(57 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 direct nasal swabs or nasopharyngeal swabs eluted in viral transport media 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 2014-2015 influenza seasons 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 or nasopharyngeal swabs eluted in viral transport media 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 carry-over 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 heated by 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 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 summary of the acceptance criteria and the study that demonstrates the device's performance, extracted from the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" with specific numerical targets for sensitivity and specificity. Instead, it presents the device's performance characteristics in a clinical study and analytical studies which implicitly serve as the basis for its substantial equivalence claim. I will present the clinical performance as the "Reported Device Performance."
| Performance Metric | Specific Target (Implicit Acceptance Criteria - based on what was demonstrated) | Reported Device Performance (vs. Comparator Method) |
|---|---|---|
| Influenza A | ||
| Sensitivity | High | 97.8% (95% CI: 94.9%-99.1%) |
| Specificity | High | 96.6% (95% CI: 95.3%-97.5%) |
| Influenza B | ||
| Sensitivity | High | 92.9% (95% CI: 86.1%-96.5%) |
| Specificity | High | 98.3% (95% CI: 97.4%-98.9%) |
| Invalid Rate (after repeat testing) | Low, acceptable for clinical use | 2.1% (95% CI: 1.5%, 3.1%) |
| Analytical Sensitivity (LOD) for Flu A | Lowest possible | Varies by strain (e.g., A/H1N1: 4.20 x 10^5 TCID50/mL, 4.59 x 10^6 Genome Equivalents/mL) |
| Analytical Sensitivity (LOD) for Flu B | Lowest possible | Varies by strain (e.g., B Victoria: 1.05 x 10^5 TCID50/mL, 2.29 x 10^6 Genome Equivalents/mL) |
| Analytical Specificity (Cross-Reactivity) | No cross-reactivity with common respiratory pathogens | No cross-reactivity with 53 tested microorganisms |
| Interference | No interference from common substances | No effect from 26 tested interfering substances |
| Carry-Over Contamination | No false positives | Minimal (one false positive for Flu B observed in one of the extensive carry-over studies) |
2. Sample Size Used for the Test Set and Data Provenance
- Test Set Sample Size:
- Clinical Study: 1,270 viral transport media specimens were initially tested. After excluding ineligible specimens (3) and invalid results after repeat testing (27), a total of 1,243 specimens were used for performance analysis.
- Analytical Sensitivity (LOD): 20 replicates per virus concentration, for multiple strains.
- Analytical Reactivity: Triplicates initially, then additional 2-fold dilutions until a negative result was obtained.
- Analytical Specificity (Cross Reactivity): Not specified per microorganism, but 53 different microorganisms were tested.
- Interfering Substances: Not specified per substance, but 26 different substances were evaluated.
- Carry-Over Contamination: 15 rounds of alternating positive and negative swabs for direct swab testing, and 30 rounds for VTM samples.
- Data Provenance: From a multi-site prospective clinical study conducted during the 2014-2015 flu season in the U.S. Analytical studies were conducted by the vendor.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number of experts or their qualifications for establishing ground truth. The ground truth for the clinical study was established using an FDA-cleared influenza real-time Polymerase Chain Reaction (RT-PCR) test as the comparator method. Discrepant samples were re-tested on a different FDA-cleared influenza real-time RT-PCR assay by Alere Scarborough Inc.
4. Adjudication Method for the Test Set
The adjudication method for the clinical study was specified for discrepant samples:
- An FDA-cleared influenza real-time RT-PCR test was used as the primary comparator.
- All discrepant samples were tested on a different FDA-cleared influenza real-time RT-PCR assay at Alere Scarborough Inc. to confirm the influenza status.
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 device is an in-vitro diagnostic assay (a molecular test) and not an imaging or AI-assisted diagnostic device requiring human reader interpretation. Therefore, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed, and the concept of "human readers improve with AI" does not apply here.
6. If a Standalone (i.e. algorithm only without human-in-the loop performance) was done
Yes, the performance presented is for the standalone device (Alere™ i Influenza A & B assay on the Alere™ i Instrument) without human-in-the-loop performance influencing the result generation. The instrument automatically reports the results.
7. The type of ground truth used
- Clinical Study: The ground truth was established by an FDA-cleared influenza real-time Polymerase Chain Reaction (RT-PCR) test, with additional confirmatory testing for discrepant results using a different FDA-cleared RT-PCR assay. This is a form of molecular diagnostic gold standard.
- Analytical Studies (LOD, Reactivity, Cross-Reactivity, Interference): Ground truth was based on the known concentrations and identities of the viral strains, microorganisms, and substances used in the laboratory experiments.
8. The Sample Size for the Training Set
The document does not explicitly mention a "training set" in the context of device development or machine learning models, as this is a molecular diagnostic assay. The analytical and clinical studies described are for validation and performance assessment of the assay and instrument.
9. How the Ground Truth for the Training Set Was Established
As no "training set" in the context of machine learning was described, this question is not applicable to the provided information. The device relies on specific nucleic acid amplification technology rather than machine learning models requiring large training datasets with established ground truth.
§ 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.