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The Alere™ i Influenza A & B 2 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 or nasopharyngeal swabs and nasal 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 2016-2017 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 characterics 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 cases unless a BSL 3+ facility is available to receive and culture specimens.

Alere™ i Influenza A & B 2 is a rapid, instrument-based isothermal test for the qualitative detection and differentiation of influenza A and influenza B from nasal swabs tested directly or after elution in viral transport media collected from patients with signs and symptoms of respiratory infection. The Alere™ i Influenza A & B 2 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 2 utilizes a pair of templates (similar to primers) for the specific amplification of RNA from influenza A and B, which occur in two separate reaction tube contains fluorescently labeled molecular beacon designed to specifically identify the amplified RNA targets. Alere™ i Influenza A & B 2 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, re-suspending the lyophilized pellets contained within the Test Base and initiating target amplification. Heating, mixing and detection by fluorescence are provided by the instrument, with results automatically reported.

Results are displayed by the Alere™ i Instrument and 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 an analysis of the acceptance criteria and study detailed in the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "the device must achieve X sensitivity and Y specificity"). Instead, it presents the device's performance, which is implicitly accepted by the FDA's "Substantially Equivalent" determination. The table below summarizes the reported clinical performance.

2. Sample Size Used for the Test Set and Data Provenance

• Sample Size:
  • Total enrolled: 1110 nasal or nasopharyngeal swab specimens.
  • Total tested:
    • 1070 for direct swab performance analysis (after excluding 36 not meeting eligibility and 4 invalid after re-testing).
    • 1057 for viral transport media (VTM) performance analysis (after excluding 36 not meeting eligibility, 11 invalid after re-testing, and 6 not meeting eligibility).
• Data Provenance:
  • Country of Origin: United States (multi-center, conducted at ten US trial sites).
  • Retrospective or Prospective: Prospective clinical study.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The ground truth for the clinical study was established using an FDA-cleared real-time Polymerase Chain Reaction (RT-PCR) test as the comparator method. The document does not mention the use of human experts (e.g., radiologists) to establish ground truth for this device, as it is an in vitro diagnostic test for viral RNA detection, not an imaging device.

4. Adjudication Method for the Test Set

The ground truth was established by a single comparator method (FDA-cleared RT-PCR). There is no mention of an adjudication method for the test set, as the RT-PCR result was considered the definitive truth. For discrepancies, secondary molecular testing was used to investigate false positives/negatives (e.g., "Flu A nucleic acid was detected in 6/21 False positive specimens using a second FDA-cleared molecular test"). This refers to investigation of the Alere™ i results against the initial RT-PCR, not an adjudication process to establish the initial ground truth.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC comparative effectiveness study was done. This type of study is typically relevant for interpretative devices (e.g., medical imaging AI) where human readers are involved in the diagnostic process. The Alere™ i Influenza A & B 2 is an automated molecular diagnostic test with automated result interpretation.

6. Standalone Performance

Yes, a standalone performance study was done. The clinical study results (sensitivity, specificity, invalid rates) reported for the device directly reflect its performance as an algorithm-only (kit + instrument) system without human-in-the-loop interpretation beyond operating the instrument and reading the automated result. The "automated result interpretation" listed in the device comparison table further confirms its standalone nature.

7. Type of Ground Truth Used

The primary ground truth used for the clinical performance evaluation was an FDA-cleared real-time Polymerase Chain Reaction (RT-PCR) test. This is a molecular diagnostic method considered highly accurate for detecting viral RNA. Secondary molecular testing was used to investigate discordant results.

8. Sample Size for the Training Set

The document does not specify the sample size for the training set. It details the clinical validation (test set) and analytical studies. Typically, for such devices, the training data would be proprietary to the manufacturer and not explicitly disclosed in an FDA 510(k) summary, which focuses on validation data.

9. How the Ground Truth for the Training Set Was Established

Since the training set data is not disclosed, the method for establishing its ground truth is also not described in this document. It is generally assumed that the training data for molecular diagnostic assays would be similarly characterized using highly accurate reference methods, potentially including PCR, sequencing, or well-characterized viral cultures.

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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."

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.

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Alere™ i Influenza A & B:

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 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 Strep A:

Alere™ i Strep A is a rapid, instrument-based, molecular in vitro diagnostic test utilizing isothermal nucleic acid amplification technology for the qualitative detection of Streptococcus pyogenes, Group A Streptococcus bacterial nucleic acid in throat swab specimens obtained from patients with signs and symptoms of pharyngitis. It is intended to aid in the rapid diagnosis of Group A Streptococcus bacterial infections.

All negative test results should be confirmed by bacterial culture because negative results do not prection with Group A Streptococcus and should not be used as the sole basis for treatment.

Alere™ i Influenza A & B is a rapid, instrument-based isothermal tests for the qualitative detection and differentiation of influenza A and influenza B from nasal swabs collected from patients presenting with signs and symptoms of respiratory infection. Alere™ i Strep A is a rapid, instrument-based isothermal test for the qualitative detection of Group A Strep from throat swab specimens. Both Alere™ i Influenza A & B and Alere™ i Strep A Systems utilize isothermal nucleic acid amplification technology and are 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 Alere™ i Influenza A & B 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.

The reaction tubes in the Alere™ i Strep A Test Base contain the reagents required for Group A Strep bacterial lysis and the subsequent amplification of the target nucleic acid and an internal control. Alere™ i Strep A utilizes a pair of templates (similar to primers) for the specific amplification of DNA from Group A Strep and a fluorescently labeled molecular beacon designed to specifically identify the amplified nucleic acid target.

Both assays are 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 reduces 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 pellets contained within the Test Base and initiating bacterial lysis (for Alere™ i Strep A) and 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 and 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.

The provided document describes the Alere™ i Instrument, Alere™ i Influenza A & B, and Alere™ i Strep A devices. This submission focuses on a software modification to the Alere™ i Instrument to allow it to run both the Influenza A & B and Strep A assays, rather than changes to the assays themselves. Therefore, the "acceptance criteria" and "device performance" in this context refer to demonstrating that the software modification does not negatively impact the performance of the previously cleared assays.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Rationale for the Study: The primary goal of this 510(k) submission (K151690) is to demonstrate that a software modification to the Alere™ i Instrument, which enables it to run both the Alere™ i Influenza A & B and Alere™ i Strep A assays, does not alter the established safety and effectiveness of these assays. The previous versions of these tests (Alere™ i Influenza A & B, K141520 and Alere™ i Strep A, K141757) were already cleared. Therefore, the study focuses on validating the software modification.

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly present a table of numerical "acceptance criteria" for clinical performance that needed to be met by a de novo study of the device. Instead, the acceptance criterion for this submission is implicitly that the software modification does not change the performance of the previously cleared assays. The reported "performance" for the modified device is that its functionality remains unchanged compared to the predicate devices.

2. Sample Size Used for the Test Set and Data Provenance

The document explicitly states: "Software verification and validation studies performed demonstrated that Alere™ i Influenza A & B and Alere™ i Strep A assay functionality remains unchanged due to this change."

However, no specific sample sizes for a "test set" (e.g., number of patient samples, artificial samples) used in these software validation studies are provided in the excerpt. The data provenance (country of origin, retrospective/prospective) is also not detailed for these specific software validation studies. Given that the submission asserts "no changes to the Alere™ i Influenza A & B or Alere™ i Strep A tests," it's highly probable that the software validation primarily involved testing with internal samples or simulated data to ensure proper functionality and integration, rather than a new full-scale clinical study with patient samples. The information indicates the tests themselves had established performance characteristics from previous submissions.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

Since the study described here is focused on software validation and demonstrating unchanged functionality of existing assays, rather than determining the initial clinical accuracy of the assays against a clinical ground truth, there is no mention of experts establishing a ground truth for a test set in this context.

4. Adjudication Method for the Test Set

As there is no mention of a clinical test set requiring expert ground truth, no adjudication method is described.

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 MRMC comparative effectiveness study was mentioned. The device is an in vitro diagnostic test, not an AI software intended to assist human readers in image interpretation or a similar task. It is a standalone instrument that provides qualitative diagnostic results.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, the performance of the Alere™ i Instrument is inherently standalone. The device processes the sample and provides an automated qualitative result ("Influenza A Detect", "Influenza B Detect", "Strep A Detect", or "Not Detected"). The "Software verification and validation studies" described would have assessed this standalone performance with the modified software.

7. The Type of Ground Truth Used (expert consensus, pathology, outcomes data, etc.)

For the original clinical performance studies of the Alere™ i Influenza A & B (K141520) and Alere™ i Strep A (K141757) assays, the ground truth would typically involve:

• For Influenza A & B: Viral culture as the gold standard, or potentially a highly multiplexed PCR reference method, on patient nasal swab samples.
• For Strep A: Bacterial culture as the gold standard on patient throat swab samples.

However, for this specific submission (K151690), the "software validation" would likely use pre-characterized samples (e.g., positive and negative control samples, spiked samples with known concentrations of nucleic acid targets) or previously run clinical samples with known results from predicate studies, to verify that the software processes them identically and yields the same results. The document does not specify the ground truth for these software validation studies, but it would not be a new clinical ground truth establishment.

8. The Sample Size for the Training Set

No training set is mentioned in the context of this software modification. The assays themselves are isothermal nucleic acid amplification tests, not machine learning algorithms that require a training set in the typical sense. Any "training" would have been part of the initial development and optimization of the assays prior to the K141520 and K141757 submissions.

9. How the Ground Truth for the Training Set was Established

Not applicable, as no training set for a machine learning model is described.

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