(158 days)
The JBAIDS Influenza A/H5 (Asian lineage) Detection Kit is intended for use in real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assays on the Joint Biological Agent Identification and Diagnostic System (JBAIDS) instruments for the in vitro qualitative detection of Influenza A/H5 (Asian lineage) viral RNA in patient nasopharyngeal swab (NPS) or throat swab (TS) specimens for the presumptive laboratory identification of Influenza A/H5 (Asian lineage) virus.
Testing with the JBAIDS Influenza A/H5 (Asian lineage) Detection Kit should be in conjunction with other laboratory testing and clinical observations for the following indications:
- Providing epidemiological information for the surveillance of human infection with Influenza A/H5 (Asian lineage) virus.
- Identifying patients who may be infected with Influenza A/H5 (Asian lineage) virus based on clinical and epidemiological risk factors.
Testing with the JBAIDS Influenza A/H5 (Asian lineage) Detection Kit should not be performed unless the patient meets the most current U.S. Department of Health and Human Services (DHHS) clinical and epidemiologic criteria for testing suspected A/H5 specimens.
The definitive identification of influenza A/H5 (Asian lineage) either directly from patient specimens or from virus cultures requires additional laboratory testing, along with clinical and epidemiological assessment in consultation with national influenza surveillance experts.
Negative results do not preclude influenza virus infection and should not be used as the sole basis for treatment or other patient management decisions.
Use is limited to laboratories with appropriate biosafety equipment and containment procedures. It is intended for use by experienced laboratory personnel who have training in standardized molecular testing procedures and expertise in viral diagnosis, and have received training on the JBAIDS Instrument.
If infection with a novel influenza A virus is suspected based on current clinical and epidemiological screening criteria recommended by public health authorities, specimens should be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to state or local health departments for testing. Viral culture should not be attempted in these cases unless a biosafety laboratory (BSL) 3+ facility is available to receive and culture specimens.
The Joint Biological Agent Identification and Diagnostic System (JBAIDS) Influenza A/H5 (Asian lineage) Detection Kit is a real-time reverse transcriptase polymerase chain reaction (rRT-PCR) test kit, which, when used with the JBAIDS instrument and software, allows the qualitative in vitro detection of Influenza A/H5 (Asian lineage) viral RNA. The kit contains two freeze-dried assays with primer and fluorescent-probe sets for the detection of Influenza A/H5 (Asian lineage) viral RNA. In particular, the two assays specifically target distinct regions of the influenza A hemagglutinin gene of the highly pathogenic H5N1 viruses from the Asian lineage, without detection of other influenza A virus subtypes, including the North American lineage influenza A/H5 viruses. The tests are performed using the previously FDA-cleared JBAIDS instrument and software. A human gene target assay will be used as an inhibition and extraction control.
Here's an analysis of the acceptance criteria and study details for the JBAIDS Influenza A/H5 (Asian lineage) Detection Kit, based on the provided 510(k) summary:
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Characteristic | Acceptance Criteria / Goal | Reported Device Performance |
|---|---|---|
| Analytical Sensitivity (Limit of Detection - LoD) | To detect Influenza A/H5 (Asian lineage) viral RNA at a specified concentration. | 50 EID50/mL demonstrated for both A/Vietnam/1203/2004 x A/Puerto Rico/8/34 reassortant and A/Anhui/01/2005/ x A/Puerto Rico/8/34 reassortant strains in NPS and TS specimens, confirmed with 20 individual samples at this level. |
| Analytical Specificity (Inclusivity & Reactivity) | To detect various Influenza A/H5 (Asian lineage) strains. | Detected all eight tested Influenza A/H5 (Asian lineage) strains. Lowest detection levels ranged from 10 TCID50/mL to 100 TCID50/mL depending on the strain. Spike levels of 500-1000 TCID50/mL showed similar performance to 50 EID50/mL egg-grown viruses. |
| Analytical Specificity (Exclusivity / Cross-reactivity) | To not cross-react with non-target organisms. | 100% negative results for all 45 tested non-target organisms (including various influenza viruses, other non-influenza viruses, bacteria, and fungi) when spiked at high concentrations. |
| Clinical Specificity | To demonstrate high specificity in clinical samples. | At least 99% specificity (with 95% confidence) for both NPS and TS specimens purified with either IT 1-2-3™ VIBE or Platinum Path Purification Kits. |
| Clinical Sensitivity (Surrogate) | To detect Influenza A/H5 (Asian lineage) in surrogate clinical samples. | 98% success (126 out of 128 positive results) for Influenza A/H5 virus-containing surrogate specimens. All seasonal influenza (48 total results) and influenza-negative specimens (24 total results) produced negative results, as expected. This also implicitly supports analytical specificity against seasonal influenza in a clinical context. |
2. Sample Sizes Used for the Test Set and Data Provenance
- Analytical Sensitivity (LoD): 20 individual specimens (from independent donors) per specimen type (NPS, TS) per purification kit (VIBE, Platinum Path) for confirmation (total 80 confirmed LoD tests). The provenance is not explicitly stated as country of origin, but it implies laboratory-prepared specimens. This was a prospective study design for LoD determination.
- Analytical Specificity (Inclusivity & Reactivity): 8 Influenza A/H5 (Asian lineage) strains, each spiked into TS specimens at multiple concentrations. The exact number of replicates per concentration is not detailed, but it was "multiple concentrations."
- Analytical Specificity (Exclusivity): 45 non-target organisms, each spiked into TS specimens at high concentrations. The exact number of replicates is not detailed.
- Clinical Performance (Surrogate Clinical Sensitivity):
- Influenza A/H5 Strains: 8 strains, each at 4 concentrations (LoD, 5x LoD, 10x LoD, 100x LoD).
- Seasonal Influenza Strains: 6 strains, each at 2 concentrations (LoD, 100x LoD).
- Unspiked samples: 6 specimens.
- All panels were spiked into TS or NPS specimens. Each specimen was purified with two different kits (IT 1-2-3 M VIBE and IT 1-2-3 ™ Platinum Path).
- This results in a total of:
- 8 (H5 strains) * 4 (concentrations) * 2 (specimen types) * 2 (purification kits) = 128 H5-containing samples.
- 6 (seasonal strains) * 2 (concentrations) * 2 (specimen types) * 2 (purification kits) = 48 seasonal influenza samples.
- 6 (unspiked) * 2 (specimen types) * 2 (purification kits) = 24 unspiked samples.
- Total test set for surrogate clinical sensitivity: 128 + 48 + 24 = 200 specimens. These were laboratory-prepared "surrogate" clinical samples. This indicates a prospective design for testing these surrogate samples.
- Clinical Specificity:
- NPS specimens: 314 (VIBE purified) + 299 (Platinum Path purified) = 613 specimens.
- TS specimens: 298 (VIBE purified) + 283 (Platinum Path purified) = 581 specimens.
- The total number of unique specimens used for clinical specificity is not explicitly stated (some could be both NPS and TS from the same patient, but the numbers suggest separate sample pools).
- Total specimens tested for clinical specificity = 613 + 581 = 1194.
- Data Provenance: Frozen, banked NPS and TS specimens previously tested for respiratory pathogens. They were obtained and tested at 3 different test sites. No specific country of origin is mentioned, but "US Department of Health and Human Services" context suggests US-based data. This is a retrospective study design using banked specimens.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not explicitly mention the number or qualifications of experts used to establish ground truth for the test set.
- For Analytical Performance (LoD, Inclusivity, Exclusivity) and Surrogate Clinical Sensitivity, the "ground truth" was established by the precise spiking of known quantities of viral strains into samples by the study designers. This is a laboratory-controlled ground truth, not based on expert interpretation.
- For Clinical Specificity, the ground truth was based on the results of a "CDC rRT Flu Panel" (the predicate device) which had previously tested the banked clinical specimens. The document states "Specimens were removed from the study if they did not have a valid result for the CDC comparator assay," implying the CDC panel's results served as the reference. The expertise involved in the original testing of these banked samples by the CDC panel is not detailed here.
4. Adjudication Method for the Test Set
The document does not describe an adjudication method for the test set.
- For analytical studies and surrogate clinical sensitivity, the ground truth was defined by the experimental setup (spiking concentrations, known positive/negative samples).
- For clinical specificity, the predicate device's results served as the comparison, implying a direct comparison rather than an adjudication process of ambiguous results. The JBAIDS software provides automated analysis (positive, negative, uncertain), and invalid/uncertain results required retesting, but this is a retest protocol, not an adjudication process involving experts to resolve discrepancies.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done.
This device is a molecular diagnostic assay (rRT-PCR kit) that provides automated results (positive, negative, uncertain). The output is interpreted by the JBAIDS software, not by multiple human readers. Therefore, there is no "human-in-the-loop" performance that would be assessed in an MRMC study or an effect size demonstrating human reader improvement with AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the studies presented are effectively standalone performance studies of the algorithm/device. The device and its accompanying software provide automated interpretation (positive, negative, uncertain) of the rRT-PCR results. The performance characteristics described (LoD, inclusivity, exclusivity, clinical specificity, surrogate clinical sensitivity) represent the device's ability to achieve these results directly from the sample, without human interpretative input into the primary result. Human intervention is limited to operating the instrument, preparing samples, and initiating retesting for uncertain/invalid results, not interpreting the raw amplification curves as "positive" or "negative."
7. The Type of Ground Truth Used
- Analytical Studies (LoD, Inclusivity, Exclusivity): Laboratory-controlled ground truth (known viral strains spiked at specific concentrations).
- Surrogate Clinical Sensitivity: Laboratory-controlled ground truth (known viral strains spiked into clinical matrices at specific concentrations).
- Clinical Specificity: Comparator Assay ground truth. The "CDC rRT Flu Panel" was used as the reference standard for the banked clinical specimens.
8. The Sample Size for the Training Set
The document does not provide information about a separate "training set" or its sample size. This is common for molecular diagnostic kits like this. The device is likely developed and validated using a structured process that involves internal data for assay optimization and parameter setting (which could broadly be considered "training" in a development sense), but there isn't a formally defined "training set" in the context of machine learning model development as typically described in AI/ML device studies. The performance characteristics are derived from the test sets described above.
9. How the Ground Truth for the Training Set Was Established
Since no specific "training set" is identified in the document, there's no information on how its ground truth would have been established. Any internal development and optimization would likely have relied on laboratory-controlled samples with known viral presence/absence and concentration.
§ 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.