(26 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 virus 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 epidemiologic 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 (rRT-PCR) assays on the ABI 7500 Fast Dx Real-Time PCR Instrument. The panel 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 text:
Acceptance Criteria and Device Performance
| Acceptance Criteria Category | Specific Criteria/Metric | Reported Device Performance |
|---|---|---|
| Analytical Sensitivity - Limit of Detection (LOD) | The lowest concentration of virus (measured by 50% egg infectious dose - EID50/ml) where InfA, pdmInfA, and H3 primer and probe sets demonstrated a uniform detection rate of ≥ 95% for influenza A(H3N2)v virus. | A/West Virginia/06/2011: InfA: $10^{0.7}$; pdmInfA: $10^{1.4}$; H3: $10^{2.1}$; Final LOD: $10^{2.1}$ EID50/mL |
| A/Indiana/12/2012: InfA: $10^{0.6}$; pdmInfA: $10^{1.3}$; H3: $10^{2.0}$; Final LOD: $10^{2.0}$ EID50/mL | ||
| Analytical Sensitivity - Inclusivity | Detection of contemporary influenza A (H3N2)v viruses near the LOD. | Testing of 5 different A(H3N2)v strains (2009-2012) at approximately $10^{2.0}$ - $10^{2.9}$ EID50/mL showed detectable Ct values for InfA, pdmInfA, and H3 markers. |
| Clinical Performance - Positive Percent Agreement | Agreement with genetic sequencing analysis for the detection of influenza A(H3N2)v virus. | 97.6% (95% confidence interval: 93.9-99.1%) |
Study Information:
2. Sample size used for the test set and the data provenance:
- Sample Size for Clinical Specimen Testing: 165 human respiratory specimens.
- Data Provenance: Retrospective. The specimens were "transferred from U.S. public health laboratories to the CDC for confirmatory testing." This indicates they were previously collected and tested. The country of origin is the U.S.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The document does not specify the number or qualifications of experts used to establish the ground truth for the test set. It mentions that specimens were "transferred from U.S. public health laboratories to the CDC for confirmatory testing" and that "Results were confirmed through genetic sequence analysis." It also states "Performance characteristics for influenza were established during a season when seasonal influenza viruses A/H1 and A/H3 were the predominant influenza A viruses in circulation and during a season when the A/H1pdm09 influenza virus was the predominant influenza A virus in circulation." This implies the original diagnoses were clinical, but the ground truth for this specific study was molecular.
4. Adjudication method for the test set:
- The document implies that genetic sequence analysis served as the definitive "comparator" or gold standard. There is no mention of a traditional expert adjudication method (like 2+1 or 3+1 consensus) for establishing the ground truth of the clinical samples. The device's results were compared directly to the genetic sequencing (molecular) findings.
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. This is a diagnostic panel for molecular detection, not an AI-based imaging or interpretive device that would typically involve human "readers" or a MRMC study. The study focuses on the device's ability to detect specific viral markers.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- Yes, implicitly. The "Performance Summary" describes the analytical sensitivity (LOD, inclusivity) and clinical performance (positive percent agreement) of the "CDC Human Influenza Virus Real-Time RT-PCR Diagnostic Panel" itself. It is evaluating the direct output of the RT-PCR assay against a ground truth, which constitutes a standalone performance evaluation of the diagnostic panel. The "human-in-the-loop" aspect comes in interpreting the results from InfA, pdmInfA, and H3 markers, but the performance metrics are for the assay's ability to produce those results.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Molecular (Genetic Sequence Analysis). For the clinical specimen testing, the "comparator" used to establish the ground truth was "genetic sequence analysis." For analytical sensitivity and inclusivity, it was based on known concentrations of spiked viral isolates.
8. The sample size for the training set:
- Not specified. The document does not describe a training set for the device's development or a separate validation study using a distinct training set. The performance data presented are for validation/testing of the device itself.
9. How the ground truth for the training set was established:
- N/A (Not Applicable). As no training set is described, there's no information on how its ground truth would have been established. The device is a molecular diagnostic panel based on RT-PCR technology, not a machine learning algorithm that requires a labeled training set in the typical sense. Its development relies on designing primers and probes specific to target genetic sequences.
§ 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.