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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 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 conjunction with clinical and epidemiological risk factors. The assay is not intended to detect the presence of influenza C virus.

Negative results do not preciude 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 and the 2014-2015 influenza seasons when influenza 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 is a rapid, instrument-based, molecular in vitro diagnostic test utilizing isothermal nucleic acid amplification technology for the qualitative detection of Streptococcus progeness, 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 preclude infection with Group A Streptococcus and should not be used as the sole basis for treatment.

The Alere™ i RSV 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 of respiratory syncytial virus (RSV) virus (RSV) virus (RSV) virus (RSV) virus (RSV) viral RNA in direct nasopharyngeal swabs and nasopharyngeal swabs cluted in viral transport media from patients with signs and symptoms of respiratory infection. It is intended for use as an aid in the diagnosis of RSV in children

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 swab specimens eluted in viral transport media 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.

Alere™ i RSV is a rapid, instrument-based isothermal test for the qualitative detection and differentiation of respiratory syncytial virus (RSV) viral RNA from direct nasopharyngeal swab (NPS) and NPS eluted in viral transport media from patients with signs and symptoms of respiratory infection.

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 swab or nasopharyngeal swabs tested directly or after elution in viral transport media collected from patients presenting with signs and symptoms of respiratory infection.

All Alere™ i assays 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 sinqle 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 and Alere™ i Influenza A & B 2 Test Base contain the reaqents 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.

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

All Alere™ i 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 Iyophilized 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.

This document describes a Special 510(k) submission for the Alere™ i Instrument and its associated assays (Influenza A & B, Strep A, RSV, and Influenza A & B 2). The purpose of this submission is to address a software modification to the Alere™ i Instrument's algorithm to mitigate issues with false invalid results due to baseline values being lower than allowed, which were incorrectly identified as "Empty Tube Values." The submission states that there have been no changes made to the chemistry of the assays.

The document highlights the substantial equivalence of the modified devices to their legally marketed predicate devices. However, it does not contain specific acceptance criteria or detailed study data to prove the device meets these criteria. Instead, it focuses on comparing the modified devices with their predicates, stating that all parameters (FDA Product Code, Assay Target, Intended Use, Intended Environment for Use, Instrumentation, Sample Type, Viral/Bacterial Target, Technology, Internal Control, Result Interpretation, Assay Result, and Time to Result) are "Same" as the predicate devices.

Given the information provided, it is not possible to complete a table of acceptance criteria and reported device performance, nor can we detail the study that proves the device meets the acceptance criteria, as this specific information is not present in the provided text. The document asserts "substantial equivalence" based on the described software modification and the consistency of other parameters with the predicate devices.

Therefore, the following information can be extracted or derived based on the provided text, with many fields remaining unascertainable:

1. A table of acceptance criteria and the reported device performance:

This information is not provided in the document. The document states that the modified devices are "substantially equivalent" to their predicate devices and lists various parameters which are "Same" as the predicates. No specific numerical acceptance criteria or performance metrics (like sensitivity, specificity, accuracy) are detailed for the modified device or its predicate.

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective):

This information is not provided in the document. The submission focuses on the software modification and states that no changes were made to the assay chemistry. It does not describe any new clinical studies or test sets with sample sizes for the modified device to demonstrate its performance against new acceptance criteria. It refers to historical performance characteristics for influenza A established during certain influenza seasons for the Alere™ i Influenza A & B and Alere™ i Influenza A & B 2 assays.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience):

This information is not provided in the document. As there is no description of a new clinical study with a test set and ground truth establishment, these details are absent.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set:

This information is not provided in the document.

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 is not applicable. The device is an in vitro diagnostic test for detecting viral/bacterial RNA/DNA, not an AI-assisted diagnostic imaging device that involves human readers.

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

The device is described as an "instrument-based, molecular in vitro diagnostic test utilizing an isothermal nucleic acid amplification technology" with "automated" result interpretation. This implies a standalone (algorithm only) performance, i.e., without human-in-the-loop performance influencing the assay result. However, specific standalone performance study details are not provided.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

For the original performance characteristics mentioned for the influenza assays, it can be inferred that the ground truth would have been established by a reference method for detecting viral RNA, likely PCR or viral culture, rather than expert consensus or pathology in the context of an IVD. However, the document does not explicitly state the ground truth used for performance characteristics, nor does it detail ground truth for any new studies related to the software modification.

8. The sample size for the training set:

This information is not provided in the document. Since this is a software modification to an existing algorithm for an IVD, it's possible the "training set" concept as used in AI/ML might not directly apply, or details about algorithm development data are not included.

9. How the ground truth for the training set was established:

This information is not provided in the document.

In summary, the provided document is a 510(k) summary for a software modification to existing IVD devices, asserting substantial equivalence to predicates without detailing new clinical studies, acceptance criteria, or performance data for the modified device.

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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 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 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 and 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 tests for the qualitative detection and differentiation of influenza A and influenza B from nasal swabs and 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 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 target amplification. Heating 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 document describes the Alere™ i Influenza A & B device, a rapid molecular in vitro diagnostic test. The acceptance criteria and the study proving the device meets these criteria are detailed in the provided text, particularly in the section regarding the modifications and comparison to the predicate device.

Here's a breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The provided text focuses on demonstrating substantial equivalence to a predicate device rather than outright acceptance criteria with specific performance thresholds. However, the intent of the study was to show that the modified device performs similarly to the predicate. The "Device Comparison" table implicitly sets the "acceptance criteria" as matching the predicate device's performance for the listed parameters.

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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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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.

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).

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