(4 days)
The Alere™ i Influenza A & B assay performed on the Alere™ i Instrument is a rapid molecular in vitro diagnostic test utilizing an isothermal nucleic acid amplification technology for the qualitative detection and discrimination of influenza A and B viral RNA in nasal swabs from patients with signs and symptoms of respiratory infection. It is intended for use as an aid in the differential diagnosis of influenza A and B viral infections in humans in conjunction with clinical and epidemiological risk factors. The assay is not intended to detect the presence of influenza C virus.
Negative results do not preclude influenza virus infection and should not be used as the sole basis for diagnosis, treatment or other patient management decisions.
Performance characteristics for influenza A were established during the 2012-2013 influenza season when influenza A/H3 and A/H1N1 pandemic were the predominant influenza A viruses in circulation. When other influenza A viruses are emerging, performance characteristics may vary.
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 department for testing. Viral culture should not be attempted in these cases unless a BSL 3+ facility is available to receive and culture specimens.
Alere™ i Influenza A & B is a rapid, instrument-based isothermal test for the qualitative detection and differentiation of influenza A and influenza B from nasal swab specimens collected from patients presenting with signs and symptoms of respiratory infection. The Alere™ i Influenza A & B System utilizes isothermal nucleic acid amplification technology and is comprised of:
- Sample Receiver single use, disposable containing the elution buffer .
- . Test Base - single use, disposable comprising two sealed reaction tubes, each containing a lyophilized pellet
- Transfer Cartridge single use, disposable for transfer of the eluted sample to the Test Base, and .
- Alere™ i Instrument repeat use reader .
The reaction tubes in the Test Base contain the reagents required for amplification of the target nucleic acid and an internal control. Alere™ i Influenza A & B utilizes a pair of templates (similar to primers) for the specific amplification of RNA from influenza A and B and a fluorescently labeled molecular beacon designed to specifically identify the amplified RNA targets. Alere™ i Influenza A & B is performed within the confinement of the Test Base, and no other part of the Alere™ i Instrument has contact with the sample during the amplification process. This minimizes the risk of instrument contamination and sample carryover between measurements.
To perform the assay, the Sample Receiver and Test Base are inserted into the Alere™ i Instrument and the elution buffer is automatically the instrument. The sample is added to the Sample Receiver and transferred via the Transfer Cartridge to the Test Base, resuspending the lyophilized pellet contained within the Test Base and initiating target amplification. Heating, mixing and detection by fluorescence is provided by the instrument, with results automatically reported.
Results are displayed by the Alere™ i Instrument separately for influenza A and influenza B. Results are also stored in an on-board archive and are assigned to a sample ID that has been entered into the Alere™ i Instrument by the operator, and the date/time the test was performed. Data can be retrieved and downloaded by the operator at any time after testing. An external Alere™ Universal Printer can be attached via USB to the Alere™ i Instrument to print test results.
Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. Table of Acceptance Criteria and the Reported Device Performance
The acceptance criteria are implied by the reported performance metrics, particularly sensitivity and specificity, as these are critical for diagnostic devices. While explicit numerical targets for "acceptance criteria" are not given in a dedicated section, regulatory submissions typically require performance within acceptable clinical ranges. For this summary, I'll extract the reported performance from the clinical study as the device's demonstrated capability.
| Criteria (Implied) | Device Performance (Alere™ i Influenza A & B) |
|---|---|
| Influenza A Performance (against Viral Culture) | |
| Sensitivity | 97.9% (95% CI: 92.6%-99.4%) |
| Specificity | 86.2% (95% CI: 82.8%-89.0%) |
| Influenza B Performance (against Viral Culture) | |
| Sensitivity | 92.5% (95% CI: 84.6%-96.5%) |
| Specificity | 96.5% (95% CI: 94.5%-97.8%) |
| Invalid Rate (Flu A) | |
| Initial Invalid Rate | 5.8% (95% CI: 4.2% to 8.0%) |
| Invalid Rate after Repeat Testing | 2.4% (95% CI: 1.4%, 4.0%) |
| Invalid Rate (Flu B) | |
| Initial Invalid Rate | 3.6% (95% CI: 2.4% to 5.4%) |
| Invalid Rate after Repeat Testing | 2.7% (95% CI: 1.7%, 4.4%) |
| Limit of Detection (LoD) | Lowest virus concentration detected ≥ 95% of the time (Details in source) |
| Reactivity (Inclusivity) | Detected all tested strains at specified concentrations (Details in source) |
| Specificity (Cross-reactivity) | Negative when tested with 53 common microorganisms |
| Interfering Substances | No effect on performance from various tested substances |
| Reproducibility | High percent agreement with expected results across sites and operators (Details in source) |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size: 585 evaluable direct nasal swab specimens.
- Influenza A performance analysis: 571 specimens
- Influenza B performance analysis: 569 specimens
- Data Provenance: Prospective study conducted in the U.S. during the 2012-2013 flu season. Specimens were collected from patients presenting with flu-like symptoms at eight investigational sites throughout the U.S.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts
The ground truth for the clinical study was established using viral culture performed according to standard virology culture procedures. The text does not specify the number of individual experts (e.g., virologists) or their specific qualifications (e.g., years of experience) involved in performing the viral cultures, beyond stating "standard virology culture procedures." It mentions that six of the eight sites shipped samples to a central testing laboratory for viral culture, and two sites performed culture on-site with a local laboratory.
4. Adjudication Method for the Test Set
Discrepant results between the Alere™ i Influenza A & B device and viral culture were investigated. The adjudication method involved:
- Testing the discrepant specimens using an FDA-cleared Influenza RT-PCR assay at a central testing laboratory. This RT-PCR assay served as a tie-breaker or confirmatory test to resolve inconsistencies.
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
This device, the Alere™ i Influenza A & B, is a fully automated in vitro diagnostic test for qualitative detection of viral RNA. It's not an AI-assisted diagnostic device that human readers interact with or interpret. Therefore, an MRMC comparative effectiveness study comparing human readers with and without AI assistance is not applicable and was not performed. The device provides an automated result.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, a standalone performance study was done. The entire clinical study, as described, evaluates the performance of the Alere™ i Influenza A & B system as an automated algorithm providing qualitative results (positive/negative) for Influenza A and B. The results are "automatically reported" by the instrument and do not involve human interpretation of complex data output from the device to arrive at the final diagnostic decision.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.)
The primary ground truth used for the clinical study was viral culture. For discrepant results, an FDA-cleared Influenza RT-PCR assay was used as a confirmatory method.
8. The Sample Size for the Training Set
The provided text describes the clinical validation study (test set) for the device. It does not specify the sample size for a training set. This is common for diagnostic assays where the "training" (development and optimization) phase might use internally developed samples or smaller pilot studies, and the submission focuses on the independent clinical validation. Analytical studies (e.g., LoD, reactivity) used contrived specimens which are distinct from training clinical samples.
9. How the Ground Truth for the Training Set Was Established
Since a dedicated training set sample size is not specified, the method for establishing its ground truth is also not detailed in this document. However, based on typical diagnostic assay development, ground truth for any internal development/training samples would likely also rely on well-characterized viral strains, viral culture, or highly sensitive and specific molecular methods to confirm presence/absence and concentration of the target analytes. For analytical studies mentioned, ground truth was established by known concentrations of verified virus strains (TCID50/mL, EID50/mL, Genome Equivalents/mL).
§ 866.3980 Respiratory viral panel multiplex nucleic acid assay.
(a)
Identification. A respiratory viral panel multiplex nucleic acid assay is a qualitative in vitro diagnostic device intended to simultaneously detect and identify multiple viral nucleic acids extracted from human respiratory specimens or viral culture. The detection and identification of a specific viral nucleic acid from individuals exhibiting signs and symptoms of respiratory infection aids in the diagnosis of respiratory viral infection when used in conjunction with other clinical and laboratory findings. The device is intended for detection and identification of a combination of the following viruses:(1) Influenza A and Influenza B;
(2) Influenza A subtype H1 and Influenza A subtype H3;
(3) Respiratory Syncytial Virus subtype A and Respiratory Syncytial Virus subtype B;
(4) Parainfluenza 1, Parainfluenza 2, and Parainfluenza 3 virus;
(5) Human Metapneumovirus;
(6) Rhinovirus; and
(7) Adenovirus.
(b)
Classification. Class II (special controls). The special controls are:(1) FDA's guidance document entitled “Class II Special Controls Guidance Document: Respiratory Viral Panel Multiplex Nucleic Acid Assay;”
(2) For a device that detects and identifies Human Metapneumovirus, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Human Metapneumovirus (hMPV) Using Nucleic Acid Assays;” and
(3) For a device that detects and differentiates Influenza A subtype H1 and subtype H3, FDA's guidance document entitled “Class II Special Controls Guidance Document: Testing for Detection and Differentiation of Influenza A Virus Subtypes Using Multiplex Nucleic Acid Assays.” See § 866.1(e) for the availability of these guidance documents.