(79 days)
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is intended for use in real-time RT-PCR (rRT-PCR) assays on an Applied Biosystems (ABI) 7500 Fast Dx Real-Time PCR Instrument in conjunction with clinical and epidemiological information:
- For qualitative detection of influenza virus type A or B from viral RNA in upper respiratory tract clinical specimens (including nasopharyngeal swabs [NPS], nasal swabs [NS], throat swabs [TS], nasal aspirates [NA], nasal washes [NW] and dual nasopharyngeal/throat swabs [NPS/TS]), and lower respiratory tract specimens (including bronchoalveolar lavage [BAL], bronchial wash [BW], tracheal aspirate [TA], sputum, and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
- For determination of the subtype of seasonal human influenza A viruses as seasonal A/H1, A/H3, and/or A/H1pdm09 from viral RNA in upper respiratory tract clinical specimens (including NPS, NS, TS, NA, NW and NPS/TS) and lower respiratory tract specimens (including BAL, BW, TA, sputum and lung tissue) from human patients with signs and symptoms of respiratory infection and/or from viral culture;
- For the presumptive identification of virus in patients who may be infected with influenza A subtype A/H5 (Asian lineage) from viral RNA in human respiratory specimens and viral culture in conjunction with clinical and epidemiological risk factors;
- To provide epidemiological information for surveillance of circulating influenza viruses.
The CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel is used in real-time RT-PCR assays (rRT-PCR) on the ABI 7500 Fast Dx Real-Time PCR Instrument. The device consists of oligonucleotide primers and dual-labeled hydrolysis (TaqMan®) probes to be used in rRT-PCR for the in vitro qualitative detection and characterization of human influenza viruses from viral RNA in respiratory specimens from patients presenting with influenza-like illness (ILI).
Here's a breakdown of the acceptance criteria and study information for the CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel, based on the provided 510(k) summary:
1. Table of Acceptance Criteria and Reported Device Performance
The 510(k) is for a modification to an existing device (K111507) to add a new enzyme kit (Quanta qScript™). Therefore, the acceptance criteria are implicitly demonstrating substantial equivalence to the predicate device (the panel using Invitrogen SuperScript™). The performance is shown as agreement with the predicate.
| Assay Result | Acceptance Criteria (Implicit: Substantial Equivalence to Predicate) | Reported Device Performance (CDC Panel with Quanta qScript™) |
|---|---|---|
| Analytical Sensitivity (LOD) | LOD same or within one 5-fold dilution of the comparator (Invitrogen SuperScript™). | In all cases, the resulting LOD was either the same or within one 5-fold dilution of the comparator. (Table 8-3 shows precise LOD values, demonstrating this.) |
| Analytical Inclusivity | 100% concordance with the predicate. | 100% concordant with the predicate. (Table 8-4 shows comparable average Ct values, supporting this.) |
| Clinical Performance (Prospective Study) | High positive and negative agreement with the predicate. | InfB: 96.3% Positive Agreement, 100.0% Negative Agreement |
| A/H1: NA (0 positives), 100.0% Negative Agreement | ||
| A/H3: 98.8% Positive Agreement, 99.8% Negative Agreement | ||
| A/H1pdm09: 100.0% Positive Agreement, 100.0% Negative Agreement | ||
| Clinical Performance (Retrospective Study - A/H1) | High positive agreement with the predicate. | A/H1: 100.0% Positive Agreement |
| Clinical Performance (Retrospective Study - A/H5) | For high and moderate concentrations, 100% agreement with the predicate. For low concentration, demonstrate detection at or near LOD. | High Concentration: 100% Positive Agreement |
| Moderate Concentration: 100% Positive Agreement | ||
| Low Concentration: 1/12 positive, 2/12 inconclusive (from Quanta qScript™) and 9/12 inconclusive (from Invitrogen SuperScript™), showing performance at low concentrations as expected given the LOD. | ||
| Clinical Performance (Retrospective Study - Negatives) | 100% agreement for negative specimens. | 100% agreement with a 95% CI of 92.9-100.0. |
2. Sample Size Used for the Test Set and Data Provenance
-
Prospective Clinical Study:
- Initial Sample Size: 1,002 respiratory specimens.
- Analyzed Sample Size: 931 specimens (after exclusions for inconclusive results, technician/instrument error, or unspecified specimen type).
- Data Provenance: Prospective, 2011-2012 influenza season. The country of origin is not explicitly stated but is implied to be the United States (references to U.S. DHHS, World Health Organization and National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories in the United States).
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Retrospective Clinical Study (A/H1 supplement):
- Sample Size: 30 positive specimens for seasonal influenza A/H1N1.
- Data Provenance: Retrospective, from a previous clinical study conducted during the 2006-2007 influenza season. Implicitly United States.
-
Retrospective Clinical Study (A/H5 simulated samples):
- Sample Size: 36 samples (12 high concentration, 12 moderate concentration, 12 low concentration).
- Data Provenance: Simulated samples prepared from a characterized and titered stock of influenza A/H5N1 virus and human A549 cells (Lednicky et al. method). This is an in vitro study, not from human patients directly.
-
Retrospective Clinical Study (Negative specimens):
- Sample Size: 50 negative specimens.
- Data Provenance: Retrospective, from a previous clinical study conducted during the 2006-2007 influenza season. Implicitly United States.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The ground truth in this submission is established by the results of the predicate device (CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel using Invitrogen SuperScript™). The submission focuses on equivalency. There is no mention of external subject matter experts being used to establish a separate ground truth for the test set independent of the predicate device's results. The predicate device itself acts as the "gold standard" or "ground truth" for comparison.
4. Adjudication Method for the Test Set
Not applicable in the typical sense for this submission. The ground truth for the comparison is the result obtained by the predicate device. The study design is a comparison of the modified device's performance against the established performance of the predicate device. Discrepancies between the investigational device and the predicate device's results would be analyzed, but there's no mention of a separate expert adjudication panel for individual cases.
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
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) molecular assay (RT-PCR) and involves laboratory testing, not human reader interpretation of images or other data where AI assistance would be relevant. The "readers" are the laboratory instruments and trained technicians interpreting quantitative PCR curves, not human experts making diagnostic decisions from primary clinical data with or without AI aid.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done
The device is a diagnostic panel that requires human operation (sample preparation, instrument loading, interpretation of results, although interpretation of the raw PCR data is instrument-assisted). There is no "algorithm only" performance reported in the context of being a standalone diagnostic decision-making system. Its performance is always within a human-operated laboratory workflow. The analytical and clinical studies evaluate the performance of the assay itself when run by trained personnel.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)
For the clinical performance evaluation:
- The primary ground truth for comparison is the results obtained using the predicate device (CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel with Invitrogen SuperScript™). This effectively means the ground truth is established by a previously validated RT-PCR assay.
- The initial patient status (influenza-like illness symptoms, viral culture results) provides context, but the direct comparison is test-to-test.
For the analytical sensitivity and inclusivity studies:
- Characterized influenza virus strains (EID50/mL or TCID30/mL values) were used as the ground truth for establishing the Limit of Detection (LOD) and for inclusivity testing.
8. The Sample Size for the Training Set
This submission does not discuss a "training set" in the context of machine learning or AI models. The device is a RT-PCR diagnostic panel. There's no training phase described for an algorithm. The "training" of the assay itself would refer to the historical development and validation of the primers and probes, which isn't detailed here but precedes this 510(k) modification.
9. How the Ground Truth for the Training Set Was Established
Not applicable as there is no "training set" for an algorithm. The development of the RT-PCR panel involves establishing the specificity and sensitivity of the primers and probes against known viral sequences and cultured viruses, which constitute the scientific basis for the assay. This information is assumed to be established for the predicate device.
§ 866.3332 Reagents for detection of specific novel influenza A viruses.
(a)
Identification. Reagents for detection of specific novel influenza A viruses are devices that are intended for use in a nucleic acid amplification test to directly detect specific virus RNA in human respiratory specimens or viral cultures. Detection of specific virus RNA aids in the diagnosis of influenza caused by specific novel influenza A viruses in patients with clinical risk of infection with these viruses, and also aids in the presumptive laboratory identification of specific novel influenza A viruses to provide epidemiological information on influenza. These reagents include primers, probes, and specific influenza A virus controls.(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Reagents for Detection of Specific Novel Influenza A Viruses.” See § 866.1(e) for information on obtaining this document.
(2) The distribution of these devices is limited to laboratories with experienced personnel who have training in standardized molecular testing procedures and expertise in viral diagnosis, and appropriate biosafety equipment and containment.