially synthetic data, all carefully confirmed by highly sensitive reference methods or gold standard assays during the R&D phase of the product.

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