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Immunoglobulin Isotypes (GAM) for the EXENT Analyser:

The Immunoglobulin Isotypes (GAM) for the EXENT Analyser is a MALDI-TOF mass spectrometry immunoassay that is used in conjunction with the Binding Site Optilite IgG, IgA and IgM assays for the semi-quantitative in vitro measurement of monoclonal IgG, IgA, and IgM as a reflex test in serum for patients with a result suggestive of the presence of monoclonal immunoglobulins by serum protein electrophoresis (gel or capillary zone electrophoresis), or with an abnormal serum free light chain concentration and free light chain ratio result.

The assay is intended for use as an aid in the evaluation of monoclonal gammopathy of undetermined significance (MGUS); and as an aid in the diagnosis of smouldering multiple myeloma (SMM), multiple myeloma (MM), Waldenström's macroglobulinaemia, and AL amyloidosis.

Assay results should be used in conjunction with other laboratory and clinical findings.

EXENT Analyser:

The EXENT Analyser is an automated analyser intended for the qualitative and quantitative in vitro measurement of analytes in human body fluids used in conjunction with the EXENT assays. The device is designed for professional in vitro diagnostic use only and it is not a device for self-testing.

The system consisting of the EXENT® Analyser and the EXENT® assays are intended for the in vitro measurements of analytes in human body fluids. It is designed to provide automation and integration of all the analytical steps (including liquid handling and MALDI-ToF mass spectrometry). The EXENT Analyser is designed to be used solely in combination with EXENT assays to measure a variety of analytes depending on the reagents. The device is designed for professional use only and it is not a device for self-testing.

The EXENT Analyser combines automated immunoassay with readout by MALDI-ToF mass spectrometry. It is a modular analyser, and the major components are described in Table 3 and illustrated schematically in Figure 1.

The EXENT-iP500 component is an automated liquid handler that prepares human body fluids using the EXENT assay specific reagents. The samples are prepared using magnetic beads that are coated with isotype-specific antibodies. Any unbound material is washed away during the sample preparation process. The EXENT-iP500 also manages the transfer of the prepared patient sample to the MALDI plate.

The EXENT-iX500 component is a MALDI-ToF mass spectrometer. Signals are produced by ionizing the compound or biological material under investigation and separating the resulting ions by means of an electrical and magnetic field according to their mass-to-charge ratios. The EXENT-iX500 is used to read samples prepared by the EXENT-iP500.

The EXENT-iQ software integrates sample preparation and MALDI-ToF mass spectrometry and is used for data storage and processing. It is the primary user interface used by the user to review and release results.

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The Panther Fusion GI Expanded Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test for the rapid and qualitative detection and differentiation of Yersinia enterocolitica, Vibrio (V. parahaemolyticus, V. vulnificus, V. cholerae), Escherichia coli O157, and Plesiomonas shigelloides. Nucleic acids are isolated and purified from Cary-Blair preserved stool specimens collected from individuals exhibiting signs and symptoms of gastroenteritis.

This assay is intended to aid in the differential diagnosis of Yersinia enterocolitica, Vibrio (V. parahaemolyticus, V. vulnificus, V. cholerae), Escherichia coli O157, and Plesiomonas shigelloides infections. The results of this assay should be used in conjunction with clinical presentation, laboratory findings, and epidemiological information and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out coinfection with other organisms that are not detected by this test and may not be the sole or definitive cause of patient illness. Negative results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this test, or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease. This assay is designed for use on the Panther Fusion System.

The Panther Fusion GI Expanded Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test for the rapid and qualitative detection and differentiation of Yersinia enterocolitica, Vibrio (V. parahaemolyticus, V. vulnificus, V. cholerae), Escherichia coli O157, and Plesiomonas shigelloides. Nucleic acids are isolated and purified from Cary-Blair preserved stool specimens collected from individuals exhibiting signs and symptoms of gastroenteritis.

The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Expanded Bacterial Assay. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion System. The eluate is transferred to the Panther Fusion System reaction tube containing the assay reagents. Multiplex real-time PCR is then performed for the eluted nucleic acid on the Panther Fusion System.

Sample processing: Prior to processing and testing on the Panther Fusion System, specimens are transferred to an Aptima Multitest tube containing specimen transport media (STM) that lyses the cells, releases target nucleic acid, and protects them from degradation during storage.

Nucleic acid capture and elution: An internal control (IC-B) is added automatically to each specimen via the working Panther Fusion Capture Reagent-B (wFCR-B) to monitor for interference during specimen processing, amplification, and detection caused by reagent failure or inhibitory substances. Specimens are first incubated in an alkaline reagent (FER-B) to enable cell lysis. Nucleic acid released during the lysis step hybridizes to magnetic particles in the wFCR-B. The capture particles are then separated from residual specimen matrix in a magnetic field by a series of wash steps with a mild detergent. The captured nucleic acid is then eluted from the magnetic particles with a reagent of low ionic strength (Panther Fusion Elution Buffer).

Multiplex PCR amplification and fluorescence detection: Lyophilized single unit dose reaction master mix is reconstituted with the Panther Fusion Reconstitution Buffer I and then combined with the eluted nucleic acid into a reaction tube. Panther Fusion Oil reagent is added to prevent evaporation during the PCR reaction. Target-specific primers and probes then amplify targets via polymerase chain reaction while simultaneously measuring fluorescence of the multiplexed targets. The Panther Fusion System compares the fluorescence signal to a predetermined cut-off to produce a qualitative result for the presence or absence of each analyte.

The analytes and the channel used for their detection on the Panther Fusion System are summarized in the table below:

Assay Components: The assay components configuration for the Panther Fusion GI Expanded Bacterial Assay is analogous to the Panther Fusion Respiratory Assays. The reagents required to perform the Panther Fusion GI Expanded Bacterial Assay are packaged and sold separately. There are 7 boxes containing 9 reagents which are required for sample processing. The Panther Fusion GI Expanded Bacterial Assay requires one ancillary kit and one specimen collection kit, neither of which are provided with the assay and can be acquired separately:

1. Aptima Assay Fluids Kit (303014)
2. Aptima Multitest Swab Specimen Collection Kit (PRD-03546)

Table 1: Reagents Required to Perform the Panther Fusion GI Expanded Bacterial Assay

Table 2: Ancillary and Collection Kits Required to Perform the Panther Fusion GI Expanded Bacterial Assay

Instrumentation: The Panther Fusion GI Expanded Bacterial Assay has been designed for and validated on the Panther Fusion system. The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Expanded Bacterial Assay.

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The Panther Fusion GI Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test for the rapid and qualitative detection and differentiation of Salmonella, Shigella/Enteroinvasive Escherichia coli (EIEC), Campylobacter (C. coli, C. jejuni) nucleic acids and Shiga-toxin producing Escherichia coli Shiga toxins 1 and 2 (undifferentiated) genes. Nucleic acids are isolated and purified from Cary-Blair preserved stool specimens collected from individuals exhibiting signs and symptoms of gastroenteritis.

This assay is intended to aid in the differential diagnosis of Salmonella, Campylobacter, Shigella/Enteroinvasive E. coli (EIEC) and Shigatoxigenic Escherichia coli (STEC) infections. The results of this assay should be used in conjunction with clinical presentation, laboratory findings, and epidemiological information and should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out co-infection with other organisms that are not detected by this test and may not be the sole or definitive cause of patient illness. Negative results in the setting of clinical illness compatible with gastroenteritis may be due to infection by pathogens that are not detected by this test, or non-infectious causes such as ulcerative colitis, irritable bowel syndrome, or Crohn's disease. This assay is designed for use on the Panther Fusion System.

The Panther Fusion GI Bacterial Assay is a multiplex real-time PCR in vitro diagnostic test developed for use on the fully automated Panther Fusion system to detect nucleic acids from Salmonella, Shigella/Enteroinvasive Escherichia coli (EIEC), Campylobacter (C. coli, C. jejuni) and Shiga-toxin producing Escherichia coli Shiga toxins 1 and 2 (undifferentiated) genes.

The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Bacterial Assay. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion System. The eluate is transferred to the Panther Fusion System reaction tube containing the assay reagents. Multiplex real-time PCR is then performed for the eluted nucleic acid on the Panther Fusion System.

Sample processing: Prior to processing and testing on the Panther Fusion System, specimens are transferred to an Aptima Multitest tube containing specimen transport media (STM) that lyses the cells, releases target nucleic acid, and protects them from degradation during storage.

Nucleic acid capture and elution: An internal control (IC-B) is added automatically to each specimen via the working Panther Fusion Capture Reagent-B (wFCR-B) to monitor for interference during specimen processing, amplification, and detection caused by reagent failure or inhibitory substances. Specimens are first incubated in an alkaline reagent (FER-B) to enable cell lysis. Nucleic acid released during the lysis step hybridizes to magnetic particles in the wFCR-B. The capture particles are then separated from residual specimen matrix in a magnetic field by a series of wash steps with a mild detergent. The captured nucleic acid is then eluted from the magnetic particles with a reagent of low ionic strength (Panther Fusion Elution Buffer).

Multiplex PCR amplification and fluorescence detection: Lyophilized single unit dose reaction master mix is reconstituted with the Panther Fusion Reconstitution Buffer I and then combined with the eluted nucleic acid into a reaction tube. Panther Fusion Oil reagent is added to prevent evaporation during the PCR reaction. Target-specific primers and probes then amplify targets via polymerase chain reaction while simultaneously measuring fluorescence of the multiplexed targets. The Panther Fusion System compares the fluorescence signal to a predetermined cut-off to produce a qualitative result for the presence or absence of each analyte.

The analytes and the channel used for their detection on the Panther Fusion System are summarized in the table below:

Assay Components
The assay components configuration for the Panther Fusion GI Bacterial Assay is analogous to the Panther Fusion Respiratory Assays. The reagents required to perform the Panther Fusion GI Bacterial Assay are packaged and sold separately. There are 7 boxes containing 9 reagents which are required for sample processing. The Panther Fusion GI Bacterial Assay requires one ancillary kit and one specimen collection kit, neither of which are provided with the assay and can be acquired separately:

1. Aptima Assay Fluids Kit (303014)
2. Aptima Multitest Swab Specimen Collection Kit (PRD-03546)

Table 1: Reagents Required to Perform the Panther Fusion GI Bacterial Assay

Table 2: Ancillary and Collection Kits Required to Perform the Panther Fusion GI Bacterial Assay

Instrumentation
The Panther Fusion GI Bacterial Assay has been designed for and validated on the Panther Fusion system. The Panther Fusion System fully automates specimen processing, including sample lysis, nucleic acid capture, amplification, and detection for the Panther Fusion GI Bacterial Assay.

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The Revogene® instrument is intended for in vitro diagnostic (IVD) use in performing nucleic acid testing of specific IVD assays in clinical laboratories. Revogene is capable of automated lysis and dilution of samples originating from various clinical specimen types. Revogene performs automated amplification and detection of target nucleic acid sequences by fluorescence-based real-time PCR.

The Revogene is a PCR instrument that automates lysis and dilution of samples, followed by nucleic acid amplification, and detection of target sequences by fluorescence-based real-time PCR. Revogene runs are orchestrated by a combination of software, firmware and instrument control protocol that ensures the adequate combination times and temperatures for sample homogenization and PCR analysis. The Revogene instrument acquires fluorescence signals generated during amplification. The signals are then interpreted by the system using embedded calculation algorithms.

The Revogene requires the use of a 'PIE', i.e., an assay-specific cartridge to which a patient sample is added. The PIE contains the reagents needed to process a sample and to perform a PCR amplification. When the number of assay PIEs to be run is lower than eight, the user fills empty spaces with "MOCK PIE", which are cartridges that simulate the presence of an assay PIE to confer thermal and rotational balance.

The Revogene instrument subject of this Premarket Notification is substantially equivalent to the Revogene instrument cleared under K222779. Meridian is submitting this 510(k) Premarket Notification to implement a photomultiplier tube (PMT) cooling system. This cooling system keeps the PMT environment at a temperature that prevents the appearance of fluorescence glitches, which may stop the Revogene instrument

The provided document is a 510(k) Premarket Notification for a modified medical device, the Revogene instrument. It focuses on the changes made to an existing device (K222779) and its substantial equivalence to the predicate device.

The document does not contain information about acceptance criteria or a detailed study proving the device meets specific acceptance criteria, as one might find in a clinical trial report for an initial device clearance.

Instead, it describes the performance characteristics of functional testing conducted to demonstrate that the modifications (PMT cooling system and Windows 10 upgrade) do not adversely affect the device's performance compared to the predicate. The goal of this submission is to show substantial equivalence, not to establish new performance acceptance criteria.

Therefore, I cannot provide a table of acceptance criteria and reported device performance in the traditional sense, nor can I answer many of your specific questions about study design, sample sizes, ground truth establishment, or expert adjudication, as this information is not present in the provided text.

However, I can extract the available information regarding the functional testing that was performed to support the substantial equivalence claim.

Summary of Available Information on Device Performance and Testing:

1. A table of (implied) acceptance criteria and the reported device performance

The document does not explicitly state quantitative acceptance criteria. Instead, it describes general observations and conclusions from functional testing. The implicit acceptance criterion is "no statistically significant differences" and "operates as expected and yields expected assay results."

2. Sample size used for the test set and the data provenance

• Sample Size for Test Set: The document states "contrived and negative samples in relevant clinical matrix using the following assays...". However, it does not specify the number of samples or runs used for this functional testing.
• Data Provenance: Not explicitly stated, but given it's a regulatory submission by a US company, the testing would typically be conducted according to established protocols within their R&D or QA departments. It is retrospective relative to the design changes, but the testing itself is performed to support the new device version. No information on country of origin of data beyond the manufacturer's location.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

• This information is not provided as the testing described is functional performance testing of the instrument, not typically involving expert interpretation of patient samples for ground truth establishment. The "ground truth" here is the expected performance of control samples within the assays.

4. Adjudication method for the test set

• This is not applicable/provided. The testing focuses on the instrument's functional output (e.g., Ct values, glitch occurrence) rather than interpretation of results that would require adjudication.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done

• No, this was not done. The device is an instrumentation for clinical multiplex test systems, meaning it processes samples and detects nucleic acids. It does not output images or data that require human readers for interpretation in the way an AI diagnostic imaging device would. Therefore, an MRMC study is not relevant to this type of device or its modifications.

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

• The device itself is a standalone instrument that performs automated lysis, dilution, amplification, and detection. The "algorithm" here refers to the embedded calculation algorithms within the system that interpret fluorescence signals to determine results. The functional testing described is a form of standalone performance evaluation for the modified instrument. There is no human-in-the-loop component mentioned for the actual nucleic acid detection and interpretation process of the instrument.

7. The type of ground truth used

• The ground truth for the functional testing appears to be based on the expected outcomes from known contrived and negative samples when run with specific IVD assays (Revogene® Strep A, Revogene® Carba C and Revogene® SARS-CoV-2). Essentially, the "ground truth" is the established performance of the assays themselves on control materials, and the instrument must correctly process these, showing no statistical degradation from the predicate.

8. The sample size for the training set

• This information is not provided and is generally not applicable in the context of hardware modifications to an existing IVD instrument as described. The "training set" concept is typically relevant for machine learning algorithms, which are not detailed here beyond "embedded calculation algorithms" that likely leverage established PCR physics and signal processing rather than iterative machine learning training.

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

• This information is not provided as there is no mention of a traditional "training set" in the machine learning sense. The established performance of the assays with known control materials serves as the reference for evaluating the modified instrument.

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The Xpert® FII & FV test is a qualitative in vitro diagnostic genotyping test for the detection of Factor V alleles from sodium citrate or EDTA anticoagulated whole blood. The test is performed on the GeneXpert® Instrument Systems. This test is intended to provide results for Factor II (G20210A) and Factor V Leiden (G1691A) mutations as an aid in the diagnosis in individuals with suspected thrombophilia.

Xpert FII & FV is an automated genotyping test for detecting Factor II and Factor V normal and mutant alleles directly from sodium citrate or EDTA anticoagulated whole blood specimens. Blood specimens are drawn into either sodium citrate or EDTA anticoagulant tubes. Following brief mixing of the sample. 50 uL of the blood sample is transferred to the bottom wall of the Sample opening of the Xpert FII & FV test cartridge. The user initiates a test from the system user interface and places the cartridge into the GeneXpert Instrument System.

The Xpert FII & FV test includes reagents for the detection of Factor II and Factor V normal and mutant alleles. The primers and probes in the Xpert FII & FV test determine the genotype of the Factor II gene (at position 20210) and/or the Factor V gene (at position 1691). The test includes a Sample Processing Control (SPC) to confirm adequate processing and to monitor the presence of inhibitor(s) in the PCR assay. The Probe Check Control (PCC) verifies reagent rehydration, PCR tube filling in the cartridge, probe integrity, and dye stability.

The GeneXpert Instrument Systems family is comprised of GeneXpert Dx System, GeneXpert Infinity System, and GeneXpert System with Touchscreen. The GeneXpert Instrument Systems automate and integrate sample processing, nucleic acid amplification and detection of the target sequences in simple or complex samples using real-time polymerase chain reaction (PCR). The systems consist of an instrument, computer or touchscreen, and preloaded software for running the tests and viewing the results. The GeneXpert Instrument Systems require the use of singleuse disposable cartridges that hold the PCR reagents and host the PCR process. Because the cartridges are self-contained, cross-contamination between samples is minimized.

The GeneXpert Instrument Systems have 1 to 80 modules (depending upon the instrument) that are each capable of performing separate sample preparation and real-time PCR tests. Each module contains a syringe drive for dispensing fluids (i.e., the syringe drive activates the plunger that works in concert with the rotary valve in the cartridge to move fluids between chambers), an ultrasonic horn for lysing cells or spores, and a proprietary I-CORE® thermocycler for performing real-time PCR and detection.

The Xpert FII & FV test performed on the GeneXpert Instrument Systems provides results in approximately 30 minutes.

This document is a 510(k) summary for the Xpert FII & FV diagnostic test, seeking to remove a limitation statement and make minor branding/catalog number changes. It does not contain a study explicitly detailing acceptance criteria and performance against those criteria for the current submission. Instead, it refers to prior clearance (K082118) for the clinical validation supporting the removal of the limitation statement, and asserts that the current changes do not impact performance.

Therefore, the following information is extracted or inferred based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance:

The document explicitly states: "No new performance data were provided in this submission." The basis for substantial equivalence relies on the device being identical to its predicate (K223046) in all technological characteristics relevant to performance. The one significant change (removal of the pediatric patient limitation) is supported by prior clinical validation data (K082118). Since no new performance data or acceptance criteria are presented for this specific submission, this table cannot be fully completed from the provided text.

However, based on the nature of a genetic mutation detection system, typical acceptance criteria would involve analytical sensitivity, analytical specificity, and clinical performance (e.g., concordance with a gold standard). Without the original K082118 submission, specific numerical criteria are not available.

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

• Sample Size: Not explicitly stated in this document. The document refers to "clinical validation data that was submitted and reviewed as part of the original device clearance (K082118)" as the basis for removing the pediatric limitation. The sample size for that original study is not provided here.
• Data Provenance: Not explicitly stated in this document. Given it's a 510(k) for a US market device, it is likely the original clinical validation (K082118) included US data, but this is not confirmed. It refers to "clinical validation data," which typically implies prospective collection of patient samples.

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

• Not explicitly stated in this document. This level of detail would typically be found in the original clinical validation report (K082118). For genotyping, ground truth is usually established by orthogonal molecular methods, not primarily by expert consensus in the same way as imaging or pathology interpretation.

4. Adjudication Method for the Test Set:

• Not applicable/Not mentioned. For genetic tests where the ground truth is often established through well-defined molecular techniques (e.g., Sanger sequencing or a validated reference method), adjudication by multiple experts in the traditional sense (like for imaging reads) is generally not performed. The ground truth is objective.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done:

• No, an MRMC comparative effectiveness study was not done. This type of study is relevant for interpretive tasks (e.g., radiologists reading images) where human performance is being evaluated and compared with and without AI assistance. The Xpert FII & FV is an automated genotyping test; it does not involve human readers interpreting results in the same manner.

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

• Yes, the performance characteristics mentioned (e.g., analytical sensitivity, specificity) for a molecular diagnostic test like the Xpert FII & FV are inherently "standalone" in nature. The device itself performs the assay and provides a qualitative genotype call. The results are automated and interpreted by the diagnostic software.

7. The Type of Ground Truth Used:

• Not explicitly stated in this document, but for genetic tests, the ground truth is typically established by orthogonal molecular methods, such as Sanger sequencing or another highly accurate, validated reference genotyping method. It is not based on expert consensus, pathology, or outcomes data in the way these terms are typically used for imaging or disease diagnosis.

8. The Sample Size for the Training Set:

• Not explicitly stated in this document. The device uses real-time PCR for detection, and while there might be algorithm tuning within the software, the foundational "training" often refers to the design and optimization of primers and probes, and establishment of cut-offs, rather than machine learning on a large training set of clinical samples. The document refers to "clinical validation data" for performance, but not specifically to a training set size for an algorithm.

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

• Not explicitly stated in this document. This would be part of the original developmental studies for the device (predating K082118). For a PCR-based test, ground truth for developing and optimizing the assay would involve samples with known genotypes confirmed through reference methods.

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The cobas liat CT/NG nucleic acid test is an automated, qualitative in vitro nucleic acid diagnostic test that utilizes realtime polymerase chain reaction (PCR) for the direction of Chlamydia (CT) and Neisseria gonorthoeae (NG) nucleic acid in male urine and vaginal swabs, all in cobas PCR Media (Roche Molecular Systems, Inc.).

This test is intended as an aid in the diagnosis of urogenital infections in both symptomatic individuals.

The test is performed on the cobas® liat analyzer which automates and integrates sample purification, nucleic acid amplification, and detection of the target sequence in biological samples using real-time PCR assays. The assay targets both the Cryptic plasmid and 23S rRNA of Chlamydia trachomatis and the pivNG and NGR9 of Neisseria gonorrhoeae. An Internal Control (IC) is also included. The IC is present to control for adequate processing of the target bacteria through steps of sample purification, nucleic acid amplification, and to monitor the presence of inhibitors in the PCR processes.

Here's a summary of the acceptance criteria and study details for the cobas® liat CT/NG nucleic acid test, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document primarily provides performance metrics rather than explicitly stated acceptance criteria with numerical targets. However, based on the demonstrated performance and the context of a 510(k) submission, the implicit acceptance criteria would be high sensitivity and specificity, indicating reliable detection of CT and NG infections.

2. Sample Size and Data Provenance

• Clinical Study Test Set (Prospectively collected):
  • Total Evaluated Subjects: 4780 (2304 males, 2476 females)
  • Male Urine Specimens: 2302 (from 2302 male subjects)
  • Vaginal Swabs: 2476 (1240 clinician-collected, 1236 self-collected from 2476 female subjects)
  • Data Provenance: Multi-site, prospective study collected at 13 geographically diverse clinical sites across the US.
• Clinical Study Test Set (Archived Specimens - Supplementation):
  • Archived Male Urine Specimens: 163
  • Archived Vaginal Swabs: 90
  • Data Provenance: Prospectively collected samples from a prior clinical trial (K173887).
• Reproducibility Study Test Set: Total 1618 tests (811 vaginal, 807 urine) across 3 external sites. Each panel member tested in triplicate. Low positive (1-2x LoD), moderate positive (3-5x LoD), and negative panel members used.
• Supplemental Precision Study (for CT in urine): 810 evaluable tests on urine panel members (negative, 1x-2x LoD, 3x-5x LoD).

3. Number of Experts and Qualifications for Ground Truth

The ground truth for the clinical study was established using a Patient Infected Status (PIS) or Composite Comparator Algorithm (CCA), which relied on a combination of three FDA-cleared NAATs (NAAT1, NAAT2, and NAAT3). The document does not specify the number of human experts used to establish the ground truth or their qualifications for the clinical study. The "ground truth" was algorithmically derived from the results of the comparator NAATs.

4. Adjudication Method for the Test Set

The adjudication method for the clinical study ground truth (PIS/CCA) followed a rule-based algorithm:

• If NAAT1 and NAAT2 were concordant, that result was the final PIS/CCA.
• If NAAT1 and NAAT2 were discordant, NAAT3 was performed as the tiebreaker.

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

• No, an MRMC comparative effectiveness study was not done. This study assesses the performance of a diagnostic test (the cobas® liat CT/NG nucleic acid test), which is an automated, qualitative in vitro nucleic acid diagnostic test. It replaced human assessment with an automated process, and the comparison was against a PIS/CCA derived from other reference NAATs, not human readers with and without AI assistance. Therefore, there is no effect size for human readers improving with AI.

6. Standalone (Algorithm Only) Performance

• Yes, a standalone (algorithm only) performance study was done. The entire clinical performance evaluation, reproducibility studies, and analytical studies assess the performance of the cobas® liat CT/NG nucleic acid test itself, which is an automated device performing real-time PCR. It is designed to operate without human intervention beyond sample loading and results interpretation from the automated output.

7. Type of Ground Truth Used

• Clinical Study: Patient Infected Status (PIS) or Composite Comparator Algorithm (CCA) derived from the concordant results of FDA-cleared Nucleic Acid Amplification Tests (NAATs).
• Analytical Studies (LoD, Inclusivity, Specificity, Interference): Known concentrations of specific strains or culture subtypes of bacteria/viruses, spiked into negative clinical specimens.

8. Sample Size for the Training Set

The document does not explicitly describe a separate "training set" for an AI/ML model for the cobas® liat CT/NG nucleic acid test. As a nucleic acid diagnostic test (real-time PCR), it operates based on established biochemical principles and does not typically involve machine learning training in the same way an imaging AI algorithm would. All the data presented is for validation and performance evaluation.

9. How Ground Truth for the Training Set Was Established

Since there is no explicitly mentioned "training set" for an AI/ML model in this context, the method for establishing ground truth for such a set is not applicable or described. The clinical performance is evaluated against a PIS/CCA derived from other NAATs, and analytical performance is against known concentrations.

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The cobas® liat CT/NG/MG nucleic acid test is an automated, qualitative in vitro nucleic acid diagnostic test that utilizes real-time polymerase chain reaction (PCR) for the direct detection of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Mycoplasma genitalium (MG) nucleic acid in male urine and vaginal swabs, all in cobas® PCR Media (Roche Molecular Systems, Inc.).

This test is intended as an aid in the diagnosis of urogenital infections in both symptomatic and asymptomatic individuals.

The test is performed on the cobas® liat analyzer which automates and integrates sample purification, nucleic acid amplification, and detection of the target sequence in biological samples using real-time PCR assays. The assay targets both the Cryptic plasmid and 23S rRNA of Chlamydia trachomatis, the pivNG and NGR9 of Neisseria gonorrhoeae, and the 23S rRNA and mgpC of Mycoplasma genitalium. An Internal Control (IC) is also included. The IC is present to control for adequate processing of the target bacteria through steps of sample purification, nucleic acid amplification, and to monitor the presence of inhibitors in the PCR processes.

The provided document describes the cobas® liat CT/NG/MG nucleic acid test, an automated in vitro diagnostic test for the direct detection of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Mycoplasma genitalium (MG) nucleic acid.

Here's the breakdown of the acceptance criteria and the study proving the device meets them:

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

The document doesn't explicitly state numerical "acceptance criteria" but rather presents the sensitivity/PPA and specificity/NPA as "performance results." Assuming the performance values achieved in the clinical study are the de facto acceptance criteria for market clearance, the table is compiled from the "Clinical Performance Evaluation" section (Tables 20, 21, and 22).

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

• Sample Size for Clinical Study (Test Set):
  • Total Subjects: 4852 subjects (2512 females, 2340 males) were enrolled.
  • Evaluable Subjects: 4780 evaluable subjects (2304 males, 2476 females).
  • Specimens:
    • 2302 male urine specimens.
    • 1240 clinician-collected vaginal swabs (females).
    • 1236 self-collected vaginal swabs (females).
  • Archived Specimens: Supplementation included archived specimens from a prior clinical trial (K173887) due to low NG prevalence in prospectively collected male urine and vaginal swabs. The exact breakdown of archived vs. prospective in the final evaluable numbers is not explicitly separated for all analytes, but separate tables are provided for "Archived Male Urine" and "Archived Vaginal Swabs" for NG (which states 163 archived male urine and 90 archived vaginal swabs were used for NG).
• Data Provenance:
  • Country of Origin: United States (13 geographically diverse intended use clinical sites across the US).
  • Study Design: Multi-site, prospective study, with supplementation from prospectively collected archived specimens for certain analytes.

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)

The ground truth was established using a Patient Infected Status (PIS) or Composite Comparator Algorithm (CCA) derived from a combination of three FDA-cleared NAATs (NAAT1, NAAT2, and NAAT3).

• Number of Experts: Not applicable, as the ground truth was established by algorithmic comparison of results from FDA-cleared NAATs, not by human expert opinion or adjudication.
• Qualifications of Experts: Not applicable.

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

The adjudication method used was a "2+1" algorithm based on FDA-cleared NAATs:

• If NAAT1 and NAAT2 were concordant, that result was taken as the PIS/CCA.
• If NAAT1 and NAAT2 were discordant, NAAT3 was performed as a tiebreaker.

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

• MRMC Study: No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done.
• Effect Size of Human Readers with/without AI: Not applicable, as this is an automated diagnostic test that detects nucleic acids, not an AI-assisted interpretation device for human readers.

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

• Standalone Performance: Yes, the clinical performance evaluation (Section 6) assesses the standalone performance of the cobas® liat CT/NG/MG nucleic acid test. The device is described as an "automated, qualitative in vitro nucleic acid diagnostic test," indicating it operates without human "interpretation" of the final result. The study compared the device's output directly against the PIS/CCA ground truth.

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

The ground truth used was a Patient Infected Status (PIS) or Composite Comparator Algorithm (CCA) result. This PIS/CCA was derived from the results of three FDA-cleared Nucleic Acid Amplification Tests (NAATs). This is a form of reference standard derived from multiple laboratory tests.

8. The sample size for the training set

The document does not provide details about a "training set" for the algorithm. This is typical for PCR-based diagnostic devices, which rely on established molecular biology principles and analytical validation rather than machine learning on large training datasets for their core functionality. The performance data presented are for clinical validation against a reference standard.

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

Not applicable, as no explicit training set for an algorithm is described. The device's underlying technology (real-time PCR) is not typically "trained" in the machine learning sense. Analytical studies (Limit of Detection, Inclusivity, Specificity, Interference) form the basis of validating the reagent and assay design.

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The Xpert Xpress CoV-2/Flu/RSV plus test, performed on the GeneXpert Xpress System, is an automated multiplexed real-time reverse transcriptase polymerase chain reaction (RT-PCR) test intended for use in the simultaneous in vitro qualitative detection and differentiation of severe acute respiratory syndrome coronavirus (SARS-CoV-2), influenza A, influenza B, and/or respiratory syncytial virus (RSV) viral RNA in nasopharyngeal swab anterior nasal swab specimens collected from individuals with signs and symptoms of respiratory tract infection. Clinical signs and symptoms of respiratory tract infection due to SARS-CoV-2, influenza B, and RSV can be similar.

The Xpert Xpress CoV-2/Flu/RSV plus is intended for use in the differential detection of SARS-CoV-2, influera A, influenza B, and/or RSV RNA and aids in the diagnosis of COVID-19, influenza, and/or RSV infections if used in conjunction with other clinical and epidemiological information, and laboratory findings. SARS-CoV-2, influenza A. influenza B, and RSV viral RNA are generally detectable in nasopharyngeal swab and anterior nasal swab specimens during the acute phase of infection.

Positive results are indicative of the identified virus, but do not rule out bacterial infection or co-infection with other pathogens not detected by the test. The agent (s) detected by the Xpert Xpress CoV-2/Flu/RSV plus test may not be the definite cause of the disease.

Negative results do not preclude SARS-CoV-2, influenza A virus, and/or RSV infection. The results of this test should not be used as the sole basis for treatment or other patient management decisions.

The Xpert Xpress CoV-2/Flu/RSV plus test is an automated in vitro diagnostic test for the simultaneous qualitative detection and differentiation of SARS-CoV-2. Flu A. Flu B. and RSV viral RNA in nasopharyngeal swab (NPS) and anterior nasal swab (NS) specimens collected from individuals showing signs and symptoms of respiratory viral infection.

The Xpert Xpress CoV-2/Flu/RSV plus test is performed on GeneXpert Xpress System, which consist of a GeneXpert IV instrument that executes sample preparation, nucleic acid amplification and real-time fluorescent signal detection for the tests, and a GeneXpert Hub with preloaded GeneXpert Xpress software for running the tests and viewing the test results. The GeneXpert Hub accessory integrates the computer, touchscreen monitor and barcode scanner. Each of the GeneXpert modules in the GeneXpert IV instrument can perform independent sample preparation and testing. The GeneXpert Xpress System requires the use of single-use disposable cartridges that hold the RT-PCR reagents and host sample purification, nucleic acid amplification, and detection of the target sequences. Because the cartridges are self-contained, cross-contamination between samples is minimized.

The Xpert Xpress CoV-2/Flu/RSV plus test cartridge includes reagents for the detection of SARS-CoV-2, Flu A, Flu B and RSV viral RNA from NPS and NS specimens. The primers and probes in the Xpert Xpress CoV-2/Flu/RSV plus test are designed to amplify and detect unique sequences in the genes that encode the following proteins: SARS-CoV-2 nucleocapsid (N), SARS-CoV-2 envelope (E), SARS-CoV-2 RNA-dependent RNA polymerase (RdRP), influenza A matrix (M), influenza A basic polymerase (PB2), influenza A acidic protein (PA), influenza B matrix (M), influenza B non-structural protein (NS), and the RSV A and RSV B nucleocapsid. A Sample Processing Control (SPC) and a Probe Check Control (PCC) are also included in the cartridge utilized by the GeneXpert Xpress System. The SPC is present to control for adequate processing of the sample and to monitor for the presence of potential inhibitor(s) in the RT-PCR reaction. The SPC also ensures that the RT-PCR reaction conditions (temperature and time) are appropriate for the amplification reaction and that the RT-PCR reagents are functional. The PCC verifies reagent rehydration, PCR tube filling, and confirms that all reaction components are present in the cartridge including monitoring for probe integrity and dye stability.

The Xpert Xpress CoV-2/Flu/RSV plus test is designed for use with NPS or NS specimens collected with nylon flocked swabs and placed into viral transport medium (VTM), Universal Transport Medium (UTM), or eNAT®. The ancillary specimen collection kits, swabs and transport media validated for use with the Xpert Xpress CoV-2/Flu/RSV plus test include:

• Nasopharyngeal Sample Collection Kit for Viruses
  • Copan UTM® 3C057N (Flexible Minitip Flocked Swab with UTM® Medium O without Beads)
  • Copan eNAT® Molecular Collection and Preservation Medium P/N 6U074S01 о (Flexible Minitip Flocked Swab with eNAT® Medium)
• Becton Dickinson Universal Viral Transport Kit P/N 220531 (Flexible Minitip o Flocked Swab with UVT Medium)
• Nasal Sample Collection Kit for Viruses
  • Copan UTM® 3C064N (Regular Flocked Swab with UTM® Medium without O Beads)
  • Copan eNAT® Molecular Collection and Preservation Medium P/N 6U073S01 O (Regular Flocked Swab with eNAT® Medium)
• Alternatively, swabs and transport media can be obtained separately: ●
  • Nylon flocked swab (Copan P/N 502CS01, 503CS01) o
  • Viral transport medium, 3 mL (Copan P/N 330C, 3C047N, BD Universal O Transport Medium, Remel M4RT or Remel M5)

These ancillary reagents allow NPS and NS specimens from patients to be collected, preserved and transported to laboratory prior to analysis with the Xpert Xpress CoV-2/Flu/RSV plus test.

The provided document is a 510(k) Summary for the Cepheid Xpert Xpress CoV-2/Flu/RSV plus test. It details the performance studies conducted to demonstrate substantial equivalence to a predicate device. Here's a breakdown of the acceptance criteria and study proving the device meets them, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly demonstrated through the reported performance in both analytical and clinical studies, aiming for high levels of agreement with established methods. The summarized performance data serves as the proof that the device meets these (implied) acceptance criteria.

Table of Acceptance Criteria and Reported Device Performance:

Since explicit acceptance criteria values (e.g., "PPA must be >= 95%") are not explicitly stated in the provided text as separate criteria, I will infer them from the reported strong performance and the nature of a 510(k) submission, where substantial equivalence to a predicate device is the goal. The reported performance is the validation that it meets the expected performance for such a device.

Study Details:

1. Sample sizes used for the test set and the data provenance:

   • Analytical Studies (LoD, Inclusivity, Specificity, Interference, Carryover, Reproducibility): These studies used "replicates" (e.g., 20, 3, 8) of contrived/simulated samples rather than patient samples for their test sets.
     • LoD: 20 replicates per virus/lot combination.
     • Inclusivity (wet-testing): 3 replicates for each of 102 respiratory viral strains.
     • Exclusivity (wet-testing): 3 replicates of each microorganism pool.
     • Microbial Interference: 8 replicates of positive samples for each target virus and microbial interference strain combination.
     • Competitive Interference: 3 replicates for each target strain and competitive strain combination (adjusted as needed).
     • Potentially Interfering Substances: 8 negative and 8 positive samples (pooled) for each substance.
     • Carryover Contamination: 40 positive and 42 negative samples (20 pairs per module, 2 modules).
     • Reproducibility: 90 observations per panel member (3 Sites x 3 Operators x 1 Lot x 5 Days x 1 Run x 2 Replicates).
   • Clinical Performance Study:
     • Total Specimens: 4561 (NPS=2300, NS=2261)
     • Test Set for SARS-CoV-2 Performance: 3147 valid specimens (1565 NPS, 1582 NS).
     • Test Set for Flu A, Flu B, RSV Performance: 4310 valid specimens (2175 NPS, 2135 NS).
     • Data Provenance:
       • Fresh (Category I): 3333 specimens (1 frozen specimen in this category). Prospectively collected in 2022 from 23 geographically diverse sites in the United States.
       • Archived Frozen (Category II): 1228 specimens. Prospectively collected during the 2016-2017 influenza season (pre-pandemic), used to supplement Flu/RSV sample size. These were collected in the US.
     • Retrospective/Prospective: Primarily prospective (Category I) with a significant portion of archived prospective (Category II) specimens.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • The document implies that the ground truth for the clinical test set was established by U.S. FDA-cleared molecular diagnostic tests (a molecular respiratory panel for SARS-CoV-2 and a molecular Flu A/B/RSV test).
   • For discrepant results, additional U.S. FDA EUA SARS-CoV-2 molecular tests or U.S. FDA-cleared molecular respiratory panels were used.
   • The document does not specify the number or qualifications of human experts directly involved in establishing the ground truth for the clinical test set. The ground truth relies on the results of the comparator molecular assays.

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

   • For the clinical performance study, results were compared "side-by-side" with a U.S. FDA-cleared molecular respiratory panel.
   • Discrepant results were investigated using a different U.S. FDA EUA SARS-CoV-2 molecular test or U.S. FDA-cleared molecular respiratory panel. This suggests an adjudication process for discrepancies, where an additional, independent test confirms or refutes the initial finding of the comparator or investigational device. The exact "X+Y" method (e.g., 2+1) is not explicitly stated, but the process of re-testing discrepant samples with a "tie-breaker" method is described.

4. 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, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This document describes the validation of an in vitro diagnostic (IVD) PCR test kit, not an AI-assisted diagnostic imaging or interpretation system that would involve human "readers" or "interpreters." The device is largely automated.

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

   • This is a standalone diagnostic test in the sense that the GeneXpert Xpress System performs the sample preparation, nucleic acid amplification, and real-time fluorescent signal detection to produce a result (qualitative positive/negative). Human input is for specimen collection, loading the cartridge, and reviewing the auto-generated results. The performance metrics presented (PPA, NPA, LoD, etc.) are of the "device only" system. So, yes, a standalone performance was done for the device.

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

   • For analytical studies: Contrived samples with known concentrations of viral strains or microorganisms, often verified against internal standards or external reference materials.
   • For clinical studies: Results from U.S. FDA-cleared and U.S. FDA EUA molecular diagnostic tests served as the ground truth (comparator method). Discrepancies were resolved using additional molecular tests.

7. The sample size for the training set:

   • The document does not provide information on a training set size. This is common for traditional IVD device submissions, where analytical and clinical validation data (test set) are collected after the assay design (analogous to "training") is complete. The "training" in this context would likely refer to the internal assay development and optimization, for which specific sample sizes might not be publicly disclosed or directly relevant to the regulatory submission for substantial equivalence.

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

   • As no explicit "training set" is mentioned in the context of device performance validation, the method for establishing its ground truth is not described. For assay development, ground truth would be established through a combination of highly characterized samples, pure cultures, and perhaps clinical samples with confirmed results from gold-standard methods (e.g., viral culture, sequencing, or highly sensitive and specific lab-developed tests).

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The Panther Fusion® SARS-CoV-2/Flu A/B/RSV assay is a fully automated multiplexed real-time polymerase chain reaction (RT-PCR) in vitro diagnostic test intended for the qualitative detection and differentiation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (Flu A), influenza B virus (Flu B), and respiratory syncytial virus (RSV). Nucleic acids are isolated and purified from nasopharyngeal (NP) swab specimens and anterior nasal (AN) swab specimens obtained from individuals exhibiting signs and symptoms of a respiratory tract infection. Clinical signs and symptoms of respiratory viral infection due to SARS-CoV-2, influenza, and RSV can be similar. This assay is intended to aid in the differential diagnosis of SARS-CoV-2, Flu A, Flu B, and RSV infections in humans and is not intended to detect influenza C virus infections.

Nucleic acids from the viral organisms identified by this test are generally detectable in NP and AN swab specimens during the acute phase of infection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory tract infective of the presence of the identified virus and aids in diagnosis if used in conjunction with other clinical and epidemiological information, and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions.

Positive results do not rule out coinfection with other organism(s) detected by the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay may not be the definite cause of disease. Negative results do not preclude SARS-CoV-2, influenza A virus, influenza B virus, or RSV infections. This assay is designed for use on the Panther Fusion system.

The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is classified as a Class II in vitro diagnostic device per 21 CFR 866.3981 and has product code QOF. The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is designed for use on the fully automated Panther Fusion System.

The Panther Fusion system is a class II exempt device under 21CFR 862.2570 that has product code OOI.

The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is a multiplex real-time reverse transcriptase PCR (RT-PCR) in vitro diagnostic test developed for use on the fully automated Panther Fusion system to detect and differentiate SARS-CoV-2, influenza A, influenza B, and respiratory syncytial virus (RSV) directly from nasopharyngeal and anterior nasal swab specimens, from individuals exhibiting signs and symptoms of a respiratory tract infection.

The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay involves the following steps: sample lysis, nucleic acid capture and elution transfer, and multiplex RT-PCR where analytes (when present) are simultaneously amplified, detected and differentiated. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion system. The eluate is transferred to the Panther Fusion system reaction tube containing the assay reagents. Multiplex RT-PCR is then performed for the eluted nucleic acid on the Panther Fusion system.

Sample lysis, nucleic acid capture, and elution: Prior to processing and testing on the Panther Fusion system, specimens are transferred to a Specimen Lysis Tube containing specimen transport media (STM). Alternatively, samples can be collected with the RespDirect Collection kit which contains enhanced specimen transport media (eSTM). STM and eSTM lyse the cells, release target nucleic acid and protect them from degradation during storage. The Internal Control-S (IC-S) is added to each test specimen and controls via the working Panther Fusion Capture Reagent-S (wFCR-S). The IC-S is the reagent used to monitor specimen processing, amplification and detection. Magnetic particles with covalently bound oligonucleotides mediate the nucleic acid capture. Capture oligonucleotides hybridize to nucleic acid in the test specimen. Hybridized nucleic acid is then separated from the lysed specimen in a magnetic field. Wash steps remove extraneous components from the reaction tube. The elution step elutes purified nucleic acid. During the nucleic acid capture and elution step, total nucleic acid is isolated from specimens.

Elution transfer and RT-PCR: During the elution transfer step, eluted nucleic acid is transferred to a Panther Fusion tube already containing oil and reconstituted mastermix. Target amplification occurs via RT-PCR. A reverse transcriptase generates a DNA copy of the target sequence. Target specific forward and reverse primers and probes then amplify targets while simultaneously detecting and discriminating multiple target types via multiplex RT-PCR. The Panther Fusion system compares the fluorescence signal to a predetermined cut-off to produce a qualitative result for the presence or absence of the analyte. The positive result for each analyte will be accompanied by the cycle threshold (Ct value).

Here's a breakdown of the acceptance criteria and the study details for the Hologic Panther Fusion SARS-CoV-2/Flu A/B/RSV assay, based on the provided document:

Acceptance Criteria and Device Performance

The document describes the performance of the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay in detecting SARS-CoV-2, Flu A, Flu B, and RSV in prospectively collected Anterior Nasal (AN) swab specimens in RespDirect eSTM.

Table of Acceptance Criteria (Implicit) and Reported Device Performance

While explicit acceptance criteria (e.g., minimum PPA/NPA values) are not stated, the document presents the observed Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) with their 95% Confidence Intervals. These values are implicitly the performance targets for the assay.

Study Information

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

• Prospective Study:
  • Sample Size: 1021 evaluable anterior nasal (AN) swab specimens.
  • Data Provenance: Prospective, multicenter study conducted in the US between January 2023 and May 2023 at nine participating medical facilities.
• Enrichment Study (Supplemental Clinical Data for Low Prevalence Analytes):
  • Sample Size: 205 evaluable anterior nasal (AN) swab specimens.
  • Data Provenance: Enrichment phase of the study, conducted in the US between October 2023 and February 2024 at six participating medical facilities. The specimens were from individuals with a positive standard of care (SOC) test result for Flu A, Flu B, and/or RSV. All were frozen prior to testing.

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 or qualifications of experts used to establish the ground truth. Instead, it refers to:

• For SARS-CoV-2: A composite comparator algorithm (CCA) consisting of up to three highly sensitive US FDA EUA SARS-CoV-2 molecular tests.
• For Flu A, Flu B, and RSV: A US FDA-cleared molecular Flu A/B/RSV assay (in the prospective study) and a U.S. FDA-cleared molecular Flu A/B/RSV assay (in the enrichment study).
• For the enrichment study, initial selection was based on a positive standard of care (SOC) test result for Flu A, Flu B, and/or RSV.

4. Adjudication Method for the Test Set

• For SARS-CoV-2 in the prospective study: A Composite Comparator Algorithm (CCA) was used. A final CCA result was assigned when two of the three composite comparator assays were in concordance.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, an MRMC comparative effectiveness study involving human readers and AI assistance was not done. This study is for an in vitro diagnostic (IVD) assay (a molecular test), not an AI-powered diagnostic imaging device.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Yes, this study represents a standalone performance evaluation of the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay. The assay itself is an automated molecular diagnostic test on the Panther Fusion system, and its performance was evaluated against comparator methods (other molecular tests or algorithms), not against human interpretation of its outputs in a clinical setting for diagnostic aid.

7. The Type of Ground Truth Used

• SARS-CoV-2: Composite comparator algorithm (CCA) based on multiple FDA EUA molecular tests.
• Flu A/B/RSV: US FDA-cleared molecular Flu A/B/RSV assay.
• Enrichment Study (Flu A/B/RSV): US FDA-cleared molecular Flu A/B/RSV assay, and initial selection based on positive Standard of Care (SOC) test results.

This represents a reference standard method ground truth, where another established diagnostic test is used as the benchmark.

8. The Sample Size for the Training Set

The document does not provide information on a specific "training set" sample size for algorithm development. The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is a real-time RT-PCR in vitro diagnostic test, not a machine learning or AI algorithm in the context of typical training/validation splits. Its development would involve analytical studies and design verification, but not typically a "training set" in the same sense as an AI model. The provided clinical data are for performance evaluation.

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

As noted in point 8, the concept of a "training set" with established ground truth in the context of AI models is not directly applicable here. The assay's performance characteristics (e.g., limit of detection, analytical reactivity) are established through various analytical studies (bench studies), not through a "training set" with a clinical ground truth. The clinical studies described are for validation and performance assessment, not for training an algorithm.

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The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is a fully automated multiplexed real-time polymerase chain reaction (RT-PCR) in vitro diagnostic test intended for the qualitative detection and differentiation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus (Flu A), influenza B virus (Flu B), and respiratory syncytial virus (RSV). Nucleic acids are isolated and purified from nasopharyngeal (NP) swab specimens and anterior nasal (AN) swab specimens obtained from individuals exhibiting signs and symptoms of a respiratory tract infection. Clinical signs and symptoms of respiratory viral infection due to SARS-CoV-2, influenza, and RSV can be similar. This assay is intended to aid in the differential diagnosis of SARS-CoV-2, Flu A, Flu B, and RSV infections in humans and is not intended to detect influenza C virus infections.

Nucleic acids from the viral organisms identified by this test are generally detectable in NP and AN swab specimens during the acute phase of infection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory tract infective of the presence of the identified virus and aids in diagnosis if used in conjunction with other clinical and epidemiological information, and laboratory findings. The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out coinfection with other organism(s) detected by the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay may not be the definite cause of disease. Negative results do not preclude SARS-CoV-2, influenza A virus, influenza B virus, or RSV infections. This assay is designed for use on the Panther Fusion system.

The Hologic RespDirect Collection Kit is cleared for NP swab specimens only for testing with the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay.

The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is classified as a Class II in vitro diagnostic device per 21 CFR 866.3981 and has product code QOF. The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is designed for use on the fully automated Panther Fusion System.

The Panther Fusion system is a class II exempt device under 21CFR 862.2570 that has product code OOI.

The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay is a multiplex real-time reverse transcriptase PCR (RT-PCR) in vitro diagnostic test developed for use on the fully automated Panther Fusion system to detect and differentiate SARS-CoV-2, influenza A, influenza B, and respiratory syncytial virus (RSV) directly from nasopharyngeal and anterior nasal swab specimens, from individuals exhibiting signs and symptoms of a respiratory tract infection.

The Panther Fusion SARS-CoV-2/Flu A/B/RSV assay involves the following steps: sample lysis, nucleic acid capture and elution transfer, and multiplex RT-PCR where analytes (when present) are simultaneously amplified, detected and differentiated. Nucleic acid capture and elution takes place in a single tube on the Panther Fusion system. The eluate is transferred to the Panther Fusion system reaction tube containing the assay reagents. Multiplex RT-PCR is then performed for the eluted nucleic acid on the Panther Fusion system.

Here's a breakdown of the acceptance criteria and the study details for the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

Note on Acceptance Criteria: The document explicitly states the goal is to demonstrate "comparable" performance to the predicate device (which uses an NP swab) for the new anterior nasal (AN) swab specimen type. While specific numerical acceptance criteria (e.g., "PPA must be >X%") are not provided in this summary, the reported performance metrics (PPA, NPA, and their confidence intervals) are presented to demonstrate this comparability and overall effectiveness for diagnostic use, as typical for molecular assays expanding their indications. The high NPA values for all targets indicate good specificity, and generally high PPA values indicate good sensitivity, especially when considering the confidence intervals. The lower PPA for Flu B in the prospective study was addressed and supported by the retrospective study, which showed strong performance.

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

• Prospective Clinical Study (Anterior Nasal Swab):

  • Sample Size: 1,268 individuals were enrolled. 1,230 AN swab specimens were tested, resulting in 1,189 evaluable specimens for analysis (not all evaluable for all analytes).
  • Data Provenance: Prospective, multicenter study conducted in the US. Specimens were collected from individuals attending nine participating medical facilities in the US during the 2022-2023 respiratory infection season.

• Retrospective Clinical Study (Anterior Nasal Swab - Supplement for Flu B and RSV):

  • Sample Size: 175 preselected retrospective specimens.
  • Data Provenance: Retrospective. The origin country is not explicitly stated but is implied to be related to the US context from the prospective study.

• Analytical Studies (Reprocessing from K222736):

  • Sample Size: Not explicitly stated as "sample size" for each analytical study detail, but refers to the number of replicates/conditions tested for LOD, inclusivity, exclusivity, etc. For example, Flu B LoD confirmation involved 28 replicates per panel.
  • Data Provenance: Already existing data from the previous 510(k) submission (K222736) using Nasopharyngeal (NP) swabs, reprocessed with the updated software.

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

The document does not mention the use of experts to establish ground truth for the clinical test sets. Instead, the ground truth was established by comparing the candidate device's results to reference molecular assays:

• SARS-CoV-2: A composite comparator algorithm (CCA) consisting of up to three highly sensitive US FDA EUA SARS-CoV-2 molecular tests. A final CCA result was assigned when two of the three comparator assays were in concordance.
• Flu A, Flu B, and RSV: A US FDA-cleared molecular Flu A/B/RSV assay.

4. Adjudication Method for the Test Set

• SARS-CoV-2 Ground Truth: For SARS-CoV-2, a composite comparator algorithm (CCA) was used. A final CCA result was assigned when "two of the three composite comparator assays were in concordance." This effectively acts as an adjudication method where agreement among a majority of reference tests determines the ground truth.
• Flu A, Flu B, RSV Ground Truth: For Flu A, Flu B, and RSV, a single "US FDA-cleared molecular Flu A/B/RSV assay" was used as the comparator method. There's no mention of an adjudication process among multiple comparators for these targets.

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

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not explicitly mentioned or conducted. This type of study is more common for imaging devices or diagnostics that involve subjective interpretation by human readers. This device is an automated molecular diagnostic assay, where the output is objective (positive/negative, Ct value).

6. Standalone (Algorithm Only) Performance Study

• Yes, the performance data presented (PPA, NPA) directly reflects the standalone performance of the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay. It is compared to a ground truth established by other molecular tests, without human interpretation of the assay's output influencing the performance metrics. The assay itself is automated, so its performance is inherently "algorithm only" in the context of generating results.

7. Type of Ground Truth Used

• Molecular Comparator Assays: The ground truth for the clinical test sets (both prospective and retrospective) was established using other legally marketed and highly sensitive molecular diagnostic tests.
  • For SARS-CoV-2: A composite of up to three US FDA EUA SARS-CoV-2 molecular tests.
  • For Flu A, Flu B, RSV: A US FDA-cleared molecular Flu A/B/RSV assay.

8. Sample Size for the Training Set

• The document does not explicitly state the sample size used for the training set. This submission focuses on the validation of an existing assay with a new specimen type (anterior nasal swab) and a software update (Adaptive Crosstalk Correction). The original development and training data for the core assay (K222736) would have been described in that prior submission, but are not detailed here for this specific submission's scope. The mention of "reprocessed with validated Results Processor Tool" for previously submitted analytical studies also suggests reuse of data rather than new training.

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

• Since the document doesn't explicitly detail a new "training set" for this specific submission, it also doesn't describe how ground truth for such a set was established. It's likely that the original assay development followed similar methods of using well-characterized samples or comparator assays for internal development and optimization.
• Regarding the Adaptive Crosstalk Correction (ACC) factor, the validation involved "testing of SARS-CoV-2 positive clinical specimens that are representative of those that yielded false positive Flu B results in the field." This indicates that the problem the ACC addresses arose from real-world performance, and the resolution was validated against specific clinical scenarios rather than a formal "training set" in the machine learning sense.

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